I’ve had my first vaccine jab. It gives me hope of liberation… but not yet

Exactly a year after his first story about coronavirus, our science editor received the Pfizer injection last week. Here he reflects on a remarkable scientific achievement

I marked a grim anniversary in an unexpected manner last week. On 18 January last year, I wrote my first story about a mysterious disease that had struck Wuhan, in China, and which was now spreading around the world. More than two million individuals have since died of Covid-19, almost 100,000 of them in the UK.

Remarkably, 12 months to the day that the Observer published my story, I was given my first dose of Covid-19 vaccine, allowing me to follow nearly six million other newly immunised UK residents who are set to gain protection against a disease that has brought the planet to a standstill. It was a rare, comforting experience after a year of unremitting sadness and gloom.

Related: World’s poor need action, not Covid ‘vaccine nationalism’, say experts

Related: The pandemic one year on: 100,000 dead in the UK from coronavirus

Related: UK bosses set up IT systems to track Covid vaccine status of staff

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Vaccine experts defend UK decision to delay second Pfizer Covid jab

Medics told they risk undermining public confidence by querying policy of three-month gap between doses

Leading vaccine experts have backed the government’s decision to delay the second dose for up to three months, after doctors warned that the strategy was proving “ever-more difficult to justify”.

The British Medical Association (BMA), which represents doctors, has suggested that the UK has become “increasingly isolated internationally” by deciding that the second dose of the Pfizer vaccine can be delayed, and called for a maximum delay of six weeks. However, several prominent scientists backed the government’s plan to maximise the number of people receiving their first dose.

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World’s poor need action, not Covid ‘vaccine nationalism’, say experts

Nations outbidding each other creates an ‘immoral race towards the abyss’

Pharmaceutical companies should do more to transfer vaccine technology to prevent the poorest countries falling behind in the distribution of Covid-19 vaccines, according to an expert.

The warning came from Dag-Inge Ulstein, the co-chair of the global council trying to speed up access to Covid vaccines for the world’s poor, known as the Act (Access to Covid-19 Tools) Accelerator. Ulstein, Norway’s international development minister, oversees the drive to ensure vaccines reach the poor – the Covax programme.

Increased transparency on the vaccine deals, including the number of vaccines, the delivery date and price.

Full value for money on the collective funds that the world has given to purchase these vaccines for the world’s poorest so they are purchased at cost price, and not to make a profit.

Increased production of vaccines can be boosted internationally by technology transfer and sharing by pharma companies to local and regional manufacturing firms.

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ViiV/J&J’s long-acting HIV regimen finally approved in US

The FDA has approved Cabenuva, a long-acting HIV treatment from ViiV and Johnson & Johnson that keeps the virus at bay with a monthly injection instead of daily pill regimen.

It follows a surprise rejection at the end of 2019, due to the information in the dossier related to chemistry, manufacturing and controls (CMC).

The clinical data supplied by ViiV was enough to support approval, however, and the FDA has finally given the go-ahead for Cabenuva.

Cabenuva is based on ViiV’s long-acting integrase inhibitor cabotegravir and the non-nucleoside reverse transcriptase inhibitor (RTI) Edurant (rilpivirine) developed by J&J’s Janssen pharma unit.

ViiV, which is a joint venture with GlaxoSmithKline as a majority shareholder, with Pfizer and Shionogi holding minority interests, noted that this is the first treatment to offer this less demanding treatment regimen.

The injection is delivered in a clinic and aside from clinical data supporting its safety and efficacy, ViiV said nine out of ten patients preferred the dosing regimen to their previous daily oral therapy in the studies used for approval.

This was based on a survey filled in alongside one of the trials used for approval, where 532 patients completed a single-item question at Week 48.

Results showed 88% preferred Cabenuva compared with 2% who preferred their previous daily oral HIV treatment.

The results were descriptive in nature and are not intended to imply clinical significance, ViiV noted in a statement, adding that only 59 patients chose not to answer the questionnaire.

The approval of Cabenuva is based on the pivotal phase III ATLAS studies that included more than 1,100 patients from 16 countries.

Before treatment with Cabenuva, oral dosing of cabotegravir and rilpivirine (lead-in) was administered for around one month to assess the tolerability of each therapy.

In these studies, Cabenuva was as effective in maintaining viral suppression as continuing a daily oral three-drug regimen when injected intramuscularly in the buttocks once a month throughout the 48-week study period.

In both studies, the most common adverse reactions 2% or more of clinical trial participants receiving Cabenuva were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness and rash.

Serious adverse events occurred in 4% (24/591) of patients taking Cabenuva, and 3% (17/591) of adverse events led to withdrawal.

 

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ConserV Bioscience works on mutation-proof coronavirus shots with US lab

UK biotech ConserV Bioscience has joined with California’s Lawrence Livermore National Laboratory to develop broad-spectrum coronavirus vaccines as concerns mount over potentially more infectious strains emerging in the UK, South Africa and Brazil.

This collaboration brings together ConserV’s expertise in identifying antigens and Lawrence Livermore National Laboratory’s (LLNL) nanolipoprotein particle technology (“NLP”) delivery system.

The vaccine has been designed to provide broad-spectrum protection against coronavirus pathogens of human and animal origin, including but not limited to MERS, SARS and SARS-CoV-2.

A genomic analysis of the SARS-CoV-2 coronavirus, which causes COVID-19, shows that the virus accumulates around two mutations a month.

The new variant identified in the UK in December shows significant mutations in the Spike protein and receptor binding domain that increase its infectivity.

The variant that originated in South Africa carries a mutation in the Spike protein that has been shown to reduce antibody recognition and could therefore affect efficacy of new vaccines.

Meanwhile the variant that originated in Brazil is thought to be more infectious and a virus closely resembling it was found in a patient reinfected with SARS-CoV-2.

The partnership aims to develop a vaccine consisting of regions of genetical material from each coronavirus that causes an immune reaction.

These will be encoded in messenger RNA (mRNA) formulated with the laboratory’s NLP technology before injection.

This will allow freeze drying of both components separately, improving storage and transport conditions compared to other mRNA vaccines – Pfizer and Moderna’s shots require ultra-cool temperatures to maintain their integrity.

Vaccine formulation was funded by the Department of Health and Social Care through an SBRI programme managed by Innovate UK.

The collaboration aims to demonstrate the immunogenicity and protective responses in pre-clinical studies with clinical studies following quickly if results are supportive.

Kimbell Duncan, CEO of ConserV Bioscience, said: “Our mission is to develop safe and effective vaccines which offer broad protection against infections from viruses that mutate frequently.

“We are pleased to be working with Lawrence Livermore National Laboratory to develop our broad-spectrum coronavirus vaccine candidate. We have identified regions within the proteins of the virus that are not susceptible to change and, if effective, the vaccine promises to protect against a broad spectrum of current circulating coronavirus strains and future emergent ones.”

NLPs are water-soluble molecules that are 6 to 30 billionths of a meter in size, resembling high-density lipoprotein (HDL) particles, which are associated with playing a role in regulating the human body’s ‘good’ cholesterol. LLNL scientists are working to use this nanotechnology, also known as nanodiscs, as a delivery platform for tularemia and chlamydia vaccines that are under development.

Feature image courtesy of Rocky Mountain Laboratories/NIH

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Single Covid vaccine dose in Israel ‘less effective than we hoped’

Surge in infections dampens optimism over country’s advanced immunisation programme

Israel’s coronavirus tsar has warned that a single dose of the Pfizer/BioNtech vaccine may be providing less protection than originally hoped, as the country reported a record 10,000 new Covid infections on Monday.

In remarks reported by Army Radio, Nachman Ash said a single dose appeared “less effective than we had thought”, and also lower than Pfizer had suggested.

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ViiV launches digital triage service for HIV patients with London hospital

ViiV Healthcare and London’s Westminster Hospital NHS Foundation Trust have launched a digital triage service for HIV patients supported by a mobile app.

ViiV, a joint venture majority owned by GlaxoSmithKline, with Pfizer and Shionogi as minority shareholders, has been working with Chelsea and Westminster Hospital NHS Foundation Trust on the service.

The new service is being gradually launched to patients at the hospital’s Kobler Outpatient Clinic, one of the largest centres of HIV care in Europe.

It is then planned to expand to larger patient populations across multiple sites at the trust in the coming months.

The organisations have already run a pilot scheme through a joint working agreement, which were presented at last year’s British HIV Association Annual Congress, showing high levels of patient satisfaction and quality of care.

The service known as Klick has also been designed to respond to the current demands on HIV healthcare services brought by the COVID-19 pandemic allowing outpatient clinics to rapidly evaluate clinical needs, provide access to care remotely and communicate effectively with patients.

Design and implementation have been led by a project team comprising individuals from ViiV Healthcare’s innovation team, along with clinical and non-clinical staff from the Kobler Clinic.

The service has been designed with a focus on ensuring digital solutions can integrate with and enhance the service model, whilst delivering a positive experience for patients.

Dr David Asboe, Clinical Director for HIV at Chelsea and Westminster Hospital NHS Foundation Trust, said: “We have made significant advances in the care of people living with HIV, but this work is not finished.

“In many regards, it has just begun. Our combined efforts have shifted HIV from an acute to a predominantly long-term condition.

“It is our duty to understand the emerging needs of our patient cohort, to design care that is responsive to these needs, and to provide care in a sustainable fashion.

“We must achieve these things with a backdrop of the challenges we now also face with COVID-19.

“The collaboration between the Trust and ViiV Healthcare has provided an opportunity to produce an evidence-based and practical service concept that provides a strong platform on which we can build.”

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Fauci backs Biden’s plan for 100 million COVID-19 shots

A promise by president-elect Joe Biden to carry out 100 million coronavirus vaccinations in his first 100 days in power is “absolutely doable”, according to the US leading infectious diseases expert Dr Anthony Fauci.

Biden has announced ambitious initiatives to fight COVID-19 ahead of his inauguration, which is due to take place on Wednesday.

While Biden’s team acknowledges that it is a steep challenge, it’s received the backing of Fauci, who is optimistic that two new vaccines from AstraZeneca and Johnson & Johnson could be approved in the US in the next few weeks.

So far only 12 million people have received vaccines in the US.

This would add to the Pfizer/BioNTech and Moderna mRNA-based shots that already have emergency approval in the US.

The US has been severely affected by the pandemic, with figures recorded on Sunday morning showing 23,760,523 cases and 395,855 deaths had been recorded by Johns Hopkins University in the US.

Fauci, director of the US-government funded National Institute of Allergy and Infectious Diseases (NIAID), told NBC’s Meet the Press that “it’s going to take a while to turn this around.”

He added: “I can tell you one thing that’s clear is that the issue of getting 100 million doses in the first 100 days, is absolutely a doable thing.”

Biden can invoke the Defense Production Act to boost supplies of the vaccine, Fauci added.

“But the feasibility of his goal is absolutely clear, there’s no doubt about it. That can be done.”

On the vaccines from J&J and AZ, Fauci said: “I would imagine within a period of a week or so, or at the most a couple of weeks, they’re going to be getting their data together and showing it to the [FDA].

“They’re going to have to get their data and safety monitoring board to look at it to see if it is appropriate to start, you know, essentially putting the package together to get an Emergency Use Authorization. But we’re weeks away, not months away, for sure.”

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UK to face short term delay in delivery of Pfizer vaccine

Overall number of doses delivered between January and March will remain the same, the firm says

The UK is set to face short-term delays in delivery of the Pfizer/BioNTech coronavirus vaccine as the pharmaceutical company upgrades its production capacity.

Pfizer is upscaling production at its plant in Puurs, Belgium, in efforts to produce more doses than originally planned for 2021 – temporarily reducing deliveries to all European countries.

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Tivicay approved in Europe in new dispersible tablet for children with HIV

ViiV’s Tivicay is to become available in Europe in a new dispersible tablet form to treat children living with HIV.

The joint venture, majority-owned by GlaxoSmithKline with Pfizer and Shionogi as shareholders, said the European Commission had granted a marketing authorisation for the new formulation.

These tablets are used in combination with other antiretroviral agents for treatment of human immunodeficiency virus type-1 infection in paediatric patients.

To be eligible, children must be at least four weeks of old, weighing at least 3kg and must not have been treated with an integrase inhibitor, although it doesn’t matter whether they have been treated with other drugs classes.

This authorisation includes updated dosing recommendations, for Tivicay (dolutegravir) film-coated tablets (10mg, 25mg and 50mg) for children six years and older and weighing at least 14kg, bringing these in line with the World Health Organization weight bands.

Approval is based on data from the ongoing P1093 and ODYSSEY studies, which are being conducted in collaboration with international paediatric research networks.

P1093 is a a safety, tolerability and dose finding registrational study in paediatric patients aged four weeks to 18 years being conducted by the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) network in the USA, Brazil, Thailand, South Africa, Zimbabwe, Kenya and Tanzania.

ViiV Healthcare, the Division of AIDS (DAIDS) at the US National Institutes of Health (NIH) are collaborating in this trial.

ODYSSEY is a randomised control efficacy trial in first and second- line treatment, in paediatric patients aged four weeks to 18 years being conducted by the PENTA network in Europe, South America, Thailand, Uganda, Zimbabwe, and South Africa.

Originally designed to support World Health Organization (WHO) guideline recommendations by WHO weight bands, this study will now also provide data to support revised dosing and continue to 96 weeks.

ViiV Healthcare, the Paediatric European Network for Treatment of AIDS (Penta) and the Medical Research Council (MRC) Clinical Trials Unit at University College London for ODYSSEY are collaborating in this trial.

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Study says COVID-19 infection provides immunity, but people can transmit virus

Previous COVID-19 infection provides some immunity for at least five months, but people may still carry and transmit the virus, according to a study by Public Health England.

A first report from PHE’s SIREN study found antibodies from previous COVID-19 infection provide 83% protection against reinfection for at least five months.

It found that reinfections in people with antibodies were rare, with only 44 potential reinfections among 6,614 participants who showed evidence of previous infection.

But a small number of people with antibodies may still be able to carry and transmit COVID-19 according to the study.

As a result, PHE stressed the importance of following “stay at home” rules currently in place in the UK to prevent the virus from spreading.

Public Health England has been regularly testing tens of thousands of health care workers across the UK since June for new COVID-19 infections as well as the presence of antibodies, which suggest people have been infected before.

SIREN study leaders are clear this first report provides no evidence towards the antibody or other immune responses from COVID-19 vaccines, nor should any conclusions be drawn on their effectiveness. The SIREN study will consider vaccine responses later this year.

Professor Susan Hopkins, senior medical advisor at Public Health England and the SIREN study lead said: “This study has given us the clearest picture to date of the nature of antibody protection against COVID-19 but it is critical people do not misunderstand these early findings.

“We now know that most of those who have had the virus, and developed antibodies, are protected from reinfection, but this is not total and we do not yet know how long protection lasts. Crucially, we believe people may still be able to pass the virus on.”

The news comes as the UK continues to endure high levels of infections despite a national lockdown.

There have been more than 74,000 deaths following coronavirus infections and nearly 43,000 new cases were recorded in the last day.

Last year the government announced that PHE is to be scrapped and merged with the NHS test and trace programme and the UK’s Joint Biosecurity Centre.

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Australia’s chief medical officer defends AstraZeneca’s Covid vaccine amid efficacy concerns

Australia has secured 54m doses of the vaccine some experts say is inferior to Pfizer’s mRNA vaccine, which Australia has bought just 10m doses of

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  • Australia’s chief medical officer Professor Paul Kelly and infectious diseases experts have defended securing 54m doses of a Covid-19 vaccine made by Oxford University and pharmaceutical company AstraZeneca, amid concerns the vaccine will not be effective enough to achieve herd immunity.

    The president of the Australian and New Zealand Society for Immunology, Prof Stephen Turner, told Nine media that Australia should halt the AstraZeneca vaccine rollout because it has “lower efficacy”.

    Related: Australia’s Covid vaccines: everything you need to know

    The choice we have is not whether to use one or the other, it is whether to use what we have

    Related: ‘How dare you leave’: confusion remains for some Victorians stranded interstate

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    Pfizer/BioNTech vaccine may work against new virus mutation, scientists say

    The Pfizer/BioNTech vaccine appears to work against an important mutation in the new coronavirus variants causing havoc in the UK and South Africa, according to research from the drugs giant.

    Findings of the lab study posted online have not yet been peer reviewed but provide some reassurance for countries like the UK, which are relying on vaccines to bring the pandemic under control.

    Pfizer joined with scientists from the University of Texas Medical Branch to conduct the study, which indicated the vaccine was effective at neutralising virus with the mutation known as N501Y.

    The mutation is responsible for greater transmissibility and there have been concerns it may also allow the virus to dodge the immune response produced as a result of the vaccination.

    The study team tested blood taken from people who had received the mRNA vaccine developed by BioNTech and Pfizer.

    However, findings are limited because it does not look at all mutations found in the new variants of the virus.

    Pfizer’s chief scientific officer Philip Dormitzer noted that the vaccine has been found to work against 15 other mutations that the company has previously tested against.

    He told Reuters: “So we’ve now tested 16 different mutations and none of them have really had any significant impact. That’s the good news.”

    However he warned that this “doesn’t mean that the 17th won’t (have an impact)”.

    He is also concerned about another mutation found in the South African variant, called E484K.

    Researchers plan to run similar tests to check if the vaccine works against this and other mutations found in the UK and South African variants.

    The advantage of the Pfizer/BioNTech vaccine is that it can be quickly tweaked to address any new mutations, and according to Reuters the changes could be made in as little as six weeks.

    It’s not clear how the changes to the virus affect the rival vaccines developed by AstraZeneca/Oxford University and Moderna.

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    UK left trailing as EU quickly approves Moderna’s COVID-19 vaccine

    The European Union has approved the coronavirus vaccine from Moderna, leaving the UK trailing because of changes to post-Brexit drug approval rules.

    With the UK reeling from one of the worst outbreaks of the disease, it’s a worrying situation for one of the countries worst hit by the pandemic that is relying on vaccines to bring the virus under control.

    The UK is in a national lockdown that could last into March, with more than 62,000 new cases and 1,000 coronavirus-related deaths recorded yesterday as a more transmissible strain threatens to overwhelm the country’s health service.

    As things stand, the two rival mRNA-based vaccines from Pfizer/BioNTech and Moderna are now approved for use in the EU.

    Meanwhile in the UK, the Pfizer/BioNTech and AstraZeneca shots have been quickly approved.

    The UK government has an order for just 7 million shots of the Moderna vaccine covering just half a percent of the population, while the European Commission has secured 160 million doses, enough to cover around 18% of the population.

    US-based Moderna said that first deliveries of the vaccine in Europe will begin next week.

    Moderna’s vaccine is arguably the most effective approved so far at around 95%, while AstraZeneca’s rival that has been swiftly approved in the UK ahead of Europe works in around 62% of cases when given its recommend dose.

    The Pfizer/BioNTech seems to be of comparable efficiency to the Moderna shot, and is being rolled out across the UK along with the AZ vaccine.

    There is evidence to suggest the AZ vaccine’s efficacy could be improved to 90% by giving a half-dose to start with, but UK regulators have not been given sufficient evidence to approve this formulation.

    After a rolling review began of Moderna’s vaccine late last year, the European Commission has issued a conditional marketing authorisation the day after it was backed by regulators from the CHMP scientific committee.

    Moderna has said it is in talks with the UK regulator over approval, where European Commission decisions on medicines no longer automatically apply because of Brexit.

    Under Brexit transition arrangements the Medicines and Healthcare products Regulatory Authority (MHRA) will continue to adopt decisions by the European Commission on medicines.

    In usual circumstances companies are required to submit an identical filing request to the MHRA after a CHMP positive opinion

    The UK regulator would then follow the decision of the European Commission, which nearly always rubber-stamps the CHMP’s decision within a few weeks.

    But on this occasion the process has not been possible because of the accelerated timelines for vaccine approval because of the pandemic.

    Questioned by pharmaphorum, the MHRA was unable to comment on arrangements for the Moderna vaccine at the time of writing.

    However Moderna said separately that it is in talks with the MHRA to get the vaccine approved.

     

     

     

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    Britain could be mass-producing its Covid shot. Shame we junked our industrial base | Aditya Chakrabortty

    The dire state of UK manufacturing has left us dependent on other nations. We may soon find out why some call this a ‘national security risk’

    Everything now hinges on a vaccine: how many more Britons die, whether the NHS finally breaks, how long the UK stays locked down. All depends on how fast the country can get vaccinated against this plague. Yet we’re in this position in large part because of government failure. When the prime minister imposes lockdowns late and with a sulky grumble; when we haven’t fixed our £22bn test-and-trace system (which, by the way, now bankrolls more outside consultants and contractors than the Treasury has actual civil servants); and when the Dominics and Stanleys are allowed to carry on as if rules are for the little people. If Boris Johnson blunts every political instrument he can lay his pale and meaty hands on, pretty soon a syringe is the only resort.

    Vaccines were always going to be how the world limped out of this pandemic; but as Taiwan and New Zealand show, even without inoculation it is possible to drive the number of Covid cases significantly down. Compare their record with the UK – which is on course to hit 100,000 Covid-related deaths before January is out, and where a staggering one in 30 Londoners is today infected. The lecterns from which Johnson and his top advisers gave their press conference this week read “Stay Home. Protect the NHS. Save Lives” – exactly as they did at the start of all this last March, as if to confirm how little progress they have made in almost a year.

    Related: For mRNA vaccines, we should stick to the schedule | Angela Rasmussen and Ilan Schwartz

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    UK vaccine minister vows ‘massive uplift’ in number of jabs this week

    Nadhim Zahawi says ‘absolute focus’ is to get 13.9 million people inoculated by mid-February

    The UK vaccine minister, Nadhim Zahawi, has pledged a “massive uplift” in the number of coronavirus vaccinations carried out this week as he said reaching the government’s target of 13.9m jabs offered by February would be “challenging”.

    Zahawi, the minister responsible for the vaccine rollout, told BBC Radio 4’s Today programme: “My absolute focus is to get to 13.9 million … offered a vaccine by the middle of February, that is my target and I’m confident the NHS has a plan and we will meet that target.”

    The government’s joint committee on vaccination and immunisation has published a list of groups of people who will be prioritised to receive a vaccine for Covid-19 in the UK. The list is:

    Related: What obstacles stand in the way of UK’s Covid vaccine rollout?

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    How is the Oxford Covid vaccine being deployed in England?

    With jab to be administered to public for first time, we look at key questions about its rollout

    The biggest vaccination programme in the UK’s history will receive a major boost on Monday, with the first use of the Oxford/AstraZeneca Covid vaccine. We answer some key questions around how it will be deployed in England.

    Related: UK hospitals receive Oxford/AstraZeneca Covid vaccine for Monday rollout

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    The Oxford Covid jab is delivered this week. But when will vaccines bring results?

    Fall or rise in coronavirus cases will not initially be a good measure of efficacy, say scientists devising ways to audit progress

    People in Britain are set to get their first shots of the Oxford/AstraZeneca vaccine on Monday, with millions of doses being given over the next few months. The mass vaccination of the UK’s population should bring an end to the country’s Covid-19 misery, but how long will it take for this immunisation programme to make a difference to our lives – and what will be the first signs that salvation is on the way?

    These key issues will be anxiously pursued as the battle against Covid proceeds and daily cases involving the new virus variant continue to spread. However, scientists have warned that simply waiting for a reduction in new cases it not the way to tell whether the vaccine is starting to have an impact.

    Related: Symptomless cases in schools could be key driver in spread of Covid-19

    Related: Why is Britain delaying second doses of Covid vaccines?

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    What difference will Oxford/AstraZeneca vaccine make in UK?

    We look at how the introduction of a new vaccine in the fight against Covid will work

    The Oxford/AstraZeneca vaccine is central to the government’s plans for ending social distancing in the UK and returning to some sort of normality. It has invested in seven different vaccines, but the biggest order is for 100m doses of the AstraZeneca jab, most of which will be manufactured in the UK. While the prime minister was jubilant that the UK was first in the world to approve the Pfizer/BioNTech vaccine, he is now able to claim a British triumph. More to the point is the ease of use of the AstraZeneca vaccine. Unlike Pfizer’s, it does not have to be kept in the long term at -70C. Pfizer’s vaccine can be stored in a fridge for five days, but AstraZeneca’s can be kept for months at fridge temperature, which is 2-8C and will be easy to take to care homes to administer to residents, the first priority group for vaccination.

    Related: BioNTech criticises EU failure to order enough Covid vaccine

    Related: World leaders urged to make Covid vaccine available to millions of refugees

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    Change in vaccine policy is a high-stakes gamble | Letters

    The effectiveness of delaying the second dose of Covid vaccines must be carefully monitored, argues Dr Grizelda George, while Jan Mortimer and Jenny van Tinteren fear the move will increase distrust and uncertainty

    The manufacturer of the Pfizer/BioNTech vaccine has said its efficacy has only been assessed for two doses given three weeks apart. Therefore the idea that a single dose will be protective beyond three weeks is speculative (Covid vaccine: chief medical officers defend rescheduling of second doses, 31 December). It would be truly tragic to vaccinate millions of recipients with the Pfizer/ BioNTech vaccine (at considerable effort and financial cost) with a twelve-week gap between doses if this doesn’t give them protection.

    It is worth noting that there is likely to be a correlation between the antibody response and protection from infection. Therefore volunteers who have already completed two doses could be asked to give a small sample of blood to check the level of neutralising antibodies present four weeks from the first dose. Recipients whose second dose has been postponed after 4 January could give a similar sample from 11 January onwards to check their levels at the four-week point. A relatively small number of volunteers (perhaps 20 or 30 in each group) might settle this.

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    Questions hang over UK’s rollout of Oxford/AstraZeneca jab

    Analysis: regulator surprises by approving 12-week gap between first and second shots of vaccine as well as Pfizer/BioNTech shot

    It’s a pragmatic solution to an incredibly urgent problem – how to immunise very large numbers of people at risk from a rampaging variant of Covid-19 in the shortest possible time. The answer that government advisers have come up with is to give them all – more than 20 million of them – a single shot of the Oxford/AstraZeneca vaccine so that they have some protection and postpone the second dose to three months afterwards, when hopefully there will be plenty of vaccine available for boosters.

    Related: How well does the Oxford vaccine work? What we know so far

    Related: The vaccine miracle: how scientists waged the battle against Covid-19

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    UK prepares for decision on AZ/Oxford vaccine as COVID cases soar

    The UK’s COVID-19 vaccination programme could get a speed boost, with the country’s drugs regulator expected to make a decision on a shot from Oxford University/AstraZeneca in the next few days.

    If the vaccine becomes available the UK will be able to step up its vaccination programme as large swathes of the country face draconian “Tier 4” restrictions due to the emergence of as more infectious variant.

    Latest figures show that there were nearly 40,000 cases recorded yesterday, the highest since mass testing began, although it’s thought infection rates were higher during the first wave of the virus in spring when tests were not readily available.

    The Medicines and Healthcare products Regulatory Agency (MHRA) began a fast-track rolling review of the vaccine in November and reports point towards a decision between Christmas and New Year.

    The UK has ordered 100 million doses of the vaccine, which is based on an adenovirus vector and is easy to handle than rivals from Pfizer/BioNTech and Moderna.

    AZ’s vaccine, dubbed AZD1222, is stored at normal refrigerator temperatures while the Pfizer/BioNTech and Moderna shots need to be kept at around -70C and -20C respectively to maintain the integrity of their RNA structure.

    According to health secretary Matt Hancock, the full dossier of trial evidence is now with the regulator, which is poised to make a decision in the coming days.

    AZ’s vaccine is safe and effective, according to the data publicly available so far, although it seems that giving a half-dose shot first following a second full dose is more effective.

    Just how this will be viewed by regulators is unclear, as are the plans to distribute the vaccine.

    With two full doses, efficacy is around 62%, according to findings released towards the end of last month based on data from nearly 9,000 patients in the UK and Brazil.

    Efficacy rose to around 90% in just over 2,700 patients given the low dose-high dose formulation, which was stumbled on by mistake because of a manufacturing error.

    Quite what the MHRA will make of this is not clear, nor is it known whether the regulator has more up-to-date figures than those announced at the end of November.

    Professor Sir John Bell, the government’s life sciences tsar and Regius Chair of Medicine at the University of Oxford, told BBC Radio 4’s Today programme yesterday:  “We are getting to be about prime time now.

    “I would expect some news pretty shortly, I doubt we will make Christmas now but just after Christmas I would expect.

    “And I have no concerns whatsoever, the data looks better than ever.”

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    Government ‘operated illegal buy British policy’ over Covid contracts

    Other firms better placed to supply antibody tests, argues case against health secretary Matt Hancock

    The government was operating an illegal “buy British” policy when it signed contracts with a small UK firm to supply Covid antibody tests, claim lawyers who have filed a case against the health secretary.

    The Good Law Project said there were a number of other companies in a better position to supply antibody tests in June and August, when the Department of Health and Social Care (DHSC) agreed deals worth up to £80m with Abingdon Health without going out to tender.

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    NHS pilots virtual assistant for flu jab bookings

    More than 1,000 NHS patients have booked flu vaccinations using a virtual assistant as part of a pilot project in the south east of England.

    The pilot project, run in collaboration with GP practices in Buckinghamshire, Brent, and Greenwich, involved patients using the Ask NHS app, which is already used by more than 375,000 patients.

    Patients in the pilot used the app developed by Sensely to self-check eligibility and quickly make appointments for flu jabs.

    Launched in 2017, the free-to-use Ask NHS app lets users easily check symptoms, book clinician appointments, access self-care resources, and connect with live video consultations.

    The app uses Natural Language Processing (NLP) and speech recognition technologies make the conversational interface easy to use, while freeing up doctors and nurses’ time.

    Citing post-usage survey data, Sensely claims the app can reduce per-patient costs by as much as 14.4%.

    Adding vaccination information, a self-service eligibility check, and booking functionality to Ask NHS lets patients, protect themselves and loved ones, quickly get the information they need and make appointments without having to call their clinic.

    Designed in partnership with NHS nurses, the tool also allows high-risk patients to be prioritised based on symptoms or underlying health issues, improving access to vaccinations for vulnerable patients while easing the strain on healthcare providers.

    The project sets the stage for the more widespread use of virtual assistants as the UK begins to roll out COVID-19 vaccines.

    Sensely is currently developing COVID-specific virtual tools and plans to begin supporting NHS coronavirus vaccination efforts with customised virtual assistant technologies in early 2021.

    Sensely CEO Adam Odessky said: “During the pandemic, more people than ever are getting flu shots — but that places an enormous strain on clinics, and those challenges will only increase as we roll out COVID-19 vaccines.

    “Our top priority, now and always, is to support the NHS and ensure patients get vaccinations quickly and easily. By using next-gen digital tools as part of an omnichannel strategy, we’re empowering patients to take ownership of their healthcare journey, and protect their families while easing the burden on hardworking doctors and nurses.”

    The app is available on iOS and Android smartphones.

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    FDA aims for fast approval of Moderna’s COVID-19 shot after panel vote

    The FDA is looking to quickly approve Moderna’s COVID-19 vaccine after it was unanimously backed by a panel of experts.

    Yesterday’s advisory panel meeting voted 20-0 in favour of approving Moderna’s vaccine and although the vote is non-binding, you could probably bet your house on the FDA backing the shot as it rarely goes against the advice of its experts after such strong backing.

    The vaccine was also given a glowing review by FDA staffers in a briefing document posted ahead of the meeting and looks set to become the second COVID-19 vaccine to hit the US market after Pfizer/BioNTech’s rival was approved last week.

    Pfizer’s vaccine was approved within a day of a positive vote from the Vaccines and Related Biological Products Advisory Committee.

    Roll-out of the Pfizer vaccine has already begun and FDA commissioner Stephen Hahn said the agency will work “rapidly” towards issuing an Emergency Use Authorization for Moderna’s shot.

    The US has agreed to buy 200 million doses and there are six million doses ready move to ship as soon as the vaccine is officially approved.

    Yesterday’s panel vote heard that the vaccine worked in 94% of cases, based on clinical data gathered so far, and is safe.

    It is also slightly easier to move around – although it is an mRNA-based shot like Pfizer the storage temperature is around -20C, considerably less demanding than temperatures of around -75C required to maintain the integrity of its already-approved rival.

    Moderna’s vaccine is also given in two shots, with the injections four weeks apart compared with the three-week interval required for Pfizer’s.

    The UK has also pre-ordered seven million doses of the Moderna vaccine, which is also being reviewed by the country’s regulator the Medicines and Healthcare products Regulatory Agency (MHRA).

    Canada also plans to get two million doses by March, part of a total 56 million doses ordered from Moderna.

    The European Union has also announced a contract to buy 80 million doses and an option to buy 80 million more once the vaccine is formally approved.

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    British American Tobacco wins approval to test Covid vaccine on humans

    Treatment grown on tobacco plants gets US backing for clinical study

    British American Tobacco has moved a step closer to producing a vaccine for coronavirus using tobacco plants, as it won approval in the US to begin testing on humans.

    The company behind cigarette brands including Lucky Strike, Rothmans and Benson & Hedges said the US Food & Drug Administration had given it clearance to begin a clinical study with adult volunteers.

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    Scheme to get Covid vaccine to poorer countries at ‘high risk’ of failure

    Risk assessment documents say cost, delays and shortages could lead to billions not vaccinated until 2024

    The global scheme to deliver Covid-19 vaccines to poorer countries faces a “very high” risk of failure, potentially leaving billions of people with no access to vaccines until as late as 2024, internal documents say.

    The Covax scheme has been beset by a number of issues, including a shortage of doses of approved vaccines, and a decision by India’s Serum Institute, which was initially earmarked to supply Covax, saying it would prioritise supplying India first.

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    AbbVie begins trials of COVID-19 antibody therapy

    AbbVie is to begin clinical development of an antibody designed to neutralise the SARS-CoV-2 coronavirus after licensing the therapy in from Harbour BioMed and Utrecht University.

    In a joint statement, the biotech and the university said that the antibody, dubbed ABBV-47D11, will be developed for prevention and treatment of COVID-19 and related coronaviruses.

    AbbVie has begun a phase 1 clinical trial of the antibody, with clinical development beginning in the US and expanding into Europe.

    The antibody has been developed by Harbour using transgenic mice, which enabled the quick discovery and development of several candidates.

    From these ABBV-47D11 was selected because of its cross-reactive neutralising nature.

    The antibody targets a conserved region of the SARS-CoV-2 spike protein and has been developed through a collaboration between Harbour (HBM) and Utrecht University (UU).

    The license agreement will help advance the development of ABBV-47D11, which in pre-clinical research demonstrated potential against SARS-CoV-2, as well as the related SARS-CoV-1 virus that caused an outbreak in Asia in 2003.

    AbbVie will conduct clinical development of ABBV-47D11, and if successful, will manufacture and market the product worldwide.

    AbbVie will pay HBM and UU an undisclosed one-time license fee and will also make payments upon achievement of certain development, regulatory and sales-based milestones.

    The pharma will also pay tiered royalties on commercial net sales of the antibody.

    Erasmus University Medical Center, based in Rotterdam, Netherlands, was involved in the fundamental science but is not involved in the license agreement.

    The phase 1 trial will be a randomised, double-blind, placebo-controlled, study to evaluate the safety, pharmacokinetics, and pharmacodynamics of single ascending doses of ABBV-47D11 in adults hospitalized with COVID-19.

    The antibody will be tested in three different doses on 24 patients across global study sites to evaluate study-drug related adverse events as primary endpoints, and several other secondary outcomes.

    Regeneron and Eli Lilly have been leading the charge to develop antibody-based therapies against the coronavirus.

    Regeneron’s cocktail, REGN-COV2 and Eli Lilly’s bamlanivimab have emergency approvals from the FDA and AstraZeneca has begun clinical development of its rival antibody cocktail last month.

    Harbour BioMed is a clinical-stage biotech specialising in antibody therapeutics with operations in Cambridge, MassachusettsRotterdam, The Netherlands; and Suzhou and Shanghai, China.

    Feature image courtesy of Rocky Mountain Laboratories/NIH

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    Family doctors begin COVID-19 immunisation drive in UK

    The roll-out of the biggest vaccination programme in the history of the UK’s NHS is gathering pace, as family doctors and their teams begin taking delivery of Pfizer/BioNTech’s COVID-19 shot.

    In a statement the NHS said that GP practices in more than 100 parts of the country are taking delivery of the vaccine today.

    Some clinics will begin immunisations this afternoon and the majority will start tomorrow (Tuesday), the NHS said.

    The vaccine, which was approved in the UK earlier this month, will be administered by teams of nurses, paramedics and pharmacists.

    Those aged over 80, as well as care home workers and residents, will get the vaccine first as they are considered to be in the group at highest risk of getting the disease.

    Care home residents will start to receive the vaccine later this week as distributors finalise the processes to deliver the Pfizer/BioNTech vaccine, which must be stored at around -70c to maintain its integrity.

    Practice teams are redesigning sites to put in processes to meet these logistical challenges and the NHS will contact people in the priority groups when it is their turn to receive the vaccine.

    Dr Simon Hodes, a GP from Watford told the BBC that his surgery is due to begin vaccinations on Monday, adding that very few of his patients had worries about the shot.

    Hodes said his surgery had introduced a “military-style operation” to ensure vaccine doses are not wasted.

    Dr Nikki Kanani, a practising GP and NHS director of primary care, said: “GPs, nurses, pharmacists and other primary care staff are eager to play their part in protecting people against coronavirus.

    “This is the greatest vaccination programme ever undertaken by the NHS and, to help vaccinate people safely we will be working with local communities to deliver it in convenient and familiar settings.

    “As a GP I am proud to be part of this huge national effort to protect our patients against the virus and I would urge the public to come forward when they are called up for the vaccine.”

    Feature image copyright BioNTech SE 2020, all rights reserved

     

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    Novartis/Incyte draw blank with Jakafi in COVID-19

    Novartis/Incyte’s Jakafi (ruxolitinib) looks unlikely to be added to the list of therapies that can be used against COVID-19, after it failed to cut complications or death in a phase 3 trial.

    Data from the phase 3 RUXCOVID study showed that there was no significant reduction in the proportion of COVID-19 patients on ruxolitinib plus standard therapy experiencing severe complications, compared to standard care alone.

    Severe complications included death, respiratory failure requiring mechanical ventilation or admission to intensive care.

    RUXCOVID is a 29-day placebo-controlled trial testing ruxolitinib in 432 patients aged 12 years or over in patients hospitalised for COVID-19 and not intubated or receiving intensive care before randomisation.

    Results were measured against a composite primary endpoint of patients who died, developed respiratory failure requiring mechanical ventilation, or required admission to ICU by day 29.

    But the proportion of people meeting this endpoint was almost identical in the two groups – 12% for those treated with ruxolitinib and 11.8% for those treated with placebo plus standard care.

    Patients were randomised 2:1 to receive ruxolitinib twice daily or oral-matching placebo for 14 days, with standard therapy decided according to the investigator’s clinical judgement.

    Ruxolitinib is already FDA approved under the brand name Jakafi to treat the bone marrow diseases myelofibrosis, polycythemia vera and graft-versus-host disease.

    Trials of the drug in other indications are not affected by the outcome, Novartis said.

    The drug is an oral inhibitor of JAK 1 and JAK 2 tyrosine kinases and the rationale behind the trial was to investigate whether the down regulation of the immune system conferred by the medicine would reduce the inflammation caused by COVID-19.

    Originally developed by Incyte, Novartis licensed in the drug for development and marketing outside the US.

    The RUXCOVID trial is sponsored by Novartis outside of the US and by Incyte inside the US.

    Many drugs are being trialled against COVID-19, with the cheap steroid dexamethasone producing some of the most promising trial results.

    Although Gilead’s Veklury (remdesivir), an antiviral originally intended to treat Ebola, is approved in the US to treat COVID-19 the World Health Organization has recommended against using it because of differing interpretations of trial results.

     

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    FDA advisers vote in favour of Pfizer/BioNTech COVID-19 shot

    Advisers to the FDA have voted in favour of approving Pfizer and BioNTech’s COVID-19 vaccine, with a near-unanimous backing from an expert committee.

    While the decision of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) is non-binding, the FDA seldom goes against the ruling of its advisers when making regulatory decisions.

    However has were some concerns raised, reflected in the 17 to 4 vote in favour of approval.

    Some experts in the public meeting were concerned about the short length of the human trial so far as well as the potential side-effects for people with allergies or pregnant women.

    Already approved in the UK, this is the first time that mRNA technology has been used to create a vaccine.

    There were also concerns about whether the vaccine should be used in 16-17 year-olds because of a lack of safety data in this group, balanced against the fact people from this age group are unlikely to fall seriously ill.

    The committee also considered two cases of allergic reactions seen in the UK this week and has asked Pfizer to monitor for severe allergic reactions.

    This may lead to further advice on the label of the vaccine if the FDA decides to go ahead with the Emergency Use Authorization that Pfizer is asking for.

    The phase 3 data demonstrated a vaccine efficacy rate of 95% in participants without prior SARS-CoV-2 infection (first primary objective) and also in participants with and without prior SARS-CoV-2 infection (second primary objective), in each case measured from seven days after the second dose.

    Pfizer pointed out that the Data Monitoring Committee for the study has not reported any serious safety concerns related to the vaccine.

    Efficacy was consistent across age, gender, race and ethnicity demographics. All trial participants will continue to be monitored for an additional two years after their second dose to assess long-term protection and safety.

     

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    Can the UK deliver on the Covid vaccine rollout? | Stephen Buranyi

    The challenge of delivering vaccines on this scale are hard, but are firmly within the world of logistics, engineering, and politics

    The UK has become the first country to approve one of the coronavirus vaccines that the entire world has been desperately waiting for. And on Tuesday it delivered the first dose, to 90-year-old Margaret Keenan in Coventry. We should be very pleased about this. But, as with every other stage of the pandemic, the final stretch brings a new set of unprecedented challenges. The world is watching as the UK becomes the first test case of our collective ability to manufacture, ship, and deliver an entirely new class of vaccines, on a scale and speed that no previous vaccination drive in history has ever approached.

    The thing everyone knows about the Pfizer-BioNTech vaccine is that it needs to be extremely cold. The mRNA that makes up the vaccine payload is the same stuff your cells use to send short-lived genetic instructions. It’s a messenger that isn’t supposed to stick around, as temporally fragile as a Snap on Snapchat. The vaccine is happiest at -70C, and after thawing can be kept at between 4C and -8C – the temperature of a regular fridge – for just five days before it degrades. Most logistics providers aren’t set up to ship at -70C, and while university labs and large hospitals generally have some -70C freezers, GP surgeries and smaller centres do not. The temperature for shipping and storage has been identified as one of the biggest challenges in getting this vaccine out.

    The Pfizer/BioNTech Covid jab is an mRNA vaccine. Essentially, mRNA is a molecule used by living cells to turn the gene sequences in DNA into the proteins that are the building blocks of all their fundamental structures. A segment of DNA gets copied (“transcribed”) into a piece of mRNA, which in turn gets “read” by the cell’s tools for synthesising proteins.

    Stephen Buranyi is a writer specialising in science and the environment

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    NHS told not to give Pfizer vaccine to extreme allergy sufferers after two people have reaction

    Anyone scheduled to receive vaccine will be asked about history of allergic reactions

    Regulators have issued a warning that people who have a history of “significant” allergic reactions should not currently receive the Pfizer/BioNTech Covid-19 vaccine after two people who had the jab on Tuesday had allergic reactions.

    Two NHS staff members who received the vaccine on the first day of the mass vaccination programme experienced an allergic reaction, the NHS in England has confirmed.

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    FDA reviewers back Pfizer/BioNTech COVID-19 vaccine ahead of panel

    Reviewers from the FDA have given their blessing to the Pfizer/BioNTech COVID-19 vaccine ahead of a key meeting tomorrow – but the regulator noted that there are still uncertainties about whether the shot can stop the disease from spreading.

    The gist of a briefing document published from FDA reviewers ahead of an expert advisory board meeting is that the vaccine is good to go.

    But there are still unanswered questions that can only be addressed once the shot is administered to the wider public.

    Thursday’s vote of the Vaccines and Related Biological Products Advisory Committee is non-binding – but the FDA seldom takes a different viewpoint from its experts when it makes a final regulatory decision.

    Pfizer and BioNTech are asking for an Emergency Use Authorization of their vaccine based on phase 3 data, which can be converted into a full licence at a later date once further trial information is published.

    Phase 3 trials are designed to test whether vaccines are safe and effective and in this regard FDA reviewers said in the document that the Pfizer/BioNTech vaccine is a success, effective in around 95% of cases and with “favourable safety profile”.

    The most common adverse reactions seen in a trial cohort of 38,000 patients were at injection sites (84.1%) followed by fatigue (62.9%) and headache (55.1%), and serious adverse reactions occurred in 0% to 4.6% of participants.

    There were four cases of Bell’s palsy – a sudden muscle weakness – in the vaccine group and none in a placebo arm.

    However the FDA noted there are currently insufficient data to make conclusions about the safety of the vaccine in subpopulations such as children less than 16 years of age, pregnant and lactating women, and those with compromised immune systems.

    The biggest issue for the FDA staffers is one that will only be resolved with time – whether or not the shot can prevent people from infecting each other.

    Reviewers said that “additional evaluations including data from clinical trials and from vaccine use post-authorisation will be needed to assess the effect of the vaccine in preventing virus shedding and transmission, in particular in individuals with asymptomatic infection”.

    Reviewers noted there was no evidence of “vaccine-enhanced disease” but whether the vaccine could lead to a more resistant strain of the virus emerging is also unclear.

    The regulator will be keeping a watching brief on this as more study data emerges over the course of the pandemic.

    This risk “needs to be evaluated further in ongoing clinical trials and in observational studies that could be conducted following authorisation and/or licensure,” reviewers said.

    Hospitals in the UK have already begun immunising high-risk patients after the country’s regulator became the first in the world to approve the Pfizer/BioNTech vaccine last week.

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    Nine out of 10 in poor nations to miss out on inoculation as west buys up Covid vaccines

    Billions unlikely to get jabs as rich countries secure 53% of most promising vaccines

    Nine out of 10 people in 70 low-income countries are unlikely to be vaccinated against Covid-19 next year because the majority of the most promising vaccines coming on-stream have been bought up by the west, campaigners have said.

    As the first people get vaccinated in the UK, the People’s Vaccine Alliance is warning that the deals done by rich countries’ governments will leave the poor at the mercy of the rampaging virus. Rich countries with 14% of the world’s population have secured 53% of the most promising vaccines.

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    Leaders in the Life Sciences Speak about the Pandemic

    We are in a global pandemic that is exposing major issues in the commercial environment in which healthcare companies operate, with changes that are completely altering the landscape for the long term. Our 3rd Annual Leaders in Life Sciences Roundtable consisted of eight industry leaders with diverse perspectives and experiences discussing these changes, their impacts, and best practices learned […]

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    FDA: Pfizer Covid vaccine data fits with guidance on emergency authorization

    Comments raise hopes that the vaccine could soon be available to Americans aged 16 and above

    US Food and Drug Administration (FDA) staff said on Tuesday that data on Pfizer’s coronavirus vaccine was in line with its guidance on emergency use authorization, raising hopes it could soon be available to Americans aged 16 and above.

    The comments were made in documents released ahead of Thursday’s meeting of outside experts to discuss whether the vaccine developed by Pfizer with German pharmaceutical partner BioNTech should be authorized for emergency use in America.

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    First COVID-19 vaccinations begin in UK hospitals

    A 90-year-old woman has become the first person given a COVID-19 vaccine as part of the UK’s mass vaccination programme.

    Margaret Keenan was given the injection at 06:31 this morning at University Hospitals Coventry and Warwickshire NHS Trust.

    Keenan turns 91 next week and the BBC said she described receiving the shot as “the best early birthday present”.

    It was the first of 800,000 doses of the Pfizer/BioNTech vaccine that will be given in the coming weeks, and up to four million more are expected by the end of the month.

    The logistical challenges of storing and distributing the vaccine, which must be kept at around -70C to retain its integrity, mean that distribution will occur at around 50 hubs nationally.

    Keenan said: “I feel so privileged to be the first person vaccinated against COVID-19, it’s the best early birthday present I could wish for because it means I can finally look forward to spending time with my family and friends in the New Year after being on my own for most of the year.

    “My advice to anyone offered the vaccine is to take it – if I can have it at 90 then you can have it too!”

    NHS nurse May Parsons said it was a “huge honour” to be the first in the country to deliver the vaccine to the patient.

    NHS England chief executive Sir Simon Stevens added: “Less than a year after the first case of this new disease was diagnosed, the NHS has now delivered the first clinically approved COVID-19 vaccination – that is a remarkable achievement.

    “Today is just the first step in the largest vaccination programme this country has ever seen. It will take some months to complete the work as more vaccine supplies become available and until then we must not drop our guard.

    “But if we all stay vigilant in the weeks and months ahead, we will be able to look back at this as a decisive turning point in the battle against the virus.”

    The vaccine has also been given to the first person in Wales, where 48 year-old Craig Atkins from Ebbw Vale became the first to receive the shot.

    Wales has been hit badly by the virus and unlike England the numbers of cases are continuing to rise, prompting the country’s devolved government to consider a third national lockdown as hospital cases rose to a record high.

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    Valneva accelerates Lyme disease vaccine R&D project with Pfizer

    Valneva has said it plans to accelerate research into its Lyme disease vaccine candidate VLA15, bringing forward a trial including children into the first quarter of 2021.

    Subject to approval from regulators the vaccine specialist said it plans the trial known as VLA15-221 as a randomised, observer-blind phase 2 study including around 600 healthy people aged 5-65 years of age.

    They will receive VLA15 at the dose of 180 micrograms, which was selected based on data from two ongoing phase 2 studies.

    First data from the study is expected by the second quarter of 2022 and all three studies will support a phase 3 pivotal efficacy trial including all main target populations for the Lyme vaccine, starting in 2022.

    Starting the next phase 2 study will trigger a milestone payment from Pfizer to Valneva of $10 million under a collaboration announced in April this year.

    Under the agreement Valneva could receive up to $308 million in cash payments, after Pfizer paid $130 million up front for marketing rights to the vaccine if it succeeds in the clinic.

    Pfizer will pay up to $45 million in development related milestone payments and up to $143 million if the vaccine hits early sales targets.

    Valneva is paying 30% of development costs and in return Pfizer will pay tiered royalties starting at 19% and will lead late-stage development.

    VLA15 is the only active Lyme disease vaccine in clinical development today, and covers six strains that are prevalent in North America and Europe.

    This investigational multivalent protein subunit vaccine targets the outer surface protein A (OspA) of the bacterium Borrelia that causes the disease, an established mechanism of action for a Lyme disease vaccine.

    OspA is one of the most dominant surface proteins expressed by the bacteria when present in the ticks that spread the disease.

    VLA15 has demonstrated a promising immune response and safety data in pre-clinical and clinical studies so far.

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    PureTech begins trial of potential ‘Long COVID’ drug as cases mount

    As the pandemic drags on there are increasing concerns about “Long COVID” – where symptoms persist long after the initial infection has been fought off.

    PureTech has joined the effort to find ways to treat the scarring and inflammation that are thought to cause the ongoing symptoms such as shortness of breath and fatigue.

    After promising results in an early stage study, the company has begun a phase 2 trial of its LYT-100 (deupirfenidone) in Long COVID respiratory complications and related sequela.

    LYT-100 is wholly owned by PureTech, which is already being developed for conditions involving inflammation and fibrosis and disorders of lymphatic flow.

    The rationale for treating inflammation and scarring comes from a growing body of evidence from patients recovering from SARS-CoV-2 infection and previous experience with the closely related Severe Acute Respiratory Syndrome (SARS) virus.

    PureTech referred to an Italian study showing that more than 40% of COVID-19 survivors reported shortness of breath an average of 60 days following symptom onset.

    LYT-100 is based on the already-approved small molecule drug pirfenidone but with the addition of deuterium its half-life has been extended to improve tolerability, allow for less frequent dosing, and potentially increase its efficacy.

    It is treated as a new chemical entity and as such fresh trials are needed to establish whether it is safe and effective.

    The primary endpoint of the trial will be the six-minute walk test distance.

    Secondary endpoints will include pharmacokinetics, inflammatory biomarkers, imaging and patient-reported outcomes and shortness of breath.

    The study is to begin in the US and Europe and results are expected in the second half of next year.

    PureTech also plans a phase 2a proof-of-concept study testing LYT-100 in patients with breast cancer-related upper limb secondary lymphedema this quarter.

    The company is also planning studies to test LYT-100 in idiopathic pulmonary fibrosis (IPF).

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    How does the Pfizer/BioNTech vaccine work and who will get it?

    Covid vaccine with an efficacy of almost 95% has been authorised by the UK medicines regulator

    The Pfizer/BioNTech Covid vaccine, which has an efficacy of almost 95%, has been authorised by the UK medicines regulator, making the UK the first western country to license a vaccine against the disease. The UK has 40m doses of this vaccine on order.

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    Oxford controversy is the first shot in international battle over vaccine efficiency

    Trials will not reveal all the facts on prevention for each new drug – that process could last for years

    In a few days, researchers plan to solve a medical mystery that threatens to erupt into a major transatlantic battle. Scientists at Oxford University say they intend to publish full, peer-reviewed data, in the journal Lancet, about trials they have completed on their Covid-19 vaccine.

    The information, they say, should end mounting controversy about the vaccine’s effectiveness and explain apparent inconsistencies in trial results. Opponents, most of them American, say this is unlikely, and insist new phase 3 trials now need to be restarted from scratch to restore confidence in the vaccine.

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    Different age groups may get different Covid vaccines, experts say

    Oxford/AstraZeneca planning new trial of lower-dose jab to see how well it works in older people

    Concerns around the efficacy of the Oxford University/AstraZeneca coronavirus jab in older people could lead to different age groups being given different vaccines, experts have said.

    The partners announced last week that the vaccine had a 70% efficacy overall. For most trial participants – given two full doses, spaced a month apart – the efficacy was 62%, but for 3,000 participants mistakenly given half a dose for their first jab, the efficacy was 90%. No participants, regardless of dosing, developed severe Covid or were hospitalised with the disease.

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    BioNTech’s Covid vaccine is a triumph of innovation and immigration | Hans-Werner Sinn

    Pioneered by a Turkish-German couple, its significance exceeds its practical value

    The world took note when the German startup BioNTech announced its breakthrough in the development of a new type of vaccine to combat Covid-19. After testing tens of thousands of people, BioNTech’s vaccine has been shown to be 95% effective in providing protection for those who would otherwise have been infected. The company was the first to apply for emergency use authorisation for a coronavirus vaccine in the US and it has announced it will soon take similar steps in Europe.

    Antiviral vaccines are usually made with devitalised viral materials fabricated outside the body but BioNTech has pursued a new method of injecting genetically modified RNA into the patient. This prompts the patient’s cells to produce a characteristic protein of the relevant Sars-CoV-2 virus themselves, enabling the body’s immune system to build up an effective response before it encounters the real virus.

    Related: Uğur Şahin and Özlem Türeci: German ‘dream team’ behind vaccine

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    Will everyone in the world have access to a Covid vaccine? – video explainer

    The hunt for a coronavirus vaccine is showing promise but it is premature to say the end of the pandemic is nigh. Several rich countries have signed a ‘frenzy of deals’ that could prevent many poor nations from getting access to immunisation until at least 2024. Also, many drug firms are potentially refusing to waive patents and other intellectual property rights in order to secure exclusive rights to any cure.

    Michael Safi, the Guardian’s international correspondent, explains why ‘vaccine nationalisation’ could scupper global efforts to kill the virus and examines what is being done to tackle the issue

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    ‘Mistake’ led to AZ’s more effective lower-dose COVID-19 shot

    AstraZeneca’s research chief has said that the more effective dosing regimen of its coronavirus vaccine was discovered by accident.

    According to Reuters, the AstraZeneca development team made a minor mistake that made them realise they could significantly boost the success rate of the vaccine, codenamed AZD1222.

    Results announced earlier this week showed that by giving a half dose, followed by a full dose a month later, the vaccine’s efficacy could be boosted from 62% to around 90%.

    AZ originally planned for trial participants in the UK to receive two full doses but researchers found that certain side effects such as fatigue, headaches or arm aches were milder than predicted.

    Mene Pangalos, executive vice-president of biopharmaceuticals R&D at AZ, said: “The reason we had the half dose is serendipity.

    Mene Pangalos

    “So we went back and checked…and we found out that they had underpredicted the dose of the vaccine by half.”

    Researchers decided to continue with the half dose group and administer the second booster shot as previously planned.

    Results showed that in the group treated with the half dose, the vaccine was 90% effective, leading to an overall efficacy of 70% across the two dosing schedules.

    “That, in essence, is how we stumbled upon doing half dose-full dose. Yes, it was a mistake.”

    The error could make all the difference, cutting the amount of vaccine required for a strong therapeutic effect and allowing greater coverage.

    Although at 90% effectiveness AZ’s shot would lag slightly behind RNA-based rivals from Pfizer/BioNTech and Moderna, AZD1222 is easier to handle and can be stored in fridges instead of at ultra-cool temperatures.

    The revelation means that the stronger regimen could be added to a growing list of medicines discovered by accident – Alexander Fleming famously discovered penicillin after noticing a mould producing the compound was killing bacteria in a petri dish.

    Pfizer’s erectile dysfunction drug Viagra was initially trialled as an angina drug before scientists at Pfizer’s laboratory in Sandwich, Kent, stumbled upon its other properties in a story so famous that Spike Lee is to direct a musical about the discovery.

    It’s still not clear whether AZ’s vaccine discovery will be celebrated in popular culture as regulators have not yet approved it, but the incident shows the unpredictable nature of drug R&D and that after years of painstaking research good fortune is sometimes needed to get projects over the line.

    The post ‘Mistake’ led to AZ’s more effective lower-dose COVID-19 shot appeared first on .

    FDA approves Roche’s Xofluza to prevent flu spreading in families

    The FDA has approved a new use for Xofluza (baloxavir marboxil) from Roche’s Genentech unit, to prevent people developing flu after coming into contact with an infectious person.

    Xofluza has already been on the market for two years, and already had licensed uses to treat uncomplicated flu and those at high risk of complications.

    With this third indication, Xofluza has become the first single-dose medicine approved for this new use also known as post-exposure prophylaxis.

    This provides a more convenient alternative to older drugs such as Roche’s own Tamiflu (oseltamivir), which is taken once daily for 10 days in this indication.

    Approval was based on the phase 3 BLOCKSTONE study, recently published in the New England Journal of Medicines, which compared Xofluxa with placebo as a preventive treatment for household members who were living with someone with flu.

    Xofluza showed a statistically significant prophylactic effect on influenza after a single oral dose in people exposed to an infected household contact.

    The proportion of household members 12 years of age and older who developed influenza was 1% in participants treated with Xofluza and 13% in the placebo-treated group. Xofluza was well tolerated in this study and no new safety signals were identified.

    The most frequently reported adverse events occurring in at least 1% of adult and adolescent influenza patients treated with Xofluza included diarrhoea (3%), bronchitis (3%), nausea (2%), sinusitis (2%), and headache (1%).

    It’s hoped that the new indication could take the pressure of health systems that are struggling to cope with the extra workload caused by the COVID-19 pandemic.

    Serese Marotta, chief operating officer at Families Fighting Flu, said: “The flu is a serious illness that burdens households and sickens millions across the U.S. every year.

    “As we are about to enter a flu season within a global COVID-19 pandemic, we welcome Xofluza as a single-dose flu medicine to be used preventively after exposure to flu.”

    Genentech is in talks with the FDA to develop Xofluza for acute uncomplicated influenza in otherwise healthy children (one to 12 years of age) and for the prevention of influenza in the same age group who have been exposed to influenza. Xofluza is currently not approved for use in this population.

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    ‘It’s a great day’: Oxford coronavirus vaccine volunteers on trial data

    Trial participants react to news that Oxford AstraZeneca Covid vaccine has up to 90% efficacy

    Dan McAteer describes his reaction more as a sense of relief than elation when his phone pinged on Monday morning with a push alert reporting that the Oxford AstraZeneca vaccine has up to 90% efficacy.

    Several months on from becoming one of thousands of volunteers in trials of the Covid-19 vaccine, the 23-year-old student is trying to comprehend the news that people could be vaccinated as early as next month

    Related: Oxford AstraZeneca Covid vaccine: everything we know so far

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    Oxford AstraZeneca results open up Covid vaccine to developing countries

    Jab can be kept in fridge and is part of global initiative to distribute doses at limited cost

    The efficacy of the Oxford University/AstraZeneca vaccine opens the way for a cheap and more easily transportable vaccine to be made available to some of the world’s poorest countries.

    Unlike the Pfizer-BioNTech vaccine, AstraZeneca’s experimental vaccine is already a part of Covax, the global initiative which hopes to distribute some 2bn doses to 92 low- and middle-income countries at a maximum cost of $3 a dose.

    Related: Latest vaccine success is good news but high price may restrict access

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    The Guardian view on coronavirus and vaccine scepticism: time to act | Editorial

    Plans for mass immunisation against Covid-19 are developing fast, but concerns must be addressed

    In the 1960s, academics studying rumours drew inspiration from epidemiology. They noted how such stories spread through communities, “infecting” some individuals while others seemed immune, and how more resistant populations could stop their spread.

    Their insights have in turn been taken up by health professionals. Hearsay can be useful, helping to catch disease outbreaks. It can also be deadly. Though vaccine hesitancy is as old as vaccines themselves, it has risen sharply in many countries in recent years. Unfounded scare stories about the safety of immunisation programmes have contributed to growing scepticism and outright refusal, with fatal consequences. In her new book Stuck: How Vaccine Rumours Start – and Why They Don’t Go Away, Prof Heidi Larson notes the paradox: we have better vaccine science, more safety regulations and processes than ever before, yet a doubting public.

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    Do mRNA vaccines for Covid signal a new era in disease prevention? | Adam Finn

    No one knew whether mRNA technology would work against this virus – but it does. It’s an extraordinary moment for science

    The past few months have brought a number of scientific terms to public attention. We’ve had to digest R (a virus’s reproduction number) and PCR (the polymerase chain reaction method of testing). And now there’s mRNA. This last one has featured heavily in recent news reports because of the spectacular results of two new mRNA vaccines against coronavirus. It stands for “messenger ribonucleic acid”, a label familiar enough if you studied biology at O-level or GCSE, but otherwise hardly a household name. Even in the field of vaccine research, if you had said as recently as 10 years ago that you could protect people from infections by injecting them with mRNA, you would have provoked some puzzled looks.

    Essentially, mRNA is a molecule used by living cells to turn the gene sequences in DNA into the proteins that are the building blocks of all their fundamental structures. A segment of DNA gets copied (“transcribed”) into a piece of mRNA, which in turn gets “read” by the cell’s tools for synthesising proteins. In the case of an mRNA vaccine, the virus’s mRNA is injected into the muscle, and our own cells then read it and synthesise the viral protein. The immune system reacts to these proteins – which can’t by themselves cause disease – just as if they’d been carried in on the whole virus. This generates a protective response that, we hope, lasts for some time. It’s so beautifully simple it almost seems like science fiction. But last week we learned that it was true.

    Related: What has to happen before a Covid vaccine can be used?

    Adam Finn is professor of paediatrics at the Bristol Children’s Vaccine Centre, University of Bristol

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    Trials to begin in UK for Covid antibody cocktail drug treatment

    Scientists say jab could be used to protect those who cannot be given vaccines

    Major trials will begin this weekend of an antibody cocktail that scientists hope will protect people against Covid-19 and could be swiftly used in care homes or on cruise ships in the event of an outbreak.

    A UK volunteer will be given the first dose of a drug that is expected to give vulnerable people immediate protection. The jab into the muscle of the arm takes effect straight away and could last for six months to a year. If it works as well as scientists predict, it could be used to protect those who cannot be given vaccines because of their state of health.

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    UK faces calls to drop opposition to patent-free Covid vaccines

    Request will be made at WTO meeting in order to allow mass production of treatments

    The UK will be asked to reconsider its opposition to waiving intellectual property rights for Covid-19 vaccines and treatments at a World Trade Organization meeting on Friday, a move that would allow mass production of treatments and inoculations against the disease and could significantly shorten the length of the pandemic, campaigners say.

    India and South Africa have proposed that WTO member states be allowed to waive patents and other intellectual property (IP) rights on any treatments and tools related to Covid-19 until the end of the pandemic, including for the Moderna and Pfizer/BionNTech vaccines that are expected to be approved for use in the coming weeks.

    Related: Covid vaccine tracker: when will a coronavirus vaccine be ready?

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    Pfizer Covid-19 vaccine has 95% efficacy and is safe, further analysis shows

    Among first 170 Covid cases in trial, eight had received vaccine and 162 were in placebo group

    The Pfizer/BioNTech vaccine against Covid-19 performs even better than previously thought, with 95% efficacy, equalling the early results from Moderna on Monday, according to an analysis of the final data from their trials, which paves the way for regulators to grant an emergency licence and vaccination campaigns to begin.

    The news will excite scientists, public health experts and politicians. Pfizer/BioNTech say they also have the necessary safety data that regulatory bodies require, and will submit the vaccine for emergency approval within days to the US Food and Drug Administration and other regulators around the world.

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    ViiV could challenge Gilead with long-acting HIV PrEP shot

    GlaxoSmithKline’s HIV joint venture ViiV Healthcare could mount a challenge to Gilead’s HIV pre-exposure prophylaxis (PrEP) medicines after the FDA granted Breakthrough Therapy Designation for its long-acting injectable drug cabotegravir.

    In the trial cabotegravir was injected every eight weeks in a formulation that the company hopes will be more appealing than Gilead’s daily Truvada pill.

    Offering patients the option of an injection every eight weeks would allow them to take the medicine more discreetly. Trial results show that cabotegravir is more effective at preventing infections than Truvada.

    PrEP drugs are taken by HIV-negative people before they have sex and reduce the risk of getting HIV.

    The FDA granted the status based on efficacy and safety results of a trial comparing cabotegravir with emtricitabine+tenofovir disoproxil fumarate (FTC/TDF) – the active ingredients in Gilead’s Truvada – in high-risk individuals.

    HPTN 08 is, a phase IIb/III randomised, multicentre, double-blinded, clinical trial comparing the two drugs for HIV prevention among 4,566 men who have sex with men and transgender women who have sex with men.

    ViiV said the final analysis of HPTN 083 showed the superiority of long-acting cabotegravir, which was 66% more effective at preventing HIV when compared to daily oral Truvada tablets.

    Results of the trial were presented at the AIDS 2020 conference in July and the blinded phase of a prevention study in 3,223 sub-Saharan African women was stopped earlier this month after an analysis by the independent safety monitoring board showed cabotegravir was superior to oral FTC/TDF.

    Viiv, which is majority owned by GSK with Pfizer and Shionogi as shareholders, plans to use the data from both studies for future filings with regulators.

    Breakthrough Therapy status is intended to expedite the development and review of drugs for serious or life-threatening diseases, which may be better than available therapies.

    The FDA requires preliminary clinical evidence showing a drug may be a substantial improvement on at least one clinically significant endpoint over available therapies.

    It may allow more frequent collaboration with the FDA to discuss a development plan and could pave the way for a faster Priority Review lasting six months.

    Gilead has also produced a follow-up to Truvada – Descovy (emtricitabine+tenofovir alafenamide) which is approved by the FDA in PrEP and to help keep the virus at bay in those infected with the virus.

    The post ViiV could challenge Gilead with long-acting HIV PrEP shot appeared first on .

    COVID-19: Helping to support momentum on antimicrobial innovation

    To mark World Antimicrobial Awareness Week NovaBiotics’s Deborah O’Neil tells us why 2021 might be the year anti-infective drugs finally demonstrate their economic value. 

    COVID-19 has reminded the world how critical infectious disease is, from both a societal and economic standpoint. Cancer is rightly seen as one of the most pressing challenges of our time: but it has not yet caused a multi-trillion hole in the world’s finances.

    For the first time in my career developing antimicrobials, I’m hearing more investors enthused by the prospect of investing in companies developing solutions to infectious diseases. We all know COVID-19 has shifted our perspective on a range of things, and in economic terms three developments have underpinned this shift.

    First, there is now a wealth of innovation, perhaps more than ever, in antimicrobial design and development (almost all of it being generated by SME businesses). Second, push incentives from government and NGO bodies, particularly the AMR Action Fund, providing $1 billion of investment, are now substantial enough to really fuel that innovation. And third, pull incentives are now in place which are beginning to make an effective commercial case for antimicrobial development.

    The NHS/NICE antibiotic subscription model announced earlier this year is potentially the most significant of these developments. The US PASTEUR Act, if enacted, would also pave the way for providing prepaid subscription contracts for antimicrobials in the US, collectively making antimicrobials viable again. Similar subscription models and other market entry reward proposals are being floated in Sweden and elsewhere.

    After years of lobbying by the industry, policymakers now accept the need for “pull” models that de-link sales (by volume) from reward; reward being for developing and launching these drugs for when they are needed, not for promoting use. Antimicrobial stewardship is now clearly linked with economic success.

    We’ve all heard the bear cases for antibiotics: the bankruptcy of Achaogen, fire sale of Tetraphase and other high-profile problems at antibiotic developers have highlighted the fact that even with the best possible support in the development phase, generating profitable versions of the ‘traditional’ antibiotic classes remains challenging. The decision by Cipla to withdraw Zemdri (plazomicin) from European marketing authorisation, is a sobering reminder that even highly effective antibiotics with proven efficacy are often not considered economically viable.

    “We need to keep up the momentum. Although welcome, the pull incentives are the first small steps to creating the economic climate required for very successful commercialisation of antimicrobials.”

    But now, just as a communicable disease poses the biggest economic challenge the world has faced in a decade, there are signs that new reimbursement models, alongside a new generation of innovation in development, have changed the rules of engagement.

    Innovative and commercial savvy companies are creating platform technologies and diversified portfolios, focusing not only on antibiotics but desperately needed antifungals and antivirals as well.

    NovaBiotics is proud to be developing antifungal and antiviral therapies alongside antibacterials, all of which mitigate resistance as they are based on platforms engineered from innate immune effector molecules – harnessing the way the body fights disease versus ‘synthetic’ approaches that introduce new resistance pressure to microbes. We are not alone in developing drugs which are designed to avoid creating antimicrobial resistance.

    There’s every reason to believe that by the time these new drugs reach the marketing approval and launch, the reimbursement and commercial landscape will allow for a good economic runway.

    We need to keep up the momentum. Although welcome, the pull incentives are the first small steps to creating the economic climate required for very successful commercialisation of antimicrobials. The forthcoming EU Pharmaceutical Strategy can perhaps create conditions to address market failure in antimicrobials and reinvigorate innovation, by taking the right actions. These include support for the SME companies which generate the lion’s share of innovation, better alignment between health systems and drug developers, the targeted use of diagnostics and a regulatory framework based around non-inferiority trials, to name a few.

    The UK government, which has already played a leading role in creating a significant pull incentive for developers, is talking about creating an equivalent to DARPA. The UK has some of the world’s most innovative antimicrobial developers so there’s a clear incentive to do this.

    This year may be the great awakening of the value of anti-infectives from a social perspective. 2021 could be the year that they demonstrate their economic case. Let’s use Antimicrobial Awareness Week to get that message out.

    About the author

    Deborah O’Neil is CEO and CSO of NovaBiotics.

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    UK in ‘advanced discussions’ to buy Moderna Covid vaccine

    Britain decided not to buy US vaccine and earliest it could be supplied to UK is spring 2021

    The UK has not acquired the Moderna vaccine but is in “advanced discussions” to ensure British access, officials have said, while cautioning that no one in the UK would be able to be given it until spring next year.

    A government spokesman said the company was scaling up its European supply chain but that it would be around four to six months before the vaccine might be available in the UK, a far longer timeframe than the Pfizer-BionTech vaccine, which the chief scientific officer has said could be available by Christmas.

    100m doses of the University of Oxford/AstraZeneca vaccine

    40m doses of the BioNTech/Pfizer vaccine, reported last week to have 90% effectiveness

    60m doses of Novavax vaccine

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    It’s the ‘vaccine hesitant’, not anti-vaxxers, who are troubling public health experts | Gaby Hinsliff

    To make vaccination work, we must reach out to the naturally cautious – a bigger proportion than you might assume

    Lydia Guthrie is not very daring by nature. A psychotherapist and mother of two from Oxford, she couldn’t be persuaded into bungee jumping for all the money in the world, and even shudders at skiing. “I’m very risk averse and a bit of a coward. I can’t even watch horror films.” Yet nonetheless, earlier this year she volunteered to be injected with an experimental Covid-19 vaccine as part of a clinical trial in the city, a partnership between the university, the NHS and drug company AstraZeneca.

    Like all the guinea pigs, she doesn’t yet know if she got the real thing or the meningitis vaccine used as a dummy. She had a headache afterwards and felt exhausted for a couple of days, but has never regretted taking part. She trusts the university’s ethics panel, having encountered it through her own degree research, and was also swayed by gratitude towards the city’s John Radcliffe hospital, where she had her own children. “If it hadn’t been for the NHS we might all have died. I feel I owe them.”

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    Moderna Covid vaccine candidate almost 95% effective, trials show

    US-based biotech firm is latest to reveal impressive results from phase 3 trials of jab

    The race for a coronavirus vaccine has received another shot in the arm with the US biotech firm Moderna becoming the latest to reveal impressive results from phase 3 trials of its jab.

    An interim analysis released on Monday, and based on 95 patients with confirmed Covid infections, found the candidate vaccine has an efficacy of 94.5%. The company said it now plans to apply to the US regulator, the Food and Drug Administration, for emergency-use authorisation in the coming weeks. In the trial, 90 of the patients received the placebo with the remaining five the vaccine.

    Related: Here are the major hurdles ahead for Covid-19 vaccine distribution in the US

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    BioNTech vaccine scientist says jab could halve Covid transmission

    Uğur Şahin ‘very confident’ vaccine candidate developed with Pfizer will cause big reduction in cases

    The scientist behind the first potential Covid-19 vaccine to clear interim clinical trials says he is “very confident” the jab will reduce transmission of the disease, perhaps by 50%, resulting in a “dramatic” reduction in cases.

    The German company BioNTech and the American pharmaceutical firm Pfizer announced to worldwide acclaim last week that their jointly developed vaccine candidate had proved 90% effective in stopping people from falling ill.

    The UK government’s joint committee on vaccination and immunisation has published a list of groups of people who will be prioritised to receive a vaccine for Covid-19. The list is:

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    Vaccination hesitancy is about lack of trust. Compulsion is not the answer | Kenan Malik

    Better to build social solidarity than to dismiss reluctance to be immunised as ignorance

    “If a strain as deadly as the 1918 influenza emerges and people’s hesitancy to get vaccinated remains at the level it is today, a debilitating and fatal disease will spread.” So wrote Heidi Larson in 2018. Larson is director of the London-based Vaccine Confidence Project and probably the most knowledgeable person on the question of “vaccine hesitancy” – the unwillingness of some to get vaccinated.

    Two years after Larson wrote those words, we do have a pandemic that so far has taken more than a million lives, including at least 50,000 in the UK. We also have the possibility of a vaccine, the first of a number that could transform the Covid-19 landscape. Whether they do depends not just on how effective they are, but also on the willingness of people to be vaccinated. In the US, just half the population seems so inclined. In Britain, the figure is higher – about 70% – but still probably insufficient to generate herd immunity.

    The UK government’s joint committee on vaccination and immunisation has published a list of groups of people who will be prioritised to receive a vaccine for Covid-19. The list is:

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    Lilly’s Monoclonal EUA

    I’ve been meaning to write about what has to be called a regulatory mystery. Eli Lilly obtained an Emergency Use Authorization for its monoclonal antibody (bamlanivimab) against SARS-Cov-2, but (as detailed in this post) the dosage that they applied for was 700mg. Which is one-quarter of the dose that showed any efficacy against the primary endpoint in the actual clinical trial. The approved 700mg dose did not reach statistical significance (nor, it should be said, did the even-higher 8g dose) in lowering viral loads at day 11 vs. placebo.

    Here’s BioCentury on this, which has to be the only EUA ever granted for a dose that failed in the clinic. To be sure, the company has said that there was no difference between the three doses on various secondary endpoints, and in fact says that they’re not sure that they’ve found the lowest effective dose yet. The FDA’s Janet Woodcock has said the same thing. That’s definitely looking on the bright side, but it suggests that the original endpoint in the trial was either too optimistic or aimed in the wrong direction, doesn’t it?

    The best spin I can put on this is that perhaps the viral loads (the primary endpoint that failed) are not well correlated with later hospitalizations (where there was a significant difference). In that case, it may be that those hospitalizations have more to do with the immune over-response to the virus than they do with the virus itself, although that’s sheer speculation on my part. But it seems clear that the mAb treatment needs to be aimed at people who are at high risk, particularly those who don’t seem to be mounting a good antibody response on their own. In that population, I think Lilly’s therapy (and Regeneron’s two-mAb cocktail) could do some real good, but that’s definitely a smaller subset of the total coronavirus population,

    Not that we have enough of the mAbs to treat the total coronavirus population, anyway! The government has contracted to buy 300,000 doses of bamlanivimab this year, and Lilly is supposed to be shipping 80,000 doses this week. We just had 163,000 cases reported yesterday, to put that in perspective. Now, it’s for sure that not all of these people would be getting a monoclonal antibody, even if we had barrels of it sitting around, but there’s clearly a need for targeting the supplies we do have. I’m not sure how that’s to be done, though: you want to catch people early in the infection who are having trouble mounting a vigorous antibody response, but how many people are being tested in a manner (that early on) to pick that up? I really don’t know, and so far I haven’t seen any information addressing this issue. But it’s surely something that’s being worked on now that the mAb is starting to appear – I’ll update as the situation becomes clearer.

    BioNTech chief rejects Trump claim it delayed Covid vaccine news

    Exclusive: Ugur Şahin says he and Pfizer CEO received results night before announcement

    The scientist behind the BioNTech/Pfizer coronavirus vaccine has defended his company from Donald Trump’s accusation that it deliberately delayed news of its rapid progress until after the election, saying “we don’t play politics”.

    BioNTech, a German company, and the US pharmaceutical giant Pfizer announced on Monday that their jointly developed vaccine candidate had exceeded expectations in the crucial phase 3 vaccine trials, proving 90% effective in protecting people from coronavirus infections.

    The UK government’s joint committee on vaccination and immunisation has published a list of groups of people who will be prioritised to receive a vaccine for Covid-19. The list is:

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    The Covid vaccine will benefit humanity – we should all own the patent | Owen Jones

    The pharmaceutical industry has long made exorbitant profits by free-riding on research carried out by the public sector

    Hooray for Pfizer! As news of a vaccine potentially offering 90% protection against Covid-19 offers a life raft for lockdown-weary humanity, perhaps those home-drawn posters on people’s windows thanking the NHS will soon be applauding big pharma instead.

    The hope of a successful vaccine to liberate us from protracted economic misery should be embraced – but we should be sparing with the bunting for the pharmaceutical industry. If you want a particularly egregious case study of “socialism for the rich”, or of private businesses dependent on public sector research and innovation to make colossal profits, look no further than big pharma.

    Related: The race to find a coronavirus treatment has one major obstacle: big pharma | Ara Darzi

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    Why a Covid vaccine doesn’t mean the end of face masks yet | David Salisbury

    Despite the Pfizer breakthrough, social distancing and remote working won’t disappear overnight

    The news this week that the Pfizer/BioNTech vaccine protected more than 90% of recipients is of huge importance. The vaccine efficacy is higher than we had hoped for.

    There appear to be no safety concerns, although the final safety data along with other data on manufacturing and the full efficacy results will need to be submitted to the Medicines and Healthcare products Regulatory Agency (MHRA) to review whether it’s safe enough to grant temporary authorisation. This would allow the vaccine to be rolled out before a full product licence is issued.

    Related: Speed trumps efficacy in UK’s Covid vaccine rollouts, says adviser

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    Where will poorer countries stand in the queue for a Covid-19 vaccine? | Clare Wenham and Mark Eccleston-Turner

    The lion’s share of the potential Pfizer vaccine is already claimed by high-income nations

    The news that joint efforts by the US pharmaceutical company Pfizer and the German biotech company BioNtech have produced a vaccine that is 90% effective at protecting people from Covid-19 has been understandably applauded – in spite of the caveats. Pfizer states that it can manufacture up to 50m doses by the end of 2020 and up to 1.3bn doses in 2021.

    Given the desire to get life back to normal, these doses will be in incredibly high demand. Some governments around the world, including the UK, have already begun to indicate to their populations that they will receive a vaccine by Christmas. But how will the distribution of this finite number of vaccines work when we only have enough for one seventh of the global population?

    Related: Pfizer and BioNTech’s vaccine poses global logistics challenge

    Clare Wenham is assistant professor of global health policy at the LSE. Mark Eccleston-Turner is a lecturer in Global Health Law at Keele University

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    Good News on T-Cell Response

    There are several recent preprints and publications that bear on the T-cell immunity story for the coronavirus pandemic, and I wanted to highlight these, since it’s been a big part of the story that’s needed more information for a long time now.

    Here, for one, is a multi-institute study from the UK. The authors are looking at 100 COVID-19 patients over a six-month period and correlating the antibody and T-cell responses. What they see is what you’d want to see: the T-cell responses appear to be durable over that time. They do seem to be correlated with the severity of the infection – responses were definitely higher in the people who had experienced symptoms, as opposed to asymptomatic cases. The T-cell response against the coronavirus nucleoproteins seemed to correlate with the degree of later decline of the antibody response to those proteins, but this did not hold true for the response to the Spike protein (the two were uncorrelated – antibody responses to the Spike protein could go down, while T-cell responses remained). 80% of the patients who had mild-to-moderate infection, however, did have Spike-specific cellular responses at the six month time point. For T-cell aficionados, the response was mostly (about 2:1) CD4+ cells with IL-2 cytokine expression, as opposed to CD8+ cells. Both types showed both Spike-directed and non-Spike-protein-directed responses, but the CD8+ were more biased towards the various non-Spike proteins.

    Overall, this work suggests that people who have experienced at least some degree of symptomatic infection should have reasonably long-lasting T-cell responses. There does seem to be a “set point” for these, correlating with that severity. What will tie this to the vaccine efforts will be the data on the T-cell responses induced by the vaccines themselves (which as of now are completely directed towards a Spike protein response), as compared to the wild-type viral infection. And I presume that we’ll be getting those numbers from the ongoing trials.

    Now here’s another new preprint from a different multicenter UK team that has some really interesting correlations. It’s a prospective study looking at 2,826 front-line workers there – they’ve been measuring their T-cell levels (using a new assay from Oxford Immunotec) and their antibody profiles since June and seeing who comes down with coronavirus infection over time. All the workers who were seropositive at the start (displaying antibodies against coronavirus proteins) also had robust T-cell response levels. In the seronegative group, there were some with robust T-cell numbers and some without. Split up another way, of the people in the study with strong T-cell responses to the coronavirus proteins, only about 55% of them had detectable antibodies to those proteins. Over time, 20 of the overall weak-T-cell group were infected with the virus, while zero of the strong T cell response group were (p = 0.006).

    That suggests that there may indeed be some protective T-cell immunity out there that is being missed by a focus on antibody levels (as has been suspected), but it also says that you can’t just extrapolate this to the whole population by any means: we don’t all have T-cells ready to go. But if you do, you may have a substantial amount of protection, and this might be detectable by a relatively simple assay.

    That last point has been the holdup in this area: the story has been all about antibodies because the assays for those are far, far easier to set up. T cell assays are very labor intensive indeed, and the sample sizes in the papers on them tend to be in the dozens. But as you can see, the Oxford Immunotec people are trying to improve that, and so is a company called Adapative Technologies here in the US (and there are others). They have a big write-up in the New York Times this week, and it’s a good article. A quote from an immunologist in it sums things up well: “There has. . .never been great demand for wading into the intricacies of T cell tests.” Adaptive’s recent work on a population in Italy suggests that its test is definitely better at determining whether a person has had a previous coronavirus infection (as opposed to antibody measurements), and if we put that together with the other papers mentioned, it could be that this extends to saying how much protection these people retain.

    So the story is coming together. And just as vaccine work is never going to be the same after the huge amounts of work during this pandemic, it looks like T-cell research is never going to be the same, either. They’re both going to be better, faster, and more detailed, and that’s good. Because we’re going to need all this again some day.

    Pfizer and BioNTech could make $13bn from coronavirus vaccine

    Johnson & Johnson and AstraZeneca pledged to make their vaccines available on a not-for-profit basis

    The US drugmaker Pfizer and the German biotech firm BioNTech stand to bring in nearly $13bn (£9.8bn) in global sales from their coronavirus vaccine next year, which will be evenly split between the two companies, according to analysts at the US investment bank Morgan Stanley.

    Pfizer’s half would be more than the US pharmaceutical group’s bestselling product, a pneumonia vaccine that generated $5.8bn last year.

    Related: Pfizer and BioNTech’s vaccine poses global logistics challenge

    Related: 6 key questions about the Pfizer/BioNTech Covid-19 vaccine

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    Pfizer and BioNTech’s vaccine poses global logistics challenge

    Europe and US create vast facilities for Covid-19 vaccine but poorer nations lack infrastructure say experts

    Two vast football-pitch-sized facilities equipped with hundreds of large freezers in Kalamazoo, Michigan, and Puurs, Belgium, will be the centres of the huge effort to ship the coronavirus vaccine developed by US drug giant Pfizer and German biotech firm BioNTech, around the world.

    Governments are scrambling to prepare for the rollout of the vaccine, which must be stored at -70C (-94F), after the announcement from the two companies that it was more than 90% effective and had no serious side-effects. The news sparked hopes of a return to normal life and a stock market rally, but now minds are turning to the practicalities of getting the vaccine quickly to populations across the world, in particular to the vulnerable people who need it most.

    Related: 6 key questions about the Pfizer/BioNTech Covid-19 vaccine

    The problem is particularly acute in the global south where many rural villages don’t even have a working vaccine fridge

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    The Guardian view on the Covid vaccine breakthrough: making it work | Editorial

    At last, there is hope of an end to this pandemic. Scientists appear to have performed an amazing feat, the rest of us must do our best too

    Medicine is only partly a matter of science; it is, very much, the business of people. The inspiring news that a Covid vaccine appears within reach, with interim results showing the Pfizer/BioNTech candidate has 90% efficacy in protecting people from illness, reflects the extraordinary efforts of scientists this year. The speed with which this one has been developed – with others close behind – is remarkable. Detailed data has yet to be published, and much remains unknown, including how long individuals may be protected, whether it prevents infection and how effective it will be for older people, who are most vulnerable to Covid-19. There are still no guarantees it will be used, though manufacturing has begun. Nonetheless, this is a potentially transformative moment.

    Now it is up to the rest of us to do our part. If this vaccine becomes available from the end of the year, as now looks likely, and others soon follow, the deployment will matter as much as its discovery. As one scientist has noted: “Vaccines don’t save lives. Vaccinations save lives.” Pfizer and BioNTech hope to make 50m doses available this year, but each patient requires two doses, and with the US, EU, UK and others all having placed advance orders, each country will get a tiny fraction of those it ultimately needs. Even if production of this vaccine is scaled up as planned, others will still be needed. The UK has a clear plan for who will be protected first, beginning with the oldest in society and those who care for them and thus might transmit the virus to them. Professor John Bell told MPs that there is a 70%-80% chance of having the most vulnerable covered by Easter if authorities “don’t screw up the distribution”. Mass inoculation will be a challenge; NHS England is planning seven-day services.

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    Will enough people in the UK take the Covid-19 jab?

    The UK usually has a high take-up for vaccines, experts say, but there are fears over misinformation and scepticism

    The spread of scepticism and misinformation about coronavirus and the development of a vaccine for it has raised questions about whether it will pose a threat to the goal of achieving widespread immunity.

    A report published on Tuesday by the British Academy and the Royal Society for the SET-C (Science in Emergencies Tasking: Covid-19) group said an 80% take up of a jab could be necessary in order for enough people to become immune to the virus and stop its spread. However, the actual threshold will depend on the efficacy of the vaccine, and the 90% achieved by the Pfizer/BioNTech candidate in trials was higher than many dared hope for.

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    Cautious optimism over Covid-19 vaccine trials | Letters

    Readers respond to news that an interim analysis has shown Pfizer/BioNTech’s vaccine candidate was 90% effective in protecting people from transmission of the virus in global trials

    The media have been awash with stories about the apparent success of the Pfizer Covid vaccine following the publication of preliminary trial outcomes (Hopes rise for end of pandemic as Pfizer says vaccine is 90% effective, 10 November). I am not surprised that the public has latched on to these, as hope and positivity have been in short supply this past year. I have even had patients contacting me about when the vaccine will be available, stating that it will allow “normal” life to resume.

    While the public can be forgiven for overoptimism, it is important that the medical profession, the media and the government keep expectations grounded and do not encourage the notion that we now have a panacea that will take us out of the pandemic.

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    6 key questions about the Pfizer/BioNTech Covid-19 vaccine

    There are grounds for optimism but also several unknowns around this coronavirus vaccine

    Hopes that the end of the coronavirus pandemic has become nearer have soared after the news that a coronavirus vaccine was found to be 90% effective in global trials.

    Although there is definite reason to be optimistic, experts have cautioned that the data from the trials conducted by Pfizer and BioNTech are not final, and there remain plenty of unknowns.

    Related: Covid vaccine could be ready for rollout next month, says Hancock

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    What does the Pfizer Covid vaccine breakthrough mean for Australia?

    Interim results show vaccine to be 90% effective, but findings have not been peer-reviewed, Australia has only secured enough for five million people, and there are concerns around its storage temperature

    • Pfizer says vaccine is 90% effective
    What has Pfizer’s vaccine trial found?
    Vaccine announcement is cause for cautious celebration

    News that pharmaceutical giant Pfizer and partner company BioNTech have developed a vaccine that proved 90% effective in protecting people from Covid-19 in global trials has been heralded a “breakthrough”. Pfizer chief executive, Dr Albert Bourla, described the results as “a great day for science and humanity”.

    But what do the findings mean for Australia, and for the other Covid-19 vaccines being researched?

    Related: Hopes rise for end of pandemic as Pfizer says vaccine is 90% effective

    Related: The race for a Covid vaccine: inside the Australian lab working round the clock to produce 100m doses

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    Don’t Make Mine Mink

    There’s a situation in Denmark that deserves some epidemiological attention. Now, put me in the (rather large) category who did not realize how large the Danish mink industry is – or that a Danish mink industry existed at all – but there are plenty of mink farmers there and millions of mink. 40% of world production is in Denmark.

    That means a high density of animals, for sure, and as always one of the big challenges under such conditions is control of disease. In my own homeland of Arkansas, the rise of large-scale catfish farming was partly a story of figuring out what the optimum fish density was that didn’t lead to finding them all floating on the surface of the pond one morning. American mink farms are already known to be a reservoir for Aleutian disease. The parvovirus responsible for that one has been mutating under the selection pressure of intense farming, and you would expect this to be the case with other infectious agents as well.

    Like the current coronavirus. Back in the spring and early summer, mink farmers in the Netherlands reported coronavirus outbreaks in their animals, and this was followed by reports from Denmark and other countries in Europe. Utah fur ranches reported coronavirus outbreaks in their mink populations (with thousands of dead animals) in August. On both continents, it’s believed that the disease spread from the human farm workers into the mink populations. Different mammals have different susceptibilities to the virus (to any virus), and it appears that Covid-19 is highly transmissible in mink. Its mortality rate is not high, fortunately, but high enough given the huge numbers of animal involved. For “herd immunity” fans, the outbreaks seem to tail off once about 90% of the population has been exposed, but that’s a lot higher number than you’d ever want to hit, and it’s also worth noting that the human population is not well modeled by the conditions on a mink farm. Yet.

    The coronavirus has spread and mutated in the Danish mink population, and now there have been cases of these strains jumping back into humans and causing infections there. This was first seen in a single case in the Netherlands in the spring (more here), and it’s happened a number of times since. It gets worse: reports have it that some of the current mink strains in Denmark are less susceptible to antibody responses.

    Now, I am not completely sure what that means. I have been trying to find published details, but it seems to be too early, and the press reports are full of other baffled scientists waiting for information. The Serum Science Institute in Denmark seems to be the place where these effects were found, and they’ve shared their findings with the WHO and the European Centre for Disease Prevention and Control. But the actual results don’t seem to have been released yet. But if I’m translating this correctly, Kåre Mølbak of that institute said at a press conference that the situation is “very serious” and that the worst case would be a restarted pandemic spreading out of Denmark. The article also says, rather alarmingly, that “The Serum Institute estimates that five percent of the viral infections among people in North Jutland are of the new type of virus mutation“, and I would very much like to hear some more about that.

    But you can see that the Danish government is taking this seriously: all 17 million mink in the country are being killed off immediately in a gigantic cull. The police, the armed forces, and the Home Guard are all involved, and apparently they’re throwing everything they have at the effort. The Netherlands has already sped up an existing proposal to ban mink farming, which is now set to take place by the end of this year, and you can bet that they’re looking at the Danish results very closely. But the places to watch are Poland and China: these are big mink pelt producers, and (as far as I can see) nothing has been heard from them about this new problem.

    I assume that we’ll be seeing sequence information very shortly, as well as the details of the antibody studies. I’ll dive right into those details as soon as they’re available, believe me!

    UK could get COVID-19 vaccines early next year, ahead of European countries

    COVID-19 vaccines could be approved and available early next year in the UK ahead of European countries, after its national regulator began its own rolling reviews of shots from AstraZeneca and Moderna.

    AstraZeneca has confirmed that the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) has begun a fast-track rolling review of its AZD1222, the COVID-19 vaccine it developed in conjunction with Oxford University.

    This followed last week’s news that the MHRA has begun a parallel rolling review of a rival from Moderna.

    The rolling review allows for a real-time assessment of the clinical data from clinical trials, accelerating a process that normally takes around a year to complete using the centralised European regulatory system.

    Using the MHRA could allow the UK to make regulatory decisions on COVID-19 vaccines ahead of the European system, where medicines and vaccines are first reviewed by the CHMP scientific committee before being passed on to the European Commission.

    But a source close to process told pharmaphorum that it is “eminently possible” that the MHRA could reach its conclusions ahead of its European counterparts as the country reaches the end of the Brexit transition period.

    A spokesperson for the MHRA said that from 1st January, it will have new powers to approve medicines, including vaccines including “greater flexibility to do this faster, while maintaining the highest standards of safety, quality and effectiveness.”

    The spokesperson said: “The MHRA will evaluate the data rigorously on the quality, safety and effectiveness of COVID-19 vaccines to reach a scientifically robust independent opinion if an earlier authorisation is necessary before the EMA (European Medicines Agency) authorises a product.”

    “Patient safety is our top priority. The independent Commission on Human Medicines will advise the UK government on the safety, quality and effectiveness of any potential vaccine. No vaccine will be deployed in the UK unless stringent standards have been met through a comprehensive clinical trial programme”

    Representatives of the MHRA used to sit on the CHMP but no longer participate as a result of Brexit, leaving the UK to make its own decisions on medicines regulation should it choose to do so.

    According to the source, COVID-19 vaccines could be available in early January depending on the length of time it takes for trial data to be published and shared with regulators.

    COVID vaccines are being developed at warp speed, with the development and review process that normally takes up to a decade to complete compressed into less than a year after research began at the end of January.

    The MHRA’s approach to the AZ and Moderna vaccines also paves the way for similar fast reviews to rivals from the likes of Pfizer/BioNTech and Novavax, which the UK government also has on order and are reaching the end of the clinical trial process.

    The news comes as the country prepares for another national lockdown, which will disrupt business and limit people’s freedoms for at least another month.

    A vaccine is seen as a potential way out of the cycle of lockdowns that have already caused severe hardship across the UK, which is one of the countries worst hit by COVID-19.

    An AstraZeneca spokesperson told pharmaphorum: “Results from the late-stage trials are anticipated later this year, depending on the rate of infection within the communities where the clinical trials are being conducted. It is then up to the regulatory bodies to review and make approval decisions based on this data, as quickly as possible.

    “The EMA announced in October that its CHMP had started a ‘rolling review’ of data for AZD1222, the first COVID-19 vaccine to be evaluated under these arrangements. We confirm the MHRA’s rolling review of our potential COVID-19 vaccine.”

     

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    Regeneron’s COVID-19 antibody cocktail therapy hits safety problem

    Regeneron’s coronavirus antibody cocktail therapy against COVID-19, famously used to treat president Donald Trump, has hit a safety issue after independent safety experts recommended it should not be given to high-risk patients in a late-stage clinical trial.

    It’s the latest blow for antibody therapies against COVID-19 after Eli Lilly last week announced it won’t resume a trial in hospitalised patients, after National Institutes of Health researchers concluded it wouldn’t help.

    Regeneron said an Independent Data Monitoring Committee (IDMC) from the REGN-COV2 trial said that based on an unspecified safety signal and an “unfavourable risk benefit profile” the committee recommends a modification to the trial protocol.

    The IDMC recommends further enrolment of patients requiring high-flow oxygen or mechanical ventilation be placed on hold pending collection and analysis of further data from those already on the trial.

    Regeneron remains blinded to the data and is implementing the recommendations.

    The company has also informed the FDA, which is reviewing REGN-COV2 data for a potential Emergency Use Authorization in patients with mild-to-moderate outpatients at high risk for poor outcomes.

    The data is also being shared with the independent committee monitoring the RECOVERY trial in the UK, which is testing the drug cocktail in hospitalised patients.

    REGN-COV2 is split into four cohorts – patients on low-flow oxygen, patients not requiring oxygen, patients on high-flow oxygen and patients on mechanical ventilation.

    The spotlight has been on antibody therapies for COVID-19 after it emerged early last month that Trump was treated with the Regeneron combination.

    Regeneron’s therapy is based on two antibodies the company has developed to neutralise the virus.

    The rationale is that by having a double therapy, the chances of the virus developing resistance to both parts of the drug are reduced.

    AstraZeneca is to begin phase 3 trials of a long-acting antibody therapy combination in the US and other countries in the coming weeks, to prevent infection happening and as therapy for those already infected.

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    Oxford Covid vaccine works in all ages, trials suggest

    Vaccine being trialled by Oxford University and AstraZeneca offers hope for all age groups

    One of the world’s leading Covid-19 experimental vaccines produces an immune response in both older and young adults, raising hopes of a path out of the gloom and economic destruction wrought by the novel coronavirus.

    The vaccine, developed by the University of Oxford, also triggers lower adverse responses among elderly people, said the British drug maker AstraZeneca, which is helping to manufacture the vaccine, on Monday.

    Related: Covid vaccine tracker: when will a coronavirus vaccine be ready?

    Related: At 75, I’ve volunteered for a Covid vaccine trial. It could set people free

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    Are we near to having a vaccine for Covid-19?

    Even a once bullish PM is now not so optimistic but there are promising signs of a vaccine on the horizon

    In March, Boris Johnson said we would turn the tide in 12 weeks and “send the coronavirus packing” and by May ministers were boasting of having a vaccine by September. Last week the prime minister sounded far less confident, telling MPs that there was still no vaccine for SARS, 18 years after it emerged. A vaccine may not be far away though.

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    Gilead’s COVID-19 drug Veklury falls short in WHO’s global trial

    Gilead’s Veklury (remdesivir) has failed to produce an effect on hospital stay and mortality in COVID-19 patients in a large global trial, casting doubt on previous supportive study findings.

    The results from the World Health Organization’s large Solidarity trial are yet to be peer reviewed but were posted online on a preprint server.

    Interim findings from Solidarity, which involved more than 11,000 patients in more than 30 countries, contradict those from the manufacturer in a US study.

    Solidarity is testing the effects of four potential drug regimens including remdesivir, hydroxychloroquine, the anti-HIV combination lopinavir and ritonavir, and interferon.

    According to the study the regimens have little or no effect on length of hospital stay or 28-day mortality, the WHO said.

    All other three options have already been shown to be ineffective, but the data from remdesivir is a surprise given the previous trial results used to support its Emergency Use Authorization from the FDA.

    Earlier this month data from the US-based ACTT-1 trial study showed Veklury resulted in five days’ faster recovery in patients hospitalised with COVID-19.

    There was a non-statistically significant trend towards a reduction in mortality, with the effect being more pronounced in patients who were on low-flow oxygen at baseline.

    A spokesperson for Gilead told Reuters: “The emerging (WHO) data appears inconsistent, with more robust evidence from multiple randomised, controlled studies published in peer-reviewed journals validating the clinical benefit of remdesivir.

    “We are concerned the data from this open-label global trial has not undergone the rigorous review required to allow for constructive scientific discussion, particularly given the limitations of the trial design.”

    The WHO said that Solidarity provides a platform that could be used to quickly test emerging treatments.

    WHO chief scientist Soumya Swaminathan said that the trial model could be used to test new therapies including monoclonal antibodies and newer antiviral drugs.

    In a separate development, Spain’s Pharmamar said it is planning a phase 3 pivotal trial of its Aplidin (plitidepsin) in COVID-19, after an early stage study showed the drug seems to be safe and reduces viral load in infected patients.

    Pharmamar specialises in developing medicines that take their inspiration from compounds found in the sea and had been focused on oncology until the pandemic began.

     

     

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    Regeneron’s antibody cocktail approved by FDA for Ebola

    An antibody cocktail from Regeneron has been approved by the FDA as the first treatment for Ebola, offering hope that a similar approach could be used to combat COVID-19.

    The FDA approved Inmazeb (atoltivimab, maftivimab and odesivimab-ebgn) for treatment of infection caused by Zaire ebolavirus in adults and children including newborns of mothers who test positive for the infection.

    Approval was based on a large clinical trial where Inmazeb showed superiority compared with other investigational agents with respect to mortality, with treatment most effective when given early in the disease.

    The therapy is based on a triple cocktail of monoclonal antibodies. Regeneron is using the same technology to develop the COVID-19 antibody combination famously given to president Donald Trump.

    Regeneron has an agreement with the Biomedical Advanced Research and Development Authority (BARDA), a US government agency, to deliver an undisclosed number of doses of the drug over the course of six years after approval.

    The New York- based company expects to receive around $10 million in 2021 under the deal signed earlier this year, and an average of $67 million per year for the next five years.

    The drug has also been developed with funding from BARDA

    In 2019, Regeneron’s randomised controlled PALM clinical trial was stopped prematurely when preliminary results showed that REGN-EB3 crossed the pre-specified superiority threshold for preventing death compared to the control arm.

    Those in the control arm were treated with Mapp’s ZMapp, a rival cocktail of monoclonal antibodies.

    Regeneron noted that its cocktail, codenamed REGN-EB3, outperformed ZMapp across several measures in the trial, including reduced mortality and fewer days until the Ebola virus was no longer detected in the bloodstream.

    The trial involved nearly 700 patients and had three serious adverse events for REGN-EB3 compared with seven for ZMapp.

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    Coronavirus re-infection case confirmed in the US

    There is growing evidence that the coronavirus may be able to re-infect patients, and a new instance of a second infection has been confirmed in the US. 

    It is the fifth confirmed reinfection worldwide after at least four other cases were confirmed in Belgium, the Netherlands, Hong Kong and Ecuador.

    The latest case was recorded in the Lancet Infectious Diseases journal and involved a 25 year-old man with no known immune disorders or underlying conditions.

    Although the authors said further research was needed, they said the findings suggested previous exposure may not confer immunity and that people should comply with control measures.

    The second infection of the patients from Washoe County, Nevada, was more severe than the first and resulted in hospitalisation and oxygen support.

    The man tested positive for the virus in April this year and later tested negative on two separate occasions.

    Genetic sequencing of the virus showed the man was infected twice by different strains of the SARS-CoV-2 virus.

    Authors suggested that more research was needed to find out low immunity could last, suggesting that the man may have developed more serious symptoms the second time round after receiving a higher dose.

    The second strain encountered may have been more virulent than the first, researchers suggested.

    Hearing loss

    Other new discoveries about the novel virus include a link with permanent hearing loss, which occurred in a 45 year-old man who contracted the disease in the UK.

    It’s the first such case to emerge with the coronavirus, although sudden hearing loss can follow other viral infections including flu.

    The BMJ Case Reports journal said that steroid drugs could help avoid hearing damage if they were given early enough.

    The patient had asthma and was admitted to a London hospital with COVID-19 symptoms and was transferred to intensive care after struggling to breathe.

    After being put on a ventilator and treatment with several drugs the man began to recover after around 30 days.

    But a week after the breathing tube the patient experienced tinnitus followed by sudden hearing loss in his left ear, with tests suggesting the loss was linked to damage to the auditory nerve rather than blockage in the ear canal.

    While steroid treatment has mitigated the damage, the man was left with some irreversible hearing loss.

    Feature image courtesy of Rocky Mountain Laboratories/NIH

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    NHS coronavirus tests threatened by Roche supply chain glitch

    Pharmaceutical firm reports ‘significant drop in processing capacity’ of reagents, kits and swabs

    Concerns have been raised over the supply of vital testing materials for a range of conditions, including Covid-19, following a supply chain problem with the pharmaceutical company Roche.

    On Tuesday, Roche said it had experienced a “very significant drop” in its processing capacity due to a problem with its Sussex distribution centre, the only one in the UK. It has been reported that the shortage includes vital reagents, screening kits and swabs.

    Related: UK government ‘thwarting independent labs’ efforts to step up Covid-19 testing’

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    Trump’s steroid Covid treatment adds to confusion over health

    Dexamethasone ‘normally reserved for people going into respiratory failure’, says expert

    The latest intervention from Donald Trump’s medical team has been to put the president on dexamethasone, a steroid that is proven, thanks to the UK’s Recovery trial, to benefit Covid-19 patients who are having breathing difficulties.

    But the decision to administer the steroid now has only added to the confusion surrounding the president’s state of health. Normally, dexamethasone is reserved for patients who have been ill for at least a week and whose oxygen levels are low.

    Related: Trump doctors say he had two oxygen dips but is ‘improving’ and may return to White House tomorrow – live

    Related: Trump and Covid: what we now know about the week he caught the virus

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    Anti-Covid treatments being given to Trump are still unproven, say experts

    Neither remdesivir nor REGN-COV2 have completed large-scale randomised trials, say UK scientists

    Scientists still lack conclusive proof that the two anti-Covid drugs given to Donald Trump are clinically effective.

    UK researchers point out that both medicines – remdesivir and REGN-COV2 – have still to complete the large-scale, randomised trials needed to demonstrate fully their ability to counter Covid-19 in patients. And many have criticised US authorities for their failures to carry out such trials. This has undermined efforts to find effective medicines to treat people affected by the disease.

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    UK doing more than most to help poor get Covid vaccine, study finds

    Campaign scoring countries for global access efforts calls for more British transparency

    The UK is doing more than most countries to support access to Covid vaccines for the poorest populations in the world, but it is not transparent enough about the deals it is doing at home, according to an international aid organisation launching a tracker.

    The One campaign has given countries and pharmaceutical companies scores for the efforts they have made to ensure the poorest get vaccines. In the vaccine access test no country or company scores green, the top rating, classed as aiding global access to vaccines.

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    Interferon and the Coronavirus

    Here’s a potentially important paper that’s out in Science and is getting a lot of attention. The wide variation in severity of coronavirus infection has been noted throughout the pandemic, and we already know about a few of the risk factors: age, of course, but also being male, and having pre-existing conditions such as obesity and heart disease (which are, of course, often found in the same patients).

    This new work, with a huge team behind it from more than 70 institutions, suggests another one: auto-antibodies to endogenous interferons. Everyone will have heard of interferon in a general sense, but getting a real understanding of that system is another thing entirely, which we can stipulate is true about immunology in general. There are three broad classes of interferon in humans (Types I, II, and III) and a bewildering network of functions and crosstalk between them. Suffice it to say for now that they are proteins whose synthesis is generally induced by some sort of viral or bacterial infection, and they go on to modulate a wide range of immune functions and affect the transcriptional activity of hundreds of different genes downstream. They’re of great interest not only in infectious disease, but in cancer and autoimmune disease as well, and we’re still working out all the pathways involved.

    It’s been known for many years that some people have inborn mutations in one or another of these interferons, with bad consequences for their response to infectious pathogens. How the human genetic background changes the course of infection and inflammation is a vast and complicated field, but here’s a recent review from experts Jean-Laurent Casanova of Rockefellar and Laurent Abel from Paris (who are part of the current paper as well). Past such inborn protein errors, that are also people who have developed an inappropriate immune response to their own interferon proteins – they have autoantibodies circulating in their blood that neutralize certain interferons when they’re produced. For reasons that are still being worked out, at some point the immune systems of such patients have been activated against these interferon types as if they were foreign proteins, and unfortunately we don’t have many techniques for resetting that sort of thing. Disease of immune tolerance such as lupus and APS-1 generally show this as one of the underlying factors.

    Interferon signaling has also been found to be important in the human response to coronavirus infection, of course, both in the direct antiviral aspect and in the overactive-immune-response part later on as well. Several different trials are underway looking at various interferon types as therapeutic options, but these are complicated by the need for good timing during the course of the infection. The complexity of the field means that the clinic is really the only place that one can sort this out: hypotheses are thick on the ground in an area like this one, but you have to go run a controlled trial to shed any light at all.

    In this latest work, the authors look for the intersection of these stories: pre-existing autoantibodies in coronavirus patients that neutralize one or more types of interferon. The results are striking: in 1,227 healthy controls, four patients were found to have such antibodies. In 663 patients with mild coronavirus infections, none were found at all. But in 987 severely ill patients, at least 101 of them had such antibodies against at least one of the Type I interferons (!) I hope that those four people identified in the first cohort are taking precautions, was my first thought, because it certainly looks like they in a newly identified risk group. Those numbers come out to p-values of less than ten to the minus sixteenth, which means that we all pretty much have to stand up take take off our hats – this one’s real. The anti-interferon antibody patients also skewed older, which suggests that the levels go up over the years (exactly what you don’t want, honestly).

    37% of the 101 patients in this group ended up dying of the disease, which is also an extreme statistical red flag. In cellular assays, it’s been shown that interferons such as IFN-alpha2 can block the coronavirus from infecting human cells. But plasma from these patients with neutralizing anti-interferon antibodies reversed that and left the cells open to infection. So the mechanism checks out as well.

    Interestingly, 95 of those auto-antibody patients were male, so this could also be one of the reasons why men add up to being a risk group of their own. You see many autoimmune disorders more commonly in women (which may be due to differences in the amounts of the transcription factor protein VGLL3), which is more expressed in women than men. This one breaks hard the other way. The connection here might be that VGLL3 promotes interferon responses, leading to a too-sensitive autoimmune situation, but autoimmunity to interferons themselves might be expected to run through a different mechanism entirely. (This last part is all my free bonus speculation; it’s not in the current paper).

    So while not all severe COVID-19 patients have antibodies against interferon, having them seems to make a person far more likely to end up with a severe infection. We’ll doubtless find more risk factors as more research comes in, but I doubt if any of them will be more firmly established than this one just was. As the paper notes at the end, these results have direct clinical implications. First off, anyone who screens with such antibodies needs to take extreme precautions, because they are clearly at far greater risk of severe disease and death than the run of the population. Second, this means that treating such patients with alpha-interferon will be a doomed effort, but beta-interferon (currently being studied intranasally) might still work, because antibodies to that one were rare. And one could also consider treatments aimed at knocking down the immune response to the Type I interferons themselves, starting with straight plasma exchange to bring down the antibody levels. And at the same time, such patients should not be part of any convalescent plasma donation program. Should they actually recover, that is. . .

    Pharmacies in England pause online flu jab bookings as demand soars

    Boots, LloydsPharmacy and Well Pharmacy report unprecedented take-up and many chemists run out of stock

    Pharmacies across England are struggling to keep up with the demand for the flu vaccine, pausing online bookings and limiting it to those most in need.

    The country’s three largest pharmacy chains – Boots, LloydsPharmacy and Well Pharmacy – have all reported unprecedented demand after a government vaccination campaign to reduce the pressure on the NHS during a second wave of Covid-19.

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    Australia’s drug regulator TGA approves Covid tests that deliver results in 15 minutes

    Healthcare workers and health departments will be among the first to use the rapid antigen tests

    Australia’s drugs regulator has approved four rapid antigen Covid-19 tests for distribution throughout the country with health workers and departments among the first to use the tests than can deliver results in 15 minutes.

    The Australian pathology and pharmaceutical companies approved to import and distribute the tests are required to provide the Therapeutic Goods Administration with data about the efficacy of the tests over time. Supply of the tests will be limited to accredited laboratories, medical practitioners, healthcare professionals in residential or aged care facilities, and to government health departments.

    Related: NSW lifts more Covid restrictions as border reopens with South Australia

    Related: Covid map Australia: tracking new cases, coronavirus stats and live data by state

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    Monoclonal Antibody Data

    We have a bit of human clinical data from the Eli Lilly/Abcellera collaboration to make a monoclonal antibody therapy against the coronavirus. A full paper is coming soon, the press release says, but for now it looks like this is all we have to go on.

    It’s a mixed assortment of news. On the cheerful side, in mild-to-moderate recently diagnosed patients, a dose of 2800mg of antibody did lower viral loads, and there were no adverse events. The prespecified mark was Day 11, but it appears that pretty much everyone in the trial, including those getting placebo, had very low viral titers by that point. Further analysis showed that the antibody treatment also lowered it at Day 3 (by an unspecified amount) and lowered the number of patients with persistently high virus at later time points (although we don’t know how many people were in that category). The other good news is that another prespecified endpoint (number of patients who went on to hospitalization) seems to have been significantly lower in the treatment group (1.7% of them as opposed to 6% in the placebo/standard of care group). The release notes that most of the hospitalizations were in patients with known risk factors, which suggests that that antibody might be best targeted towards these groups.

    But now the less good news. The trial looked at 3 doses: 700mg, 2800mg, and 7000mg, and there was no dose-response: only the middle dose worked. That’s worrisome; I’m having a hard time figuring why the higher dose would not have shown effects (and I’ll bet that Lilly is, too). This was not a tiny trial, but it wasn’t huge either (about 300 in the treatment group and 150 in the control), and there’s a nagging worry that the effect size just wasn’t large enough to see a solid answer in a group this size. I would have to think that Lilly expected better, and that’s why the trial was designed with this number of patients. And when I say “solid answer”, that cuts both ways – if that’s the statistical problem here, then a larger trial might show the 7000mg dose having some benefit, but it might also show that the 2800mg dose didn’t. These are the thoughts that a lack of dose response provokes.

    Lilly and Abcellera are still in the clinic, with this antibody and another candidate that binds at a different epitope on the coronavirus Spike protein. They’re testing the combination in a larger group of higher-risk patients, and I very much hope that the data that come out of that trial are more solid than these numbers, which are honestly weaker than I expected. The combination is similar to what Regeneron is in the clinic with now. It’s worth noting that the press release mentions that coronavirus mutations that would lead to resistance against this single antibody were seen in about 6% of the controls and 8% of the treated patients, which is reason enough to think that the combination could be a better idea.

    The other issue that these numbers raise is the dosage. For the hypothetical 70kg patient, a 2800mg dose is 40 mg/kg, which is about what had been ballparked for a therapeutic mAb in infectious disease. And of course that was a lower dose in the high-BMI risk group patients, who seemed as if they might have responded better to the therapy. But any way you look at it, that’s a lot of monoclonal antibody to produce and to dose. The companies involved know this, of course, and have been anticipating it, but that makes it all the more important to find out what patient groups will benefit the most from the treatment. This is not going to be something that’s rolled out to hundreds of millions of people.

    Matthew Herper has a good story on this release in Stat, and he has a statement from Lilly that they’re considering asking for an Emergency Use Authorization. I think that’s a bad idea. For one, these data (although promising in some ways) are not so promising in others, particularly that lack of dose-response, the fuzziness of the readout on overall efficacy, and in the possibility of resistant mutations with the single-antibody therapy. This one needs to go back into the oven, I’d say. An EUA might well make things worse for the mAb-versus-coronavirus field overall, because it could well disrupt the trials that are already underway. We’ve had a fiasco in the convalescent plasma field already; we don’t need one for the targeted antibodies as well.

    Beware of big pharma in rush for Covid-19 vaccine | Letter

    Heidi Chow on why the pharmaceutical industry must not be left in the driving seat to supply an effective Covid-19 vaccine

    The biggest gamble that governments are taking is not on specific vaccine candidates, but on the pharmaceutical industry itself (The Covid-19 vaccine gamble: where bets have been placed and why, 11 September). The pharmaceutical industry has long been criticised for defending intellectual property rights and profiteering. For decades, countless patients the world over have been denied access to life-saving treatments and vaccines because of high prices propped up by patent monopolies.

    Once an effective vaccine is discovered, we will need open sharing of the technological process so that as many suppliers as possible can make it, to ensure an adequate supply across the world. This is not a time for monopolies. While governments leave big pharma in the driving seat, there will be vaccine scarcity and the global race to hoard vaccines will deplete global stocks, leaving very little – if any – for the WHO to supply to poorer countries. This is not just morally wrong, it is also counterproductive, because we will only be safe if everyone is safe.
    Heidi Chow
    Global Justice Now

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    Show more empathy to boost confidence in vaccines, scientists told

    Expert behind vaccine confidence report points to halting of Oxford Covid trial as example

    Doctors and scientists need to show more empathy towards volunteers in coronavirus vaccine trials who fall ill if the public is to have full confidence in the safety of the vaccines being developed, say experts.

    The temporary halting of the Oxford University/AstraZeneca trial after one volunteer in the UK was admitted to hospital was good news, not bad, said Heidi Larson, who leads the Vaccine Confidence Project at the London School of Hygiene and Tropical Medicine, as it showed that scientists and the company were putting safety first.

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    Oxford Covid-19 vaccine is still possible this year, says AstraZeneca chief

    Pharmaceutical firm’s boss says 2020 deadline possible if regulators move fast

    AstraZeneca’s coronavirus vaccine could still be available by the end of the year, or early next year, according to the company’s chief executive, Pascal Soriot, despite clinical trials being paused after a volunteer fell ill.

    AstraZeneca and Oxford University, which are jointly developing the vaccine and testing it on 50,000 to 60,000 people around the world, halted trials on Wednesday to investigate the “potentially unexpected illness” of one participant.

    Related: Covid vaccine tracker: when will a coronavirus vaccine be ready?

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    Oxford Covid vaccine trial suspension: what happens next?

    Tests have been paused after a UK volunteer became ill. How will it affect the search for a cure?

    One of the volunteers in the UK has become ill and it is crucial that the researchers find out whether this could be related to the vaccine. This is not uncommon in vaccine trials – and in fact it is said to be the second time it has happened with this vaccine . Very large trials are essential to pick up any rare side-effects. Something that affects one in 10,000 people, for instance, will probably not be detected in the early trials of just a few thousand.

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    The Oxford University AstraZeneca Covid-19 vaccine trial has been paused – should we be worried?

    Is this the end for hopes of an early breakthrough in the race to find a coronavirus drug?

    The halt in development of the University of Oxford’s Covid-19 vaccine due to a possible adverse reaction in a trial participant has triggered fears of a delay in finding a solution to coronavirus restrictions.

    A spokesman for AstraZeneca, the company working with the academic team to produce the vaccine, said the voluntary pause is “routine”.

    Related: Oxford University Covid vaccine trial put on hold due to adverse reaction in participant

    Related: Why are Australian church leaders opposing the Oxford coronavirus vaccine?

    Related: Covid-19: ‘possible’ Oxford vaccine data will be put before regulators this year

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    Oxford University Covid vaccine trial put on hold due to possible adverse reaction in participant

    A spokesman for AstraZeneca, the company working on the coronavirus vaccine, said pausing trials was common during vaccine development

    The development of a promising Covid-19 vaccine has been put on hold due to a possible adverse reaction in a trial participant.

    A spokesman for AstraZeneca, the company working with a team from Oxford University, told the Guardian the trial has been stopped to review the “potentially unexplained illness” in one of the participants.

    Related: Covid vaccine tracker: when will a coronavirus vaccine be ready?

    Related: Let’s get real. No vaccine will work as if by magic, returning us to ‘normal’ | Jeremy Farrar

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    Preparing For the Vaccine Results

    So let’s take a few minutes to think about what happens when the vaccine trials start to read out. I’m making the assumption that the data will be freely available in a timely manner (which means before any decisions are made), because the alternative to that is Not Real Good. Another not-real-good alternative would be to declare the first one to read out the instant winner, because (as noted by Anthony Fauci) that would certainly screw up the trials of the others. But if we avoid these mistakes (no guarantees are expressed or implied), there are still a number of fairly likely things that I don’t believe the general public is quite ready for.

    One of those: what if the first vaccine results aren’t very impressive? This could happen. I’m really hoping it doesn’t, but anyone in the business will tell you that you don’t know what efficacy is really going to be like until you run an efficacy trial, and that goes for vaccines as much as for anything else. I will say that the available biomarkers (antibodies and T cells) are much stronger in vaccine work than they are in many other areas, but on the other hand, it’s immunology. Which is full of fun and interesting surprises. So if the first trial to really give a solid efficacy read comes in lower/weaker than we’d all like to see, my guess is that the press and the public won’t take it too well. There will be a rush to “OMG We Can’t Make A Vaccine To Corona” takes, I think, which will sow some despair and panic. I would expect the stock market not to take the news well, either.

    But even if the first results aren’t great, it doesn’t mean that we’re (necessarily) hosed. That’s the good thing about having several different vaccines going, with different platform technologies. We are really going to have to wait and see what the various approaches are going to produce, even though “wait and see” is not exactly the zeitgeist right now. We have the different adenoviruses (and other vectors, which will come later), the inactivated-virus vaccines, the mRNA candidates, the recombinant proteins – there’s no reason to think that these are all going to come out the same, and that’s going to be important to keep in mind.

    To that point, here’s another possibility that’s quite possible: the Patchwork Quilt of Efficacy. What if we get a mixture of results, with Vaccine A being pretty good, but not in older patients, while Vaccine B seems better in that cohort but is harder to roll out for distribution, while Vaccine C showed more even results over various patient cohorts but is beaten by some other candidate in most any particular one, while Vaccine D was strong but definitely had more adverse events. . .you see what I mean. I can easily imagine something like this happening, and the thing is, it’s not just going to drop all at once. We’re going to get those various results one after the other and will have to fit them into an unavoidably messy picture, adjusting our plans as more data points become available. Overall, I think it could be a serious mistake to declare a winning vaccine too early (unless something comes in just kicking coronavirus ass all over the field, which would frankly be fine), but telling everyone to wait while we see what the next ones bring is probably not going to go over well. There will be tremendous pressure to just start dosing people with anything that looks reasonable, and you can’t blame anyone for it.

    Regarding those adverse events, I’m no immunologist, but the one that I’m worried most about is probably Guillain-Barre syndrome. Pronounce that one something like gee-YAH bur-RAY for maximum effect, but I’ve heard plenty of other more Anglicized pronunciations in the wild. No matter how you say it, GBS is an autoimmune response that leads to an attack on the myelin sheaths of the nervous system – bad news, obviously, but the good part is that most cases resolve. Not all of them do, though, and even many of the resolved ones involve spending time in a hospital in pretty serious condition. GBS happens spontaneously after some respiratory infections, for immunological reasons that are still being worked out, and is most commonly seen in younger women. It can come on after vaccination, in the same way as it can come on after infection, and it’s widely recognized as one of the big problems with the 1976 swine flu vaccine rollout, and is certainly something that vaccine developers in general keep an eye out for. We do not want to have to wrestle with this problem, but it’s a rare enough event that only the large Phase II/Phase III trials will have a chance of giving us a read on it at all. For context, the 1976 vaccine is believed to have caused one extra case of GBS per 100,000 people vaccinated – it’s the sort of thing you might well not pick up on at all until you’re going out into the broader population. “Teenager Rushed to Hospital After Coronavirus Shot” is not a headline that will do anyone any good.

    That wider population is always the worry, immunologically. We all have different immune systems – that’s the point, otherwise one plague or another would have wiped us off the planet by now. The number of rare immune-linked disorders is large and various because of this, and that means that the response to any new vaccine could show some oddities as you start heading out into millions of people Tens or hundreds of millions – yeah, you would have to expect some rare and bad events to poke up, and if one of them happens with major media coverage, things could get ugly.

    Even if things go well, though – and I continue to think that for at least one of the vaccine candidates they will – there are some complications. All but one of the vaccines being tested now (J&J’s is the exception) will need a booster shot some weeks after the first one. And from the antibody titers we’ve seen in the Phase I trials, you wouldn’t necessarily expect that much protection with just one shot. People are going to have to realize this: the first shot will not mean that you’re in the clear, as ready to shed your mask and hit the streets as you might be. For that matter, it’s still going to take some time after the second shot to reach protective levels, so it seems, so it’s not like even the booster will mean that you can make hit the karaoke bar that evening. We will need to be ready for “I Got the Vaccine And I Got Coronavirus Anyway” reports that will turn out to be due to one of these situations. The logistics of getting everyone through a two-shot immunization course will be nontrivial, in any event.

    OK, I don’t want this post to be too depressing – we need to keep our eye on the likelihood that we’re going to see an effective vaccine in the coming months. That’s going to be great, but nothing says that launching it into the world has to happen smoothly. One last point: when we launch that vaccine (or those vaccines), we are not only going to have to be transparent about why the choice was made the way it was: we’re also going to have to be transparent about who gets it first and why. Frontline medical workers, surely, and others in similar positions. People who do economically vital jobs (supply chains, etc.) whose work unavoidably puts them at higher risk. You can come up with more categories easily, but one category that I hope we avoid is People Who Know Some People. If there’s a perception that the well-connected are cutting the line, that’s not going to go over well, either, and it shouldn’t. I would recommend being completely open about the order of vaccination and trying to stick to it, visibly. Ideally, this should be publicized before we even start getting vaccine readouts, but we’ll see. . .

    AstraZeneca starts Covid-19 antibody drug trial in UK

    Volunteers are receiving doses of drug, which has potential both as a vaccine and a treatment

    The pharmaceutical group AstraZeneca has started a clinical trial of a drug to help prevent and treat Covid-19, with the first volunteers already receiving doses.

    The company, which is separately developing a potential Covid-19 vaccine together with scientists at Oxford University, said the drug, known as AZD7442, is a combination of two monoclonal antibodies.

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    Six of the most promising treatments for Covid-19 so far

    While a cure-all drug or therapy is a long way off, there have been some breakthroughs

    Many different drugs and therapies are being trialled and used on patients with Covid-19. There are some positive results, which may be beginning to bring the hospital death toll down, but there is still a long way to go towards something that will cure all comers. These are some of the most promising.

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    Oxford University Covid-19 vaccine firm denies Trump talks

    AstraZeneca says it has not discussed ‘emergency use authorisation’ with the US

    The company manufacturing the Oxford University coronavirus vaccine has denied it is in talks with the Trump administration about fast-tracking its vaccine for emergency use ahead of November’s presidential elections.

    With both Russia and China pressing ahead with inoculations involving experimental vaccines yet to pass final efficacy and safety trials, the Trump administration has become increasingly frustrated with the Food and Drug Administration (FDA), which the president has tried to suggest is slowing approval of a vaccine for “political reasons”.

    Related: Covid vaccine tracker: when will we have a coronavirus vaccine?

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    Coronavirus pharma news round-up 21/08/20

    New insights into smell and taste loss symptoms, artificial intelligence and further encouraging data from a vaccine candidate hit the headlines this week as the COVID-19 coronavirus pandemic continues.

    Here we highlight the biggest R&D, market access and digital coronavirus news of the past week.

    • Pfizer and BioNTech have said their COVID-19 vaccine could be ready for regulators to review by October and approved by the end of the year after releasing more favourable data from an early-stage trial. There are no vaccines approved for COVID-19 and governments across the world are striking deals with various manufacturers to get early access once regulators give them the rubber stamp.
    • Could AI prevent future pandemics by developing an armoury of drugs that work against all coronaviruses? This is a question that a consortium of European pharma companies hopes to answer as it aims to rapidly develop new therapies to combat the pandemic.
    • Roche has agreed to help Regeneron manufacture its COVID-19 antibody cocktail REGN-COV2, which started late-stage clinical testing a few weeks ago, in a deal that could more than triple supplies of the drug if it gets approved.
    • Smell and taste loss associated with COVID-19 differs from that experienced by patients with common colds or flu, according to researchers who said the symptom could be used to quickly identify coronavirus infections in settings such as airports or emergency departments.
    • Health Secretary Matt Hancock is planning to dissolve Public Health England and replace it with a new agency dedicated to responding to pandemics, according to reports. The plan is to implement a new body modelled on the independent Robert Koch Institute in Germany, which has been held up as having done well in weathering COVID-19, in part at least because of a well-organised and large-scale testing programme early on.
    • Shares in Netherlands biotech Kiadis rose sharply on the news that it would start developing a natural killer (NK) cell therapy for COVID-19, but later lost most of the gains on what looks like profit-taking.
    • The European Commission has placed its first advance order for a coronavirus vaccine, snapping up 300 million doses of AstraZeneca’s ChAdOx1 candidate developed by the University of Oxford, with an option on another 100 million.

     

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    Pfizer/BioNTech say COVID-19 jab on track for approval by year-end

    Pfizer and BioNTech have said their COVID-19 vaccine could be ready for regulators to review by October and approved by the end of the year after releasing more favourable data from an early-stage trial.

    There are no vaccines approved for COVID-19 and governments across the world are striking deals with various manufacturers to get early access once regulators give them the rubber stamp.

    The latest data from a phase 1 study in the US showed that seven days after a second dose at 30 micrograms, the vaccine produced 3.8 times more neutralising antibodies than in younger patients aged 18-55 recovering from SARS-CoV-2 infection.

    In older adults aged 65-85 treated with the vaccine candidate codenamed BNT162b2 there were 1.6 times more neutralising antibodies than in recovering patients.

    Across all populations, BNT162b2 was well tolerated with mild to moderate fever in fewer than 20% of the participants, the companies said.

    The data builds on results announced last month, which also showed the antibody response and suggested that the vaccine produces a T-cell response against the virus.

    Those results helped the companies choose BNT162b2 from a group of similar candidates for an ongoing phase 2/3 global study in up to 30,000 participants.

    This began in July and has so far enrolled more than 11,000 participants, including in areas with significant SARS-CoV-2 transmission.

    Assuming the trial is a success, Pfizer and Germany’s BioNTech said they are on track to ask for a regulatory review as early as October, paving the way to supply up to 100 million doses by year end if the vaccine is authorised.

    Pfizer and BioNTech are running a parallel trial in Germany and plan to announce further results from that in the “near future”.

    There could be up to 1.3 billion doses manufactured by the end of next year, the companies said.

    The vaccine is one of 30 potential vaccines identified by the World Health Organization as being in clinical development, with AstraZeneca and Oxford University top of the list.

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    Here’s everything you need to know about the potential Oxford University Covid vaccine

    The vaccine is designed to mimic the coronavirus and train the immune system to react if a person is later infected

    The vaccine developed and tested by a team at Oxford University is one of the most promising of the many candidates being developed around the world to protect against Covid-19. Australia has now signed a letter of intent with pharmaceutical company AstraZeneca to supply Australians with the vaccine if it clears safety and effectiveness trials, with the prime minister now saying it won’t be compulsory but will be encouraged.

    Here’s what you need to know about the vaccine.

    Related: Covid vaccine tracker: when will we have a coronavirus vaccine?

    Related: Global report: WHO warns against dangers of ‘vaccine nationalism’

    A Phase II/III trial aims to enrol up to 10,560 adults and children across the UK.

    A Phase III trial in the US is looking for 30,000 participants.

    Brazil started a Phase III trial of the vaccine in June, which will enrol 5,000 volunteers.

    A team in South Africa is looking to enrol 2,000 people to trial the vaccine.

    Related: Will a vaccine or recovery from the virus give us long-term immunity to Covid-19?

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    Smell and taste loss could help identify COVID-19 at airports, say researchers

    Smell and taste loss associated with COVID-19 differs from that experienced by patients with common colds or flu, according to researchers who said the symptom could be used to quickly identify coronavirus infections in settings such as airports or emergency departments.

    The study published in the journal Rhinology, was published as London’s Heathrow Airport unveiled plans for a testing facility to replace quarantine measures.

    Authors say it is the first to compare how smell and taste disorders in people with COVID-19 differ from those with other upper respiratory tract infections.

    According to the research the main differences are that although COVID-19 patients also lose their sense of smell, they can breathe freely, do not tend to have a runny or blocked nose, and they cannot detect bitter or sweet tastes.

    Authors added that findings lend weight to the theory that COVID-19 infects the brain and central nervous system.

    The research team hope that their work could help develop smell and taste tests for fast COVID-19 screening – in places such as airports, primary care and emergency departments.

    The research team from the University of East Anglia’s Norwich Medical School carried out smell and taste tests on 10 COVID-19 patients, 10 people with bad colds and a control group of 10 healthy people – all matched for age and sex.

    Lead researcher professor Carl Philpott said: “We found that smell loss was much more profound in the COVID-19 patients. They were less able to identify smells, and they were not able to identify bitter or sweet tastes.

    “In fact it was this loss of true taste which seemed to be present in the COVID-19 patients compared to those with a cold.

    “Although such tests could not replace formal diagnostic tools such as throat swabs, they could provide an alternative when conventional tests are not available or when rapid screening is needed – particularly at the level of primary care, in emergency departments or at airports.”

    Philpott noted that the sweet and bitter taste receptors affected by COVID-19 are known to play an important role in innate immunity.

    “More research is needed to see whether genetic variation in people’s bitter and sweet taste receptors might predispose them to COVID-19, or conversely, whether COVID-19 infection changes how these receptors function, either directly or through a cytokine storm – the over-reaction of the body’s immune system,” Philpott added.

    This research was led by the Cliniques Universitaires Saint-Luc (Belgium), Université catholique de Louvain (Belgium) in collaboration with researchers at University of East Anglia/The Norfolk Smell and Taste Clinic at the James Paget University Hospital (UK), Aristotle University (Greece), Acibadem Taksim Hospital in Istanbul (Turkey), Biruni University (Turkey) and University Hospital of Foggia (Italy).

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    Encouraging News About Coronavirus Immunity

    We’ve had some good news on coronavirus immunity recently – good because it gives us some more clarity on the whole situation, and because it suggests that both people who have already recovered from the infection and people who will be getting vaccinated can have good protection.

    We have this preprint from several of the Boston/Cambridge area institutions, comparing antibody levels in 259 infected patients (out to 75 days post-symptoms) with 1548 pre-pandemic samples. They’re looking specifically at IgM, IgG, and IgA comparisons. IgM is the first antibody type to appear in response to an infection – they’re the ones I mentioned in this post as being five of the Y-shaped units put together. IgG are the ones that most people are talking about when they talk about antibodies in the blood, and IgA are secreted mucosal antibodies, found in the saliva and nasal/lung tissues. That mucosal immunity is surely an important factor in a disease that appears to be spread largely by inhaled airborne droplets.

    They estimate that it takes about 11 days to “seroconvert” after infection, that is, to show evidence that your immune system has raised these new antibodies to the coronavirus. Looking at hospitalized individuals versus milder cases, the former actually seroconverted a couple of days earlier, and their IgM response tended to drop off a bit more quickly. One limitation of this paper is that the coronavirus patient cohort was skewed towards the hospitalized patients, rather than mild infections. But overall they found that IgG antibodies were still detectable in serum 75 days out (the last time point measured) and were a very useful marker for infection, although IgM and IgA had mostly gone back down by then. The paper concludes that although we don’t yet know the optimum levels of antibodies for protection (and we’re still collecting later time points!), “the association between RBD-IgG with neutralizing titers and the persistence of these antibodies at late time points is encouraging“.

    Here’s a report on the same topic from a multicenter team in Canada that’s comparing antibody level both in the blood and in saliva.  In contrast to the report just mentioned, the authors here found IgA against the coronavirus persisting for at least three months after infection, and correlating well with IgG in the blood. Not every study has shown that sort of persistence, but the authors believe that this might be due to the techniques used for detection. They also found that several of their negative controls – samples banked from people pre-pandemic, who had definitely not been exposed to coronavirus – also showed IgA titers in saliva, presumably cross-reactive antibodies that were raised from some other infection. “It is tempting to speculate“, they write, “that these preexisting IgA antibodies may provide some stop-gap protection against SARS-CoV-2 in the oral cavity, and if so, it is essential to ascertain their original antigenic specificity.”

    Then there’s this preprint from a team in Arizona, which confirms these results by finding that antibodies against the RBD part of the coronavirus Spike protein persisted for at least three months. “In contrast to other reports“, they say, “we conclude that immunity is durable for at least several months after SARS-CoV-2 infection“. They also checked antibodies to the nucleocapsid protein (N) as well as to the spike and found that the N response was more variable. One possibility they raise is that there are cross-reactive antibodies to other coronavirus N proteins (which is a more conserved domain across the various types than the Spike), and that these were raised by previous infections with different viruses.

    Moving past antibodies, we have this paper on T-cell responses. The authors, a multinational team led out of the Karolinska Institute in Sweden, have put in a lot of work looking at the T-cell situation in unexposed individuals, people with acute coronavirus infections and those who have recovered, and family members of those patients as well. The acute phase subjects had just the sort of cellular profile you’d expect: highly activated and cytotoxic, out there killing virus-infected cells as T-cells were born to do. In the convalescent patients this had calmed down, as it’s supposed to, and they detected stem-memory-type cells, which is just what you’d want to see. Importantly, these were also found in people who had recovered from much milder infections and in the asymptomatic family members tested as well. (The paper provides a great deal of detail on the exact sorts of responses in the various T-cell types that I’m not going into, but it’s valuable information).

    They also detected potentially cross-reactive T cells in 28% of people who had donated blood before the pandemic even hit, which is consistent with several other reports. 41% of the overall patients who were seronegative in antibody tests were still positive for T-cells (CD4+ and CD8+ alike) against coronavirus proteins (Spike, nucleocapsid, and membrane). They conclude that the T-cell response is indeed non-redundant and apparently an important part of immunity to this virus, and that using seroprevalence (antibody levels) as a marker for exposure in a population will almost certainly underestimate the real situation. That’s good news, since it would mean that more people have already been exposed (and are to some good degree immune) than we would think. But that doesn’t mean that we can blow the all-clear whistle, either, as the various surges in infection around the world have shown: the situation may be better than feared, but we don’t seem to be anywhere near “herd immunity” levels yet. And we would be killing off an awful lot more people to get there without a vaccine.

    And finally, we have this report from the University of Washington, which is about as direct a measure of immune protection as we’re likely to get before the vaccine efficacy trials read out. The authors studied the crew of a fishing vessel, before and after its voyage. Three crew members showed a positive antibody response beforehand, indicating that they had been infected earlier in the epidemic – they were not positive in RT-PCR testing, though, indicating that they did not have active infections. In fact, none of the other 120 crew members tested (out of 122 total) had such a positive reading on departure.

    But an outbreak occurred on the ship anyway – someone was early enough in the infection that they hadn’t shown positive yet. This crewmember became sick and the vessel returned to port on Day 18 of the voyage. (Sequencing of viral samples from a number of crew members confirmed that the outbreak seemed to originate from a single source). Testing then and over the next few days showed that 104 of the 120 crew members were now positive for the coronavirus – but not the three who had antibodies beforehand. This high attack rate (!) and apparent protection makes a strong case for protective immunity, because God knows everyone on board had plenty of chances to catch the disease.

    How long this protection lasts, what part of it is due to antibody response and what part to T cells, and what the exact cutoffs are for those – these are the important things we don’t quite know yet. But the picture is becoming clearer. And what we’re seeing is that this virus, which it has definitely has some unusual features, is also something that our immune systems are dealing with in the just the way that you would hope to see. That gives us hope that the vaccines are in turn going to raise protective, lasting responses. We just have to see the details!

     

    Could AI avert a future coronavirus pandemic?

    Could AI prevent future pandemics by developing an armoury of drugs that work against all coronaviruses?

    This is a question that a consortium of European pharma companies hopes to answer as it aims to rapidly develop new therapies to combat the pandemic.

    The Corona Accelerated R&D in Europe (CARE) has been hastily set up by Europe’s Innovative Medicines Initiative (IMI), focusing on tackling the pandemic that has wreaked so much havoc across the world this year.

    The consortium aims to rapidly develop drugs to fight SARS-CoV-2 and find virus neutralising antibodies.

    But also included in the 77.7 million euro project funded by European Union cash and European pharma companies is a work stream that aims to find drugs that work against coronavirus strains that may emerge in the future.

    The UK-based artificial intelligence (AI) drug discovery firm Exscientia is heavily involved in this project and is using its technology to screen existing small molecules to see if they could be used against the coronavirus class that causes diseases such as SARS, MERS and COVID-19.

    Exscientia is finishing off work already done on the SARS-CoV-2 virus to identify the targets that could be used – but chief operating officer Dave Hallett told pharmaphorum in an interview that the likely lines of attack are already well known.

    The trick is to look for proteins that are used across all coronavirus types and tend not to vary much from one virus species to another.

    Hallett said that the targets being explored are the proteins involved in viral replication – the protease, the RNA polymerase, the papain-lie protease and elements of the “Spike” protein that allows the virus to infect cells.

    He said: “If you could find a small molecule now that had SARS, MERS, and COVID-19 activity there is a reasonable chance it could have activity against another beta-coronavirus in the future.”

    The work will involve using AI to screen a library of 12,500 molecules held by Scripps Research to identify small molecules that could be active against the virus class.

    All of the drugs in the library have previously been used in humans, which means their side effects are better known, hastening development.

    “If we can find any drugs that have gone into human beings if one of those has activity against COVID-19 proteins those would make it more rapidly through clinical trials.”

    CARE is a five-year project funded by the cash contributions from the EU, 11 European Federation of Pharmaceutical Industries and Associations (EFPIA) companies, and three IMI partners.

    Companies include Johnson & Johnson’s Janssen unit, Takeda and Boehringer Ingelheim.

    Hallett noted that the project is an example of how European countries and organisations can work together, something that he hopes will continue as the UK heads for Brexit.

    “It’s a reflection of what the IMI was set up to do. It’s shame we are leaving as it’s a good example of what Europe can do when it comes together.”

    “We can move forward quickly with this, fingers crossed.”

    Feature image courtesy of Rocky Mountain Laboratories/NIH

     

     

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    UK signs coronavirus vaccine deals with J&J and Novavax

    The UK is to buy millions more doses of potential coronavirus vaccines from Johnson & Johnson and Novavax, with the latter expanding its manufacturing operation in the country.

    Johnson & Johnson’s Janssen pharmaceuticals unit will supply an initial 30 million doses on a not-for-profit basis for emergency use in the pandemic, with an option for an additional 22 million doses.

    Novavax said separately that the UK is buying a further 60 million doses of its vaccine candidate, NVX-CoV2373 for a phase 3 clinical trial.

    Both the UK and the US have six COVID-19 vaccine deals between them as governments from across the world race to strike deals with drugmakers for vaccines.

    Reuters reported that J&J is also working with the UK government on a phase 3 trial testing a two-dose regimen of its vaccine candidate, running in parallel to a phase 3 trial of its single-dose vaccine.

    Novavax is based in the US but is collaborating with Fujifilm Diosynth Biotechnologies on a manufacturing operation in Stockton-on-Tees in the UK in addition to sites in North Carolina and Texas in the US.

    The UK site is expected to produce up to 180 million doses annually, which further boosts the global supply of NVX-CoV2373 for other markets.

    Novavax is planning a phase 3 trial in the coming weeks after encouraging results from an early study showing the vaccine produced higher levels of neutralising antibodies than in recovered patients.

    The phase 3 trial could provide enough data to support approval before the end of the year, the company has said.

    According to the World Health Organization there are now 29 potential vaccines in clinical trials, none of which have yet been proven to work.

    The most advanced is from the University of Oxford and AstraZeneca – and the UK has already ordered 100 million doses of this should it prove effective in ongoing phase 3 trials.

    The UK government has also ordered 90 million doses of two other COVID-19 vaccines from BioNTech/Pfizer and Valneva.

     

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    UK agrees deals for 90m doses of two potential coronavirus vaccines

    Government secures early access to those being developed by Novavax and Janssen

    The UK government has reached agreements it says will give British citizens early access to 90m doses of two more potential Covid-19 vaccines.

    The vaccines are being developed by the US biotech company Novavax and the pharmaceutical business Janssen, which is owned by Johnson & Johnson and has its headquarters in Belgium.

    Continue reading…

    Around 3.4m people infected with coronavirus in England – study

    Just under 6% of England’s population – around 3.4 million people – had been infected with coronavirus by the end of June according to an estimate based on antibody tests.

    More than 100,000 people tested themselves for antibodies against the SARS-CoV-2 virus that can lead to COVID-19.

    The results from the study by Imperial College, London, have yet to be peer reviewed but are available in a report published online.

    London had the highest numbers at over twice the national average (13%), while the South West had the lowest (3%).

    Key workers in care homes and health care were among those most likely to have already been infected with the coronavirus.

    Black, Asian and minority ethnic (BAME) individuals were between two and three times as likely to have had COVID-19 compared to white people, the study showed.

    The overall infection fatality ratio – the proportion of infected people who died – was calculated to be 0.9%, similar to other countries such as Spain.

    Antibodies were found in almost all (96%) of those who had a previous infection confirmed by a swab test.

    People who had severe symptoms from the disease were twice as likely to have antibodies than those with no symptoms when they were diagnosed with or suspected having COVID-19 (29% vs 14%).

    The highest numbers of positive results were in people who reported confirmed or suspected COVID-19 in March and April, and were shown across all regions of England.

    More than 16% of care home workers with client-facing roles and 12% of healthcare professionals that have direct patient contact had positive results. In non-key workers, the rate was around 5%.

    For Black, Asian and other ethnicity individuals, the rates of positive results were 17%, 12% and 12%, respectively, compared to 5% for white individuals.

    The gap was reduced after the researchers took into account factors such as age and key worker status, but rates were still higher overall for BAME individuals.

    Other factors not explored included transport use and behaviour, authors said.

    Young people aged 18-24 had the highest rates (8%) and were more than twice as likely to test positive than adults aged 65 to 74, who were least likely to have the virus (3%).

    Authors said that understanding trends and geographical variations could help guide local public health responses, identify groups at risk and inform actions to control the disease.

    The REACT study was commissioned by the Department of Health and Social Care and is being carried out in partnership with Imperial College London, Imperial College Healthcare NHS Trust and Ipsos MORI.

    The study will be repeated in the autumn, testing 200,000 people, and research on the accuracy of different tests is ongoing to ensure that the best available test is used as the programme continues.

    Feature image courtesy of Rocky Mountain Laboratories/NIH

     

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    Scepticism as Russia claims coronavirus vaccine breakthrough with Sputnik V

    Russia has become the first country in the world to approve a coronavirus vaccine, amid scepticism from international experts who have been unable to review or verify clinical data from the jab called ‘Sputnik V’.

    According to press reports the vaccine has been tested on one of President Vladimir Putin’s daughters.

    But World Health Organization leaders have said that they want to review the vaccine, called Sputnik V after Russia’s pioneering space probe, as the vaccine took just two and a half months to develop.

    Sputnik V is not among the WHO’s list of six vaccines that are in phase 3 development and despite the accelerated trial timelines it is unlikely that one will become widely available until next year.

    Russia plans to begin mass vaccinations against the coronavirus in October with the vaccine, which is based on adapted strains of the adenovirus that usually causes the common cold.

    According to several press reports the vaccine has been approved before completion of a phase 3 trial, which would give a strong indication of the efficacy and safety in a large cohort of patients.

    Putin has vouched for the safety of the vaccine, saying that it led to a one-degree temperature rise in his daughter to 38°C, which subsided after a day.

    In cancer, drugs can be approved conditionally on the basis of earlier data, but regulators for COVID-19 outside Russia are requiring data from larger trials for approval.

    They are looking for clear evidence that the vaccinations would provide immunity from the coronavirus.

    Russia’s vaccine is also veiled in secrecy: the Gamaleya Institute in Moscow has not yet released safety or immunity data from studies for independent scientists to review.

    According to the WHO, there are now 28 coronavirus vaccines in clinical development, with one from Oxford University and AstraZeneca top of the list.

    This is followed by several vaccines from China, and another from US biotech Moderna.

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    The Russian Vaccine

    Many will have heard Russia’s announcement that they have approved a coronavirus vaccine. I’ve already had several people ask me what I think of it, so let me be clear: I think it’s a ridiculous publicity stunt. If it’s supposed to make Russia look like some sort of biotechnology powerhouse, then as far as I’m concerned it does the opposite. It makes them look desperate, like the nation-state equivalent of a bunch of penny-stock promoters. The new airliner design prototype just got off the ground – time to sell tickets and load it full of passengers, right?

    Why so negative? Look at what’s being claimed – the first coronavirus vaccine to receive regulatory approval. But “regulatory approval” is not some international gold standard, and these sorts of decisions show you why. Let’s be honest: there is no way that you can responsibly “approve” a vaccine after it’s only been into human trials for what numerous reports say is less than two months. That’s about enough time to do the first steps, a Phase I trial that gives you some idea of immune response across more than one dose. It is simply not enough time to do a reasonable efficacy workup as well, and absolutely not enough time to get any sort of reading on safety. Here’s a good article going into those timelines in more depth.

    Look, we’re pushing safety and efficacy trials harder than they’ve ever been pushed already, and many people already are jumpy about the safety evaluations of the various vaccine candidates as it is. Declaring regulatory approval and taking a public victory lap in the world press before you’ve even done that safety work at all inspires pity rather than respect. The various news stories on this “approval” generally have quotes from outside experts saying that it’s important to see if Russia is following best practices and such, but that’s easy to answer. They aren’t. There are several other vaccines that could be “approved” already if we thought that this was a good idea. But it isn’t.

    So what is this vaccine candidate, anyway? It’s being developed by the Gamaleya Research Institute, and it’s reported to be a mixture of two adenovirus vectors, Ad5 and Ad26. I’m still not sure what the idea behind giving both of those might be, but those two approaches are of course being used separately by other vaccine developers. The Gamaleya folks seem to like these mixed-vector vaccines – here’s a VSV/Ad5 Ebola candidate they were working on. Overall, the idea behind the vaccine doesn’t seem to be bizarre at all, though – just the development timelines.

    This is just naked “vaccine nationalism”, which is really the last thing we need right now. I don’t want to see any country (including the US) beating its chest in this fashion and using the pandemic to declare the superiority of its system or its scientists. Coronavirus research needs to be as international as possible, with ideas, approaches, publications, and trials coming from around the world. This sort of stunt is taking us backwards – now people will be agitating for the “approved” Russian vaccine and wondering why the others aren’t ready yet, etc. It just creates confusion and discord – don’t we have enough of those already? Unless, of course, creating confusion and discord is the point. . .

    Gilead files COVID-19 drug remdesivir with FDA

    Gilead has filed its COVID-19 drug remdesivir with the FDA, to treat patients with severe disease, under the brand name Veklury.

    The drug is currently available to US patients under an Emergency Use Authorisation for treatment of hospitalised patients with severe COVID-19.

    This filing is the last part of a rolling submission with the FDA that the company began in early April and could lead to a full licence for the drug, which was the first to show significant improvements in recovery time in patients with severe disease.

    The filing is supported by data from two randomised, open-label, multi-centre phase 3 clinical studies of Veklury conducted by Gilead.

    It also includes the phase 3 randomised, placebo-controlled study of Veklury conducted by the National Institute of Allergy and Infectious Diseases (NIAID).

    Data from the studies showed treatment with Veklury led to faster time to recovery compared with placebo and that a 5-day or 10-day treatment duration led to similar clinical improvement.

    Across studies, Veklury was generally well tolerated in both the 5-day and 10-day treatment groups, with no new safety signals identified.

    The filing with the FDA follows approval by several regulators across the world, including in the European Union and Japan.

    Originally intended as a treatment for Ebola virus, Veklury is a nucleotide analogue with broad-spectrum antiviral activity both in vitro and in vivo in animal models against several emerging viruses.

    There are ongoing phase 3 trials testing its safety and efficacy in patients infected by the SARS-CoV-2 coronavirus that causes COVID-19, including combination trials with other drugs.

    Veklury must be administered via intravenous (IV) infusion and is supplied two ways: Veklury (remdesivir) for injection, 100 mg, lyophilised powder, or Veklury (remdesivir) injection, 100 mg/20 mL (5 mg/mL), concentrated solution.

    Last week Pfizer signed a multi-year agreement with Gilead to manufacture and supply the COVID-19 antiviral remdesivir, which is also being tested in combination with other drugs in an effort to fight the pandemic.

    Under the terms of the agreement Pfizer will become one of several external partners who manufacture the investigational treatment for the disease.

    Pfizer will provide contract manufacturing services at its facility in McPherson, Kansas, to supply the drug to Gilead.

    Several other drugs are being tested as a treatment for the disease: one of the most promising is the off-patent steroid dexamethasone, which lowered mortality in a UK-based phase 3 trial and is much cheaper than Veklury.

    Feature image courtesy of Rocky Mountain Laboratories/NIH

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    The Guardian view on Brexit bureaucracy: tied up in red tape | Editorial

    Businesses already struggling with the fallout from Covid-19 will be forced to deal with a mountain of new bureaucracy in the middle of a deep recession

    The government did not quite achieve the Brexit breakthrough it was seeking on Friday, when there was hope that a fast-tracked trade agreement with Japan might be reached. But it seems likely that a deal, essentially replicating one signed by the EU and Japan last year, will be done by the end of the month. Some kind of morale booster for Britain’s battered and bruised businesses would certainly be welcome.

    As the clock runs down to the end of the transition period on 31 December, ministers are no longer bothering to offer the false hope of a relatively frictionless trade agreement with the EU. Even a Canada-style free trade deal will mean a vast infrastructure of compliance and checks: permits for lorry drivers to enter Kent, huge customs clearance centres and tracking apps are all in the mix. The government estimates that, from 2021, there will be over 400m extra customs checks a year on goods going to and from the EU.

    Continue reading…

    Pfizer signs deal with Gilead to manufacture COVID-19 antiviral remdesivir

    Pfizer has signed a multi-year agreement with Gilead to manufacture and supply the COVID-19 antiviral remdesivir, which is also being tested in combination with other drugs in an effort to fight the pandemic.

    Under the terms of the agreement Pfizer will become one of several external partners who manufacture the investigational treatment for the disease.

    Pfizer will provide contract manufacturing services at its facility in McPherson, Kansas, to supply the drug to Gilead.

    It is part of a five-point plan by Pfizer launched in March that urged all pharma companies and biotechs to work together with government agencies and academic institutions to tackle the COVID-19 pandemic.

    Remdesivir has not yet been approved in the US to treat COVID-19, although it can be used to treat the disease under an Emergency Use Authorization issued by the FDA.

    Remdesivir was the first drug to show activity against the SARS-CoV-2 coronavirus earlier this year and is a broad-spectrum antiviral drug that was originally developed as a potential agent against the Ebola virus.

    After the initial first success as a monotherapy, scientists are now trialling it in combination with other drugs to see if the antiviral effect is enhanced.

    Earlier this week the US-government backed National Institutes of Health begun a trial testing remdesivir in combination with interferon beta-1a – Merck KGaA’s Rebif – against COVID-19.

    The Adaptive COVID-19 Treatment Trial 3 (ACTT 3) study is run by the National Institute of Allergy and Infectious Diseases and is expected to recruit more than 1,000 hospitalised adults with COVID-19 at as many as 100 sites in the US and abroad.

    Rebif has the same amino acid sequence as a naturally occurring protein called interferon beta, which is part of a class of proteins called type 1 interferons.

    Infected cells normally produce type 1 interferons to help the immune system fight pathogens, especially viruses. Interferon beta has both antiviral and anti-inflammatory properties.

    This is the third iteration of the ACTT trial. Results from the first part of the trial published at the end of May found that patients who received remdesivir had a statistically significant shorter time to recovery compared to patients who received placebo.

    Feature image courtesy of Rocky Mountain Laboratories/NIH

     

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    Vaccine Data From Novavax

    Several days after making some headlines with a press release about the data, the Novavax vaccine effort has published on Medrxiv. The is the first look at human data we have at an approach using recombinant coronavirus proteins (plus an adjuvant, in this case a proprietary saponin natural product). The protein itself is produced in the good ol’ Sf9/ baculovirus cell expression system, a real workhorse over the years for recombinant proteins. I’m glad to see this one, because we need as many different techniques as we can get. So how well does it work?

    This was done in 131 adults, with two injections three weeks apart. These were either 5 micrograms or 25 micrograms of protein, with and without the company’s proprietary adjuvant. As seen in some of the other trials, there were six patients in a “sentinal” group who underwent the first dosing with observation before the rest of the groups were vaccinated (five groups, 25/group, with a placebo cohort). The antigen itself is the full-length Spike protein, with the furin protease site mutated and two proline substitutions introduced to stabilize the conformation. That’s pretty much the protein that the J&J vaccine is causing cells to produce via its adenovirus vector, so in this case it’s just being injected directly.

    The reactions to the vaccine itself look fine – the usual soreness at the injection point, and a couple of reports of mild transient fever. These were more noticeable in the adjuvant group, which basically tells you that the adjuvant is probably just doing its immunogenic thing. Overall, there seem to be no overt safety signs to cause any concern.

    And indeed, the adjuvant does really help a great deal. At Day 21 (before the second injection), antibody levels against the Spike protein antigen were tenfold higher in the adjuvant group as opposed to the plain injections. The response was also stronger after the second injection, and by 14 days after that one (Day 35 overall) the antibody levels for the adjuvant groups were at least 100x over the non-adjuvant ones. So that settles that! Interestingly, the levels were quite similar for the 5 microgram and 25 microgram groups, so that should help with overall vaccine manufacturing as well.

    The effect on neutralizing antibodies was even more striking – it’s adjuvant or bust when measured that way (which is really the key figure, anyway). After the second vaccination, the preprint reports that neutralizing antibodies were 4x those seen in convalescent serum of outpatient-treated coronavirus cases, and spanning the same range as hospitalized convalescent cases. 16 patients were selected at random from the treatment groups to check T-cell response, and these showed CD4+ cells that were heavily biased towards Th1. We don’t know how long either response lasts – this paper covers out to two weeks past the second dose, but you can be sure that these numbers are being collected.

    These look like strong results, and I’m glad that this candidate is in human efficacy trials. That’s something to emphasize – we’re all (naturally enough) trying to make what calls we can based on the Phase I immunogenicity data and the non-human-primate challenge experiments. But what matters is real human data from out in the field via the Phase II/III clinical trials. Right now, we have several vaccines that look like they will have good chances of working (this one very much among them). And we’re going to sort them out the only way that they can be sorted.

    Novavax says COVID-19 vaccine could be approved by year-end

    Novavax’s COVID-19 vaccine produced higher levels of neutralising antibodies than produced by recovered patients in an early trial, paving the way for a phase 3 trial and potential approval by year-end.

    The US biotech is gearing up to produce two billion doses of the vaccine in 2021 following the results from its vaccine candidate, codenamed NVX-CoV2373.

    Maryland-based Novavax said that adding its adjuvant, which aims to boost the body’s immune response, did enhance the vaccine’s effectiveness.

    Novavax has received funding from Operation Warp Speed, the Trump administration’s scheme to accelerate development of vaccines and treatments in the effort against the coronavirus pandemic.

    Early last month Novavax said it received $1.6 billion in funding from the scheme, which will fund the scale-up of manufacturing and a phase 3 trial involving around 30,000 people.

    This trial could produce enough data to support approval before the end of the year, a company spokesperson told Reuters.

    Results came from the phase 1 portion of a phase 1/2 clinical trial testing two doses of the vaccine (5 and 25 micrograms).

    Novavax said the vaccine produced neutralising antibodies after two doses in a cohort of 131  healthy adults aged between 18 and 59 years.

    The company added that the vaccine was well-tolerated and reactions were generally mild – tenderness and pain were the most frequent local symptoms after the first dose.

    Systemic events such as headache, fatigue and muscle pain were less frequently reported, the company said, and duration of these events was less than two days.

    The vaccine is based on an antigen derived from the Spike protein found on the surface of the SARS-CoV-2 coronavirus, which is the most commonly used target for the other vaccines in development against COVID-19.

    It works by causing the body to produce antibodies that can bind to the Spike protein and neutralise the virus, preventing it from taking hold in the body.

    There are 26 potential vaccine candidates in clinical trials, according to the World Health Organization’s reckoning, with the most advanced being from the University of Oxford and AstraZeneca.

    This is in phase 3 development and a “challenge trial” where healthy patients are inoculated and infected with the virus could be up and running by the end of the year.

    Feature image courtesy of Rocky Mountain Laboratories/NIH

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    Regeneron’s Monoclonal Antibody Cocktail in Primates

    I’m very glad to see some data emerging on the monoclonal antibody therapies that have been in the works. Regeneron  and Eli Lilly/Abcellera are two of the front-runners in this field, which could pick up some very much needed slack while the many vaccine trials are going on. And late yesterday a preprint emerged from the Regeneron effort, looking at challenge studies in animal models. Since we were just looking at the primate challenge studies in the various vaccine efforts the other day, this is timely indeed.

    This team has a mixture of two monoclonal antibodies (REGN10933 and REGN10987). The isolation of these has already been described, as well as a study looking at their effectiveness versus Spike protein mutations. That latter paper illustrates some key points – when a patient develops their own antibody response to an infection like this one, there’s a wide variety of antibodies that get raised. Some of them are neutralizing by themselves, and some not, but that simultaneous defense by a number of different antibodies is definitely a good feature. By contrast, look at what happens if you try the one-antibody-only technique of treating a pathogen with an injected monoclonal antibody: you’ll hit the target hard, but at the same time you’re applying strong selection pressure for any viable mutants that can escape the attack. And that’s what Regeneron saw in their model systems with single antibody treatments – mutants that would normally have a low profile with no particular advantage suddenly had a chance to amplify if they escaped the binding of the monoclonal antibody. Thus the mixture of two monoclonals, which bind to non-overlapping regions of the Spike protein. Now a virus needs two separate escape mutations, which is extremely unlikely.

    The paper shows two rhesus challenge experiments, each done by injecting the animals with 50 mg/kg of the mAb mixture (25 mpk of each antibody), followed three days later by exposure (both intranasal and intratracheal) to either 1×105 or 1×106 PFU (plaque-forming units) of coronavirus. Those doses, when compared to the ones we’ve been seeing for the vaccine challenge experiments, are bracketed on the low side and the high side of the range. For the lower dose (Figure 1B in the paper), it looks like subgenomic RNA (which is indicative of replicating virus) in the nasal swabs is pegged at the low limit of detection in all animals at all time points, and sgRNA in the lungs is only detectable in one animal at Day 1. In the higher-dose experiment (Figure 2B), sgRNA is detected (low level) in the nasal swabs at Day 1 and Day 2, but not thereafter. The animals were also checked via oral swab, and the sgRNA was also cleared very strongly from these samples. I should note that they also tried a much lower dose of the antibody cocktail (0.3 mpk) in that second experiment, which was ineffective.

    There’s also a treatment experiment, where the animals are not pre-treated, but dosed at the higher challenge level and then after a day are given either 25 or 150 mpk of the antibody cocktail to see if it can deal with the infection once it gets going. The sgRNA data show significantly enhanced clearance of the virus for both doses – in fact, the two look pretty similar, except (oddly) the 150 mpk group shows higher viral titers on Day 1. Not sure what’s going on there, but it looks like the mAb cocktail would be an effective treatment as well as a prophylaxis. Lung histology on all the infected animals confirmed this – the signs of viral pneumonia were far milder in the treated animals than in the controls.

    The paper goes on to examine a golden hamster model. That’s because although rhesus macaques are certainly a lot closer to human, they don’t really get hit hard by coronavirus symptoms. The virus infects them and replicates, so it’s a good model in that sense, but the animals don’t show any severe symptoms. The hamsters, on the other hand, have it rough: severe lung pathology, high viral load, and noticeable weight loss. The same sorts of prophylactic experiments on the hamsters showed that all the doses tried (0.5, 5, and 50 mg/kg) protected the animals from weight loss, with a strong decrease in viral sgRNA load in lung tissue at 5 and 50 mpk. A treatment experiment (as done with the monkeys) showed significant effects at the 5 and 50 mpk doses as well.

    I was also glad to see an analysis of Spike protein mutants before and after antibody treatment in the monkeys. The good news is that nothing worrisome seems to have been raised up by the treatment – there were new mutant forms picked up, but these showed up in both the antibody-treated animals and in the placebo controls, which just shows you that the virus was indeed replicating in these animals (and throwing off mutations, as viruses do), but that the antibody treatment wasn’t causing anything new to be selected. There was also no sign of antibody-dependent enhancement in any of the treated animals.

    What we don’t know from this study is the duration of prophylaxis: how long would someone be protected after a dose of the antibody cocktail? That really has to be answered in humans, though – it would be nice to get a number from a primate study, but you’d never be sure how well it would extrapolate to humans over such a longer time. But what this work demonstrate is certainly enough: the antibody cocktail appears to be effective both as a preventative and as a treatment, and it seems to have effects on viral replication that are in the same range as those seen in the vaccine studies reported to date (the more promising ones, at that). This is good news, and I am very eager to see human data.

    Covid-19: Gilead Sciences urged to study drug that showed promise with cats

    Activists are calling on the pharmaceutical firm Gilead Sciences to study a drug for the treatment of Covid-19 that showed promise in curing cats of a coronavirus.

    The drug, called GS-441524, is chemically related to remdesivir, an antiviral also made by Gilead, and one of the only treatments to successfully shorten the duration of Covid-19 recovery.

    Related: US secures world stock of key Covid-19 drug remdesivir

    Continue reading…

    Gilead loses $3.3bn in Q2, blaming COVID-19 and cancer drugs firm acquisition

    Gilead has blamed a $3.3 billion loss in Q2 on its acquisition of immune-oncology company Forty Seven – but revenues are declining as the pandemic bit into sales of its hepatitis C drugs.

    Product sales in Q2 were down nearly 10% compared with last year to just over $5 billion, and the company recorded a net loss of $3.3 billion.

    The overall trend in Gilead’s hepatitis C franchise is down as the market is shrinking as patients are cured by its drugs and those of rivals such as AbbVie.

    Gilead said COVID-19 has made things worse because fewer patients have been visiting clinics and hospitals for visits and screenings.

    Sales of HIV drugs were down 1% to $4 billion in Q2, although over the first half they increased by 6% to $8 billion.

    Hypertension drug Letairis and chest pain drug Ranexa have also been hit by generic competition in the US in the first half of the year.

    In the second quarter of last year Gilead also benefited from rebate adjustments worth around $160 million, related to sales of its HIV and hepatitis C drugs in Europe.

    These favourable adjustments did not reoccur in this year’s Q2, further impacting the company’s underlying performance.

    Other factors were lower sales of HIV drugs such as Truvada, and COVID-10 affecting demand for HIV pre-exposure prophylaxis (PrEP) drugs.

    However the company said that this was partially offset by continued uptake of its newer PrEP drugs Biktarvy and Descovy.

    CAR-T cancer therapy Yescarta generated sales of $156 million in Q2, up from $120 million in the same period last year driven by continued uptake in Europe.

    On top of all this Gilead also took a charge of $4.5 billion following its acquisition of cancer immunotherapy Forty Seven.

    R&D expenses have also increased because of Gilead’s focus on developing remdesivir as an antiviral against COVID-19, and donations to the US healthcare system in June.

    Gilead expects to have manufactured more than two million remdesivir treatment courses by the end of 2020, and several million more treatment courses in 2021.

    Investment in remdesivir research will continue, the company plans to test the drug early in the disease and has already launched a phase 1a study testing an inhaled solution.

    It also plans to test remdesivir in combination with Eli Lilly’s Olumiant (baricitinib), a JAK inhibitor already used in inflammatory diseases, and Roche’s IL-6 drug Actemra (tocilizumab).

    The company is sticking by full-year guidance announced in February of product sales in a range of $21.8 – $22.2 billion and earnings per share of between $5.15 and $5.55.

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    Coronavirus Challenges in Primates, Compared

    We have a sudden influx over the last few days of preclinical rhesus challenge studies with various coronavirus vaccines, and it’s only natural to try to compare them. I have worked up a table with all four of the current results and the previously reported SinoVac inactivated virus vaccine, whose rhesus challenge numbers were officially published earlier this month. This is the closest to Phase II human data that we’re going to have until later in the summer, so let’s see what we can make of it!

    Here is the Oxford/AstraZeneca vaccine, ChAdOx1, which is (as many have had the chance to memorize by now) a chimpanzee adenovirus repurposed with genetic material from the coronavirus Spike protein. This is the final published version of a preprint that came out earlier this year, whose results attracted wide comment and some criticism at the time. Since this one has already been discussed here, I’ll defer it to the comparison table I’m putting together.

    And here we have Moderna’s mRNA-1273 results. The short readout is that the vaccine induced an antibody response in the monkeys similar to that seen in convalescent human serum, and a T-cell response that was heavily biased towards CD4+ Th1, with no detectable CD8+. That’s quite similar to what the company has reported in the human Phase I trials, which may add to one’s confidence in trying to learn something from the primate viral challenge studies. We’ll go into the actual numbers in the comparison table, but although the challenge in this case showed strong effects, it was not quite “sterilizing immunity” where the possibility of viral infection is completely shut down.

    Then comes J&J, and I believe that these are the first numbers from their vaccine, which is another adenovirus vector, but an obscure human strain (Ad26) rather than a chimpanzee one. It’s been a bigger effort than we knew: the paper shows that they investigated seven different forms of an Ad26 vaccine, coding in various amino acid mutations for stability, different “leader sequences” to try to get the genetic material expressed more robustly once into cells, and different antigen sequences entirely. All of the latter are variations on the Spike protein, but some are full-length, while some had the cytoplasmic “tail” region or the transmembrane region deleted. They also tried mutations in the furin protease cleavage site and (like the first now-dropped Pfizer mRNA candidate), tried a foldon trimerization domain to present the antigen in multiple ways.

    The one that stood out in antibody response was the “S.PP” candidate: wild-type leader sequence, full-length Spike protein, furin cleavage site mutated, and proline stabilizing mutations, so that’s what will be in the comparison below. Interestingly, this candidate had the lowest T-cell response of all seven that they tried (their paper’s Figure 3). After looking over the challenge data, the paper has some conclusions (their Extended Figure 6) on immune correlates (what markers are most indicative of efficacy): “these findings suggest that serum antibody titers may prove a useful immune correlate of protection for SARS-CoV vaccines. By contrast, vaccine-elicited ELISPOT responses, CD4+ ICS responses, and CD8+ ICS responses did not correlate with protection“. Which is interesting!

    And finally, we have the Inovio DNA vaccine (INO-4800), which I’m glad to finally be seeing more data on. This is a DNA construct for the Spike protein, delivered intradermally. We need various technologies and routes of delivery to be running simultaneously, so the publication of this preprint is very timely. INO-4800 also produced antibody and T-cell responses, which will be summarized below.

     

    There are a number of take-aways from this. I particular want to draw attention to the “Virus Challenge” row, since not all of these studies have been performed with an equivalent amount of virus. I have taken the various measurements as given in the papers and converted them all to Plaque Forming Units, using the conversion factor between that and the TDIC50 measurement given in the Moderna paper. You will note that Inovio’s challenge is the weakest of all those in the table, but at the same time their response is also the weakest: none of their animals ever go down to zero when measuring subgenomic RNA (which is more indicative of replicating virus). I am not optimistic, based on these numbers, about how their candidate will perform in Phase II/III human studies, both on the absolute scale and relative to their competition.

    The second lowest is J&J. Their efficacy number are very good indeed, but one has to wonder if Moderna (whose viral challenge dose appears to have been tenfold higher) and the other competitors might have shown similar numbers at that same dose. On the other hand, that was only one dose of the J&J vaccine, which is impressive – they are the only company so far to report such a dosing protocol, and that’s a very big deal, from a logistics standpoint. But on the third hand, that single dose was tenfold more viral particles than the other adenovirus vector in the table (Oxford), so is J&J prepared to manufacture five times more active viral vector? They will, on the other hand, be using up only half as much fill-and-finish capacity after that. And so on – isn’t drug development a blast? Don’t you just wish that you could have decisions like this hanging over your head for a living?

    I wish that we had similar primate challenge data for the Pfizer/BioNTech candidate, but I honestly don’t even know if they ran that experiment, or when we’ll see it. I still like that one from what we’ve seen of what we now know was its inferior competitor in Phase I, and I like the J&J vaccine as well. Those would be my personal front-runners, with Moderna and Oxford right behind them. Unknown factors in the human efficacy trials could rearrange that list in any direction, though, so my handicapping isn’t worth that much. That said, I don’t have similar hopes for the Inovio candidate based on what we’re seeing, and I don’t really know what to make of three-dose SinoVac inactivated-virus vaccine. Two boosters would be a major pain, and the data package on this one is, in retrospect, the thinnest of the bunch (although it does indeed appear to have worked). I’m not sure if anyone knows what they’re doing in their clinical trials.

    On to Phase II!

    Understanding COVID-19 and varying responses across the globe

    While lockdown eases across England, local lockdowns are becoming an ever-growing threat across the country. This is a unique response in comparison to other countries across the world and could be indicative of a second spike in infections.

    At the beginning of the pandemic, The London School of Hygiene and Tropical Medicine launched a course focussed on understanding COVID-19 and the varying response across the globe. The course provided a good foundation on understanding the virology of COVID-19. Members of our team took part in the course to gain a better understanding of the pandemic, so we could best serve our clients during this challenging time. Here are some of the key learnings.

    COVID-19, also known as SARS-COV-2, is a type of coronavirus that is characterised by crown-like spikes and can cause a range of illnesses in humans from the common cold to severe disease. Coronaviruses are commonly found in animals, but rarely people get infected with a new type of virus which they catch from an animal.

    Humans have been affected by these types of viruses before such as SARS (from civet cats) and MERS (from dromedary camels). However, COVID-19 is thought to have come possibly from bats.

    The symptoms can range from mild to severe, all affecting the respiratory system, from fever and fatigue to complete respiratory failure.

    The severity of the disease can be measured by the case fatality rate (CFR). This is the number of people who die from that condition out of the total of number of cases with the condition.

    At the time of writing this article, the global CFRs for MERS, SARS, and COVID-19 are 37%, 10%, and 5% accordingly. However, for the UK the current CFR is 14% which is nearly three times higher than the global average.

    How did COVID-19 become a global pandemic?

    To understand how the pandemic has come to be, it is important to understand the route of transmission which has no doubt contributed to the accelerated spread of the disease. There are three main ways that respiratory viruses are known to spread. First, droplets which are larger particles that are greater than 5mm that travel under 1m.

    To read the rest of the article, click here

    The post Understanding COVID-19 and varying responses across the globe appeared first on .

    Coronavirus: UK signs deal for 60m doses of potential vaccine

    GlaxoSmithKline and Sanofi Pasteur could supply vaccine by early next year if it is successful

    The government has signed a deal with the pharmaceutical firms GlaxoSmithKline (GSK) and Sanofi Pasteur for 60m doses of a potential Covid-19 vaccine.

    If the vaccine proves successful, the UK could begin to vaccinate priority groups, such as frontline health and social care workers and those at increased risk from coronavirus, as early as the first half of next year, the Department for Business, Energy and Industrial Strategy said.

    Related: Coronavirus vaccine tracker: how close are we to a vaccine?

    Continue reading…

    Covid-19 is Big Pharma’s chance to impress. But who’ll do best?

    AstraZeneca and GSK both release results this week. But picking winners in the sector may be complicated

    It was the press announcement heard around the world: a potential Covid-19 vaccine from the University of Oxford and pharmaceutical company AstraZeneca had not only been “tolerated” by patients, but “generated robust immune responses against the Sars-CoV-2 virus in all evaluated participants”. The project will now proceed to all-important phase 3 trials in Brazil and South Africa to test if it actually stops infection.

    For a global population that has seen its movement curtailed and its health threatened, it was a welcome dose of good news. It is also a large feather in the cap for AstraZeneca, whose boss, Pascal Soriot, will unveil financial results for the first half of 2020 on Thursday.

    Continue reading…

    ‘Major’ breakthrough in Covid-19 drug makes UK professors millionaires

    Synairgen’s share price rises 540% on morning of news of successful drugs trial

    Three professors at the University of Southampton school of medicine have this week made a “major breakthrough” in the treatment of coronavirus patients and become paper millionaires at the same time.

    Almost two decades ago professors Ratko Djukanovic, Stephen Holgate and Donna Davis discovered that people with asthma and chronic lung disease lacked a protein called interferon beta, which helps fight off the common cold. They worked out that patients’ defences against viral infection could be boosted if the missing protein were replaced.

    Epidemics of infectious diseases behave in different ways but the 1918 influenza pandemic that killed more than 50 million people is regarded as a key example of a pandemic that occurred in multiple waves, with the latter more severe than the first. It has been replicated – albeit more mildly – in subsequent flu pandemics.

    Very proud of my husband’s efforts!!
    He is the CSO of this company. He and has team have worked their socks off over the last 5 months to make this happen.

    And the results are stunning! #COVID19 #Synairgen #SNG #clinicaltrials https://t.co/NThZDV1k0O

    Continue reading…

    The world needs a ‘people’s vaccine’ for coronavirus, not a big-pharma monopoly | Helen Clark and Winnie Byanyima

    AstraZeneca and others should not own a lucrative patent on a medicine that is needed by poor as well as rich nations

    See all our coronavirus coverage

    • Helen Clark is a former prime minister of New Zealand and Winnie Byanyima is UN undersecretary general

    To bring an end to the pandemic, the world needs a vaccine. Promising early trial results for the vaccine developed by Oxford University suggest we’re inching closer to discovering one.

    Related: Oxford offers best hope for Covid-19 vaccine this year, MPs told

    Continue reading…

    Bacteria and Colon Cancer

    Let’s catch on some non-coronavirus research today with an interesting approach against a very bad disease, metastatic colon cancer. This new paper (from groups at Virginia Tech and Wake Forest) adds to our understanding of something that’s been noticed for some time: colon cancer tissue is often infected with Fusobacterium nucleatus. This bacterium (an anaerobic Gram-negative beast) especially seems to be associated with accelerating or metastatic disease, but it’s been unclear what the relationship is. Is this an accident, or is there a causal effect – and if so, what causes what? F. nucleatus, I should note, is already known as a problem: it’s normally considered one of the major players in peridontal disease and (weirdly) may also have an as-yet-unexplained relationship with preterm births and other complications of pregnancy.

    Using the well-known HCT116 colon-cancer cell line, this paper shows that the bacteria bind to the cell membrane and actually force their way into the cells themselves. There’s a good amount of work in the paper going into just what surface proteins are involved in this process and what the entry mechanism might be, but I’m going to skip ahead to what happens after the infection: the cells start to secrete significant quantities of the cytokines IL-8 and CXCL1, as measured floating around in the culture medium. And that’s not good news, because both of those have already been shown to be associated with colon cancer progression and invasiveness.

    That’s just what this group saw in their cell culture: as the amounts of these cytokines increased, the cells became more mobile and less attached to their original positions. And the mobile ones weren’t just the cells that had the bacteria inside their cytoplasm: the cytokine secretion meant that cells that weren’t infected at all felt the effects and became more mobile themselves. The entry into the cells is a key part of the process, though – the paper shows that when key surface proteins were knocked out (blocking the whole entry process) that the cytokines don’t get secreted like this.

    So it appears that the relationship is indeed causal, and it’s the bacterial infection that makes colon cancer worse. That immediately suggests some therapeutic options, of course. The paper shows that administering antisera (a mixture of antibodies) to F. nucleatum in the cell assay decreased this whole process, but did not eliminate it entirely. But what if you were to take it out of commission before it even got to the colon? The belief, in both colon cancer and pregnancy complications, is that the bacterium migrates from the mouth into the bloodstream (bleeding gums) and from there into other organs. A vaccine against it could potentially clear it from the blood before it has a chance to cause trouble later on. Given this species’ association with human disease, this sounds like it could be a good idea, and I hope that it’s taken up. More immediately, this bacterium seems to respond to a number of well-known antibiotics, and you have to wonder if treatment with those might improve outcomes in early-stage colon cancer. The problem there is, of course, that you don’t often even catch it early enough, but in patients who are diagnosed with non-metastatic disease it might be worth a look.

    As a side note – gotta work in some coronavirus-related content somehow – it has been reported that our old friend chloroquine might inhibit colon cancer cell mobility in vitro. This paper found, though, that it doesn’t appear to do this through effects on this F. nucleatus-driven pathway – treatment with chloroquine didn’t make secretion of the two cytokines go down at all. So there’s another mechanism at work here. . .

    New report shows more than 400 medicines and vaccines in development to tackle infectious diseases, including COVID-19

    Throughout history, infectious diseases caused by pathogens such as bacteria or viruses have taken a devastating toll on the lives and security of people around the world. With the ongoing COVID-19 pandemic gripping the world, we are experiencing a challenging situation that we haven’t seen since the influenza pandemic of 1918-1919, when a third of the world’s population became infected with the virus and about 675,000 Americans died from the disease.

    New Data on the CanSino Vaccine

    And now we have more data on the CanSino vaccine, another adenovirus vector (but this one using Ad5, a much more common one in the human population). Their initial Phase I data are discussed here. So what else do we know now?

    Well, that one was open label and non-randomized, whereas this one is fully controlled. It also is much larger, and has a wider range of ages and should be more of a real-world look. There are two doses (5 x ten to the tenth, 129 patients, and 1 times ten to the eleventh viral particles, 253 patients, and a comparison to a placebo group of 126 patients as well). 52% of them had high pre-existing immunity to adenovirus-5, which has always been a concern with this effort.

    There were no serious adverse events in either dosing group, and the events that did take place were exactly the sort of thing we’ve been seeing before – pain and soreness at the injection site, general fatigue and aches, mild fever. It doesn’t look like we’re going to get away from any of those, so we should all remind ourselves that it damn well beats getting the coronavirus.

    Both doses produced similar titers of neutralizing antibodies, as it turns out, and these kicked in sometime between Day 14 and Day 28. But when you look at the half of the subjects who already had high levels of antibodies to the Ad5 vector, you find that their titers were 2 to 3 times lower than the ones who didn’t start out that way. The patients who were older than 55 also showed noticeably lower antibody response – still above placebo, true, but nowhere near as robust as the younger patients. Older patients were more likely to have the Ad5 antibodies, which is surely a good part of the reason for this. None of the data in the paper go out past 28 days, so we can’t say much of anything about whether there’s a dropoff in antibody titers.

    Both doses of vaccine produced a similar T-cell response, and in that case there’s no real difference between the ones with higher pre-existing Ad5 antibodies and the lower ones. These data are only shown as a snapshot at Day 28. Only about 1% of the patients showed any T-cell response at the baseline pre-dosing, interestingly. Another thing to note: the age of the patients seemed to make no difference in the T-cell response, as opposed to what was seen with the antibody levels. There are no data on CD4+ versus CD8+ cells, unfortunately.

    Overall, then, this is a useful but limited publication. It tells us more about the CanSino vaccine’s profile, but it also raises some worries about just what everyone was already worried about: the pre-existing Ad5 immune response. This should come as no surprise to anyone, and the paper states clearly that this is their biggest concern going forward. In the Chinese population, about 50% of the population is in that category – in India it’s 80%, and in the US around 30%. The question is what differences one might see in the Phase II efficacy readouts. Remember, giving a booster shot with one of these viral-vector agents is quite problematic – after the first dose, the number of your patients who have neutralizing antibodies to the vector is now 100%. One the other hand giving one shot instead of two is potentially a big advantage – but only if that one shot is enough. Yet again, we’re going to have to let this shake out in Phase II. Maybe it won’t make a difference, but. . .given these concerns, if I were a betting man – perish the thought – this vaccine is not where I would be putting my money just now.

    New Data on the Oxford/AZ Vaccine

    The hype began building late last week around the Oxford vaccine results released today, and I will confess to wondering just what was going on. The British press has a history of going berserk over drug research – I wouldn’t care to count how many times Alzheimer’s “breakthroughs” have hit the headlines over there, and I figured this might be part of the problem. But now we have the numbers. So how are they?

    Recall this this one is an adenovirus vector vaccine – a chimpanzee adenovirus (used because humans don’t have exposure and thus pre-existing immunity to it) has had its own genetic material stripped out and the genetic sequence for the coronavirus Spike protein added instead. There are four groups in this study: Group 1 had 88 participants who received either the ChAdOx vaccine or a commercial meningitis vaccine as a control and who were followed up on at Days 3, 7, 14, 28, and 56. These were the true “Phase I” part of the current work. Group 2 had 412 (also split 50/50) who were vaccinated and assessed for both antibody and T-cell counts. Group 3 (10 patients) all had the ChAdOx vaccine, and then a booster at Day 28. And Group 4 (567 patients, split 50/50) were only evaluated for antibodies. These latter groups are the Phase II trial, who are being evaluated for how many in each group actually contracted the coronavirus (data not available yet!) Everyone got the same dose: 5×10 to the tenth viral particles.

    The adverse events are (as in the other vaccines that have reported so far) just what one would figure: pain and tenderness at the injection site, along with fatigue, muscle and joint pain, fever in some cases, etc. There were no severe events. Some participants got prophylactic paracetamol (acetaminophen), and this did indeed lower the side effects, as it should. I found it interesting that the second dose (in those ten patients who got one) did not seem to bring on a more robust reaction than the first (the paper’s Figure 2).

    OK, antibodies: overall antibody titers hit their peak at Day 28 and had declined a bit at Day 56 (albeit with a rather wide spread in response in both sets of data – see the paper’s Figure 3 and note the log scale on the y axis). The ten patients who got the booster shot definitely saw raised antibody titers. As for neutralizing antibodies (the paper’s Figure 4), the booster-shot people did have a higher response than the single-dose cohort, an effect that’s most noticeable as you move to more stringent assays (in some of the others, they look nearly the same). But from what I can make of the actual neutralizing antibody titers, they all seem comparable (if not perhaps a bit lower) than those seen in the convalescent plasma control group. The activity for that comparison group does not seem to be reported in those other assays; it would be good to have that comparison. It’s also worth noting in those figures that there were a couple of patients who started out with high antibody titers to the coronavirus – as the paper notes, there was not time to check everyone as the trial was enrolling, so they picked up some people who are already had the infection.

    As for T cells, the text of the paper says that induced T cell levels peaked at Day 14 and were maintained out to at least Day 56, with no real effect of a booster in that case. There are no actual data presented, and there’s nothing on CD4+ cells versus CD8+ ones.

    These results, overall, are fine – but I think that they would have been more impressive had they come out before the Moderna and Pfizer mRNA ones. As it is, I have trouble reconciling the big buildup from the British media (and, I have to add, from the editorial staff at The Lancet) with what’s actually presented here. I’m very glad that I don’t have to pick which vaccine to get based on the limited data we have (there are no efficacy numbers to compare, to pick the biggest gap in our knowledge!) But if I were forced to make such a choice, right now I’d take the Pfizer/BioNTech candidate. But let’s see how everyone performs where it counts.

     

    More Pfizer Phase I Results: Antibodies, Viral Mutations, and T Cells

    Recent posts here have gone into Moderna’s Phase I vaccine data, Pfizer’s Phase I vaccine data, what we don’t know yet about the relationship between T-cells, antibodies, and immunity to the coronavirus, and some new data that are starting to fill in those gaps. This morning comes a new preprint from the Pfizer/BioNTech team that lands squarely in this territory, and let me say up front that I think they have some very encouraging results. It’s a good way to start the day.

    The previous Pfizer/BioNTech publication (a randomized double-blinded trial) focused on the antibody response (which looked pretty solid), but said nothing about T-cells, and as those two posts linked above make clear, I (and many others!) believe that that part of the immune response looks to be of great importance. This new paper makes up for that gap: it’s from a second study of the same mRNA vaccine candidate BNT162b1, this one non-randomized and open-label. I’m not as concerned about that in this case, since this same vaccine is being studied under controlled conditions at the same time – this work seems to be a “let’s get a read on T cells and dosing protocols”, and I’m fine with that, since those are not going to be very susceptible to placebo effects or investigator bias.

    This work has five groups, with 12 patients each. One of them got a 60 µg dose of the mRNA formulation at Day a, and that’s all. The other groups got 1, 10, 30, and 50 µg doses, respectively, on Day 1 and again at Day 22, so this design provides a broader look at dose-response and at the effect of boosters versus a single injection. There were no serious adverse events – but remember, in the regulatory lingo, a serious event is a serious one indeed. What were observed were dose-responsive reactions (worst at the highest doses) of just the sort you’d expect: pain or soreness at the injection point, and overall feelings of fatigue, headache, muscle and joint pain, and some fever. It’s hard to do a head-to-head just yet, but these might be a bit less than Moderna’s Phase I results – at any rate, it seems clear that you’re definitely going to know that you’ve been vaccinated with these mRNA species. It will be interesting to compare the responses to the adenovirus vectors and others (word is expected on the Oxford/AstraZeneca work later today, in fact, and I’ll blog on that as soon as it appears as well).

    There were changes in C-reactive protein and lymphocyte counts that are consistent with the “self-adjuvant-ing” nature of mRNA vaccines in general, but no other blood chemistry events. Consistent with the earlier trial data, there was a robust antibody response. What you find when you look at the paper’s Figure 1 and Figure 2 is that total antibody production kicked in somewhere between day 8 and day 22 (pre-booster shot), at all doses – and honestly, the doses don’t really look that different in that data. The 1 µg dose is weaker than the others (although not hugely so), and the 10, 30, 50, and 60 µg ones look quite similar. The booster shot (in those first four doses) raises things by about 10-fold.

    When you look at neutralizing antibodies, the picture sharpens up (as it did in the Moderna data). There’s a more pronounced dose-response (the 1 µg dose is clearly inferior), and you can see, again as in the Moderna data, that the booster is really needed to get up to strong titers of neutralizing antibodies. The 60 µg-dosed-once data just can’t compete – the antibodies go up a bit and just stay there, and it’s clear that even 1 µg dosed twice is superior. The levels reached were in the upper range of those found in a convalescent serum panel for comparison, similar to what Moderna found with their candidate. Another very interesting point: I noted in the earlier post that Moderna’s neutralizing antibody data looked best at Day 43, and then went down a bit. These Pfizer/BioNTech numbers look best at Day 29, and have gone done a bit at Day 43. The effect is not huge, but it’s real. The text of the paper says “still increasing up to Day 43”, but that’s not what I see in Figure 2, and I don’t think I would have used that language, myself. More on this below,

    On the other hand, there’s some valuable good news on the antibody front. Many people have been wondering about the effects of mutations in the Spike protein of the coronavirus – both on infectivity and severity of disease, and what these might mean for both monoclonal antibodies and for vaccines. Here’s a paper that just came out in Cell with a comprehensive look at the mutational landscape (100 variations), and it finds that the D614G mutant (which has been becoming more common, a post on that is here) does indeed appear to be more infectious. Moreover, it notes several variants that appear to be more resistant to neutralizing antibodies. This Pfizer/BioNTech manuscript (in Figure 2c) shows how well the neutralizing antibodies raised by this vaccine perform in a pseudovirus infection assay against 17 variations (including D614G), and they are all within error bars of each other, from what I can see. Moreover, one of the antibody-resistant variants from the Cell paper (V483A) is in this panel, and it’s also no different. So it looks like (from what we can see so far) that the neutralizing antibody response brought on by this vaccine candidate can handle a wide range of mutations in the Spike protein and its receptor-binding domain.

    But (as I was going on about above), antibodies are not the whole story in the immune response to the coronavirus. Read those two posts linked on the subject if you haven’t, but the short form is that it appears that T-cell responses may be (1) longer-lasting, (2) important for some degree of protection against infection, and (3) perhaps already present (pre-COVID-19) in some fraction of the population due to exposure to as-yet-uncharacterized animal-derived coronavirus infections that we haven’t even noticed over the years. Moderna characterized their T-cell responses, and saw mostly CD4+ (as opposed to CD8+), and in those, mostly a Th1 response (see that earlier post for more on that). In this case, BNT162b1 produced CD4+ responses in 34 of 36 patients (one of these did have low levels of pre-existing reactive CD4+ cells, by the way – a lower percentage of people than found in the recent Nature paper, but it does confirm that such people are out there). The CD4+ responses correlated with the antibody titers raised in individual patients. And as with the Moderna results, these seemed to be almost entirely Th1 instead of Th2 – the authors believe that this is potentially a good thing, but as noted in the Moderna post, you can find arguments both ways about that point.

    But as opposed to the Moderna candidate, there was also a robust CD8+ T-cell response (29/36 patients), which did not necessarily correlate with the antibody titers raised by the vaccine. Interestingly, neither of these T-cell effects were very dose-responsive. 6 out of 8 patients tested in the 1 µg dose cohort raised a T-cell response, and their CD4+ and CD8+ levels were almost the same as the 50 µg group! As a per cent of total circulating T cells, the levels seen after vaccination were significantly higher than those seen in the blood of convalescent patients, which could be a real difference. Recall that in the case of the 2003 SARS coronavirus, that antibodies disappeared from recovered patients, but that T-cell immunity has persisted for up to 17 years.

    So while one would want to keep an eye on the antibody levels with this candidate (and believe me, you can be sure that Pfizer and BioNTech are doing that), the T cell response looks promising (and probably better than the Moderna candidate). We’ll have to keep all this in mind as the actual Phase II/III data hit, and we’ll see what difference all this makes in the real world!

     

    New Data on T Cells and the Coronavirus

    Well, I was writing just the other day about what we don’t know about the T-cell response to coronavirus infection, and as of today we know quite a bit more. And from what I can see, we have encouraging news, mixed with some things that we’re going to need to keep an eye on.

    Here’s a post from May on a paper in Cell that looked at T cell responses in recovering SARS CoV-2 patients and compared them to reports of people who had been infected with “original SARS” back in 2003, and to people who had never encountered either. It also has some background on T cells in general, which might be useful if you don’t have that info right at the top of your brain’s queue. That’s the paper that showed that the T-cell response to this virus is less “Spike-o-centric” than it was to SARS. It also showed that there are, in fact, people who have both CD4+ and CD8+ T cells that recognize protein antigens from the new coronavirus even though they have never been exposed to SARS, MERS, or the new virus. The paper speculated that this might be due to cross-reactivity with proteins from the “common cold” coronaviruses”, and raised the possibility that there might be a part of the population that has at least some existing protection against the current pandemic.

    Now comes a new paper in press at Nature. It confirms that convalescent patients from the current epidemic show T-cell responses (mostly CD4+ but some CD8+ as well) to various epitopes of the N (nucleocapsid) protein, which the earlier paper had identified as one of the main antigens as well (along with the Spike and M proteins, among others, with differences between the CD4+ and CD8+ responses as well). Turning to patients who had caught SARS back in 2003 and recovered, it is already known (and worried about) that their antibody responses faded within two or three years. But this paper shows that these patients still have (17 years later!) a robust T-cell response to the original SARS coronavirus’s N protein, which extends an earlier report of such responses going out to 11 years. This new work finds that these cross-react with the new SARS CoV-2 N protein as well. This makes one think, as many have been wondering, that T-cell driven immunity is perhaps the way to reconcile the apparent paradox between (1) antibody responses that seem to be dropping week by week in convalescent patients but (2) few (if any) reliable reports of actual re-infection. That would be good news indeed.

    And turning to patients who have never been exposed to either SARS or the latest SARS CoV-2, this new work confirms that there are people who nonetheless have T cells that are reactive to protein antigens from the new virus. As in the earlier paper, these cells have a different pattern of reactivity compared to people who have recovered from the current pandemic (which also serves to confirm that they truly have not been infected this time around). Recognition of the nsp7 and nsp13 proteins is prominent, as well as the N protein. And when they looked at that nsp7 response, it turns out that the T cells are recognizing particular protein regions that have low homology to those found in the “common cold” coronaviruses – but do have very high homology to various animal coronaviruses.

    Very interesting indeed! That would argue that there has been past zoonotic coronavirus transmission in humans, unknown viruses that apparently did not lead to serious disease, which have provided some people with a level of T-cell based protection to the current pandemic. This could potentially help to resolve another gap in our knowledge, as mentioned in that recent post: when antibody surveys come back saying that (say) 95% of a given population does not appear to have been exposed to the current virus, does that mean that all 95% of them are vulnerable – or not? I’ll reiterate the point of that post here: antibody profiling (while very important) is not the whole story, and we need to know what we’re missing.

    There are still major gaps in our knowledge: how many people have such unknown-coronavirus-induced T-cells? How protective are they? How long-lasting is the T-cell response in people who have been infected with the current SARS CoV-2 virus, and how protective is it in the declining-antibody situation that seems to be common? What sorts of T cell responses will be induced by the various vaccine candidates? We just don’t know yet. But we’re going to find out.

    Moderna’s Phase I Data

    Well, it’s finally here – eight weeks to the day after press-releasing some top line results, the full paper is out on the Moderna mRNA vaccine candidate’s Phase I trial. I’m very glad to see it – it’s going to be very important for the full data sets on all the vaccine candidates to be made public.

    So how’s it look? As we found out back in May, we’re looking at three groups of 15 volunteers each, 18 to 55 years old, getting 25 µg, 100 µg, or 250 µg of mRBA-1273 in two doses 28 days apart. The vaccine itself is an RNA sequence for a trimer form of the S (Spike) protein of the coronavirus (similar to the Pfizer/BioNTech mRNA vaccine in that way). It comes with a transmembrane anchor and the S1-S2 cleavage site between the subunits still intact, stabilized in the “prefusion” conformation that it will present in the wild-type virus before it infects cells. That stabilization is through the substitution of two residues at the top of the S2 subunit with proline residues, the “S 2P” form, and the same trick has been used to stabilize other surface proteins of other viruses entirely. (For those who aren’t into protein engineering, proline is unique among amino acid residues in forcing a much more limited conformation in the protein chain, particularly when you have two of them back-to-back). It’s in a lipid nanoparticle (LNP) formulation

    As mentioned before, all patients seroconverted within 15 days of the first dose. The antibody titers generated were dose-dependent and were much higher (several-fold) after the second round of injections. Adverse events (fever, chills, pain at the injection site) were definitely more common after the second injection, too, which is just what you’d expect. With that in mind, it’s worth noting the design of the trial, a standard one that’s quite sensible when you’re stepping in to tweak the immune system. The dosing started off with four “sentinel” patients at the lowest dose, followed by four in the middle dose. After those showed nothing serious, both of those groups were then fully enrolled. After Day 8 of the full dosing, four sentinel patients were injected in the highest-dose group, and after them, the rest of that group were enrolled. For the wrong way to try out a new immunology approach, see here.

    The patients were assayed for antibody levels (in a standard ELISA format), for neutralizing antibodies (by looking for inhibition in various cell-infection assays), and for T-cell levels. As you’d expect, none of the patients’ plasma showed the ability to neutralize the coronavirus before the trial dosing began. And neutralization was still low after the first injection, although the antibody titers had gone up. By Day 43, though (post-second injection), all participants were able to neutralize the effects of the virus in the cell-infection assays by at least 80%, with those responses also being dose-dependent. A comparison showed that this activity was the same or higher than that found with the plasma of convalescent patients (samples from 38 people, collected 23 to 60 days after onset of symptoms). But one thing that you do notice as you look over the data was that day 43 was the best – there was a further evaluation at day 57, and all three groups had gone down a bit in just those two weeks. You can see this happening in the pseudovirus neutralization assays in the paper’s Table 2 and in Figure S8. These patients are no doubt continuing to be monitored, and it is of great interest to see how their neutralizing antibody titers hold up.

    That said, antibody levels are not the only thing that determines immunity. T cells are a big part of this story, although we don’t know all the details – you’ll generally hear a lot more about antibody titers because they’re a lot easier to measure, and to be fair they are often a good proxy for overall immunity. But not always. As for the T-cell data here, CD4+ cell responses were noted, but there was much weaker CD8+ activity (and that only after the second dose in the 100 µg group). Those CD4+ cells can be further differentiated into Th1 and Th2 cells, which each produce a different suite of cytokines. In this case, the vaccine seemed to mostly elicit Th1. The balance between those two types is a complex subject indeed (they have different modes of action and can influence each other’s activity as well), and that also goes for the balance between the CD4+ and CD8+ T cells in general.

    I’m not enough of an immunology geek to be able to tell you what profile we would be looking for, and I don’t think we even quite know yet. My impression is that CD8+ cells are more well-established as being important in clearing viral infections (especially respiratory viruses), but the CD4+ ones (and the ratio of the two) are real players as well. As for the Th1 and Th2 subsets of those CD4+ cells, there’s evidence that the Th1 type are more powerful against viral pathogens, at least for some viruses. The general belief, in fact, has been that Th1 cells are more important in fighting intracellular pathogens in general, with Th2 cells going after extracellular parasites and the like, but (like everything else in immunology) that framework has only become more complicated as we learn more about it.

    So from my bozo-immunology perspective, I think at first glance that I would rather see a more robust CD8+ response than what Moderna has shown here. Others seem to feel similarly. But that said, I don’t know what the convalescent patient T-cell situation is, either: what kind of response did these people have when they cleared the virus on their own? We don’t have the figures from the set of patients in this paper (they just took plasma to evaluate antibodies). But we know from a study of 10 infected patients with respiratory distress that those patients had a higher CD4+/CD8+ ratio, and that they had a higher Th1 response among the CD4+ cells. But you’d want to hear about the people who recovered smoothly as well as about the ones who ended up on respirators, wouldn’t you? The main thing I’ve been able to find on that is this paper, which also showed a shift towards CD4+ cells in pooled plasma from convalescent patients, and among those cells a very pronounced Th1-driven response (note: more on this one here, and in a separate blog post, coming shortly). So the Moderna data might well resemble the profile of recovered patients, which doesn’t sound so bad, although keep in mind that there might still be better ways to clear the virus than the response that we tend to get. We’re just going to have to see how things play out in Phase II/III, aren’t we? One also would like to see such profiles for the other vaccines in the race, and I assume that we will.

    The comparisons are going to be pretty darn interesting. As you can see, Moderna’s candidate is absolutely going to need two injections (as did the Pfizer/BioNTech vaccine candidate), and the reaction to the second dose is pretty vigorous. Will that cause trouble in moving into a larger and more diverse patient cohort? The Moderna neutralizing antibody response seems broadly similar to the Pfizer study, but we don’t have any T-cell profiling from Pfizer yet, so it’s impossible to make any comparisons in that department. The Pfizer/BioNTech adverse event profiling looked a bit better – is that going to be a distinguishing characteristic as the various vaccines go on? Will there be (can there be?) a single-dose vaccine from someone, which would make life and logistics much easier? What will the differences be in the strength of  real-world protection against infection, and in its duration? I have no earthly idea, and neither does anyone else: that’s why everyone is charging into the later clinical trial phases.

     

    Pfizer’s Progress

    I wanted to point out an interesting interview given by Pfizer’s CEO Albert Bourla to Time. I have made some pointed remarks about Pfizer over the years, but this is one of the better Q&A pieces like this that I have seen – you’ll see why in some of the answers below.

    Bourla is actually quite optimistic about the Pfizer/BioNTech vaccine program (four different mRNA attempts, as fans will recall). He says that they should have enough data “in the September time frame” to submit to the FDA, with approval, he hopes, in October if the data are strong enough. Is that realistic? Well, if the data are strong enough, yes. But as with all these timelines, that’s what can happen if everything works right the first time (and with enough vaccines being tried, one or more of them could indeed come through like this). What we’ll have are short-term efficacy and safety data: real-world data on protection against coronavirus infection and on adverse reactions on dosing. What we won’t have are the data on duration of that protection, nor a read on long-term safety. But we’re not going to know those for *any* of the vaccine candidates – those are the big corners that the world is going to cut, and I agree that it’s the right move.

    He goes on to say that

    “. . .it was the moment when I saw the data, plus many other data that we haven’t published yet, [that] made me say that until now I was thinking if we have a vaccine. Now I’m discussing when we’re going to have a vaccine. . .We have a lot of indications that make me feel that really it should make it.”

    Remember that earlier this month the company published Phase I data on one of the four vaccine candidates; I very much look forward to more information of this kind. This is where I should mention that (at least as I write this) we still don’t have such information about the competing mRNA vaccine from Moderna, and it has now been eight weeks since they press-released their first results. (Update: they just published this afternoon! Blog post on the way). Meanwhile, on Monday morning Pfizer announced that the candidate they published on (BNT162b1) and one of the other three (BNT162b2) have been fast-tracked by the FDA for development. The former is one of the two base-modified RNA candidates, and despite some digging around this evening I have been unable to figure out which is the other one. From the looks of the number code, it might be the other base-modified one? We shall see. At any rate, they apparently have enough convincing data on that one to show the agency as well.

    Bourla goes on to say that they will be starting manufacturing soon on a risk basis (something they’ve never done with a vaccine candidate), and that the company plans to be ready with up to 100 million doses by the end of the year – and over a billion doses next year. When the Time reporter asked what they’ll do if the vaccine doesn’t turn out to work in Phase II/Phase III, Bourla responded “We will just have to write it off and call it a day. We will throw it away. It’s only money we’re going to lose.” More in this vein:

    . . .if you were calculating return on investment, we would never do these things. We were discussing that back in March, what that means to human lives, to the economy of the world. So it was a must, that we must take those measures. . .The vaccine should be free to all people. We are not giving it away to governments. We are going to charge governments … a very, very nominal value. But our intent is to ask governments that they should, for these prices, they should provide it free of charge to all citizens.

    He makes the point, as others have, that this is a chance for the drug industry to show what it can deliver for the world. And he’s right: no one else can do the things that the biopharma industry of the industrialized countries are doing right now. If there’s going to be a cure, it’s going to come from us. No one’s going to combine two things from the grocery store and find the wonder drug – that’s what you get from lazy screenwriters cranking out a cheap movie. “My God, that’s it! Nutmeg and anchovies! Under our noses all along!” Nope. It’s going to be the result of a lot of hard work and a lot of expertise in immunology, molecular biology, formulations, pharmacokinetics, protein science, clinical trial design, statistics, toxicology, manufacturing logistics and a whole lot of other subjects that many people would rather break rocks all day than have to pass an exam on. Oh, and a lot of money, too: Pfizer (just one company in the race) is apparently spending about $2 billion this year on this program, and as many have noted, in their case none of it has come from the US government. The folks who claim that new drugs only cost a few million and that they all come from the NIH anyway are going to have to make an exception this time, looks like.

    So good luck to Bourla and to the Pfizer/BioNTech collaboration as they push on in the clinic. Those Phase II/III trials are where all of this is going to be settled, because there is simply no other way to find out what works. Not everything will. We’re heading into an immense, unprecedented, and incredibly expensive and nerve-shredding pile-up in the clinic later this summer and fall, and I’ve said it before – we’ve never seen anything like this, and I hope we never have to again. Hold on tight.

     

     

    More on T Cells, Antibody Levels, and Our Ignorance

    I wrote here about the reports of rather short antibody persistence in recovering coronavirus patients, and what’s been coming out in the two weeks since then has only made this issue more important. In that post, I was emphasizing that although we can measure antibody levels, we don’t know how well that correlates with exposure to the virus nor to later immunity from it, and that T cells are surely a big part of this picture that we don’t have much insight into.

    This Twitter thread by Eric Topol is exactly what I mean, and this article that he references is an important read. Its schematic at right (see also here) will help make clear that antibody levels are only one aspect of the immune response to the infection – it’s an important one, but we’re making it look even more important than it is because it’s by far the easiest part of the process to measure. The T-cell response (much harder to get good data on) is known to be a key player in viral infections, and is also known to be highly variable, both between different types of pathogens and among individuals themselves. The latter variations are also beginning to be characterized among patients in the current pandemic. We have to get more data on it across a broader population of patients in order to make sense of what we’re seeing.

    Many readers will have seen, for example, this new paper from The Lancet on a large study in Spain. Testing tens of thousands of people across the country continues to show that (on average) only about 5% of the population is seropositive (that is, has antibodies to the virus). There are a lot of interesting findings – such as rather large differences in those positive testing rates in different regions of the country, as well as the realization that at least one-third of the people who now test positive never showed any symptoms at all. But we are still not sure if this means that 95% of the Spanish population has never been exposed to the virus, because we don’t know how many people might have cleared it without raising enough of an antibody response to still be detectable. This paper does show that seroprevalence was about 90% in people 14 days after a positive PCR test, which indicates that most people do raise some sort of antibody response, but we don’t know how many of these people will still show such antibodies at later testing dates. Remember the paper discussed in that link in the first paragraph above, which found that 40% of asymptomatic patients went completely seronegative during their convalescence.

    In other words, the Spanish survey may appear to show that 95% of the country has not yet been exposed to the coronavirus, but that’s almost certainly not true. The authors do mention that cellular immunity is important and not something that they were able to address, but the combination of that factor plus the apparent dropoff in antibody levels with time makes these large IgG surveys almost impossible to interpret. But note that if there are indeed many people who have been exposed but do not read out in such surveys, that we also have no idea how immune they are to further infection. At a minimum, you’d want to know antibody levels over time, T-cell response over time, and (importantly) what a protective profile looks like for both of those. We barely have insight into any of this: the large-scale data are just a snapshot of antibody levels, and that’s not enough.

    We have similar data here in the US: several surveys of IgG antibodies show single-digit seroconversion. You could conclude that we have large numbers of people who have never been exposed – and indeed, the recent upswing in infections in many regions argues that there are plenty of such people out there. But we need to know more. We could have people who look vulnerable but aren’t – perhaps they show no antibodies, but still have a protective T-cell response. Or we could have people who look like they might be protected, but aren’t – perhaps they showed an antibody response many weeks ago that has now declined, and they don’t have protective levels of T-cells to back them up. Across the population, you can use the limited data we have and our limited understanding of it to argue for a uselessly broad range of outcomes. Things could be better than we thought, or worse, getting better or deteriorating in front of our eyes. We just don’t know, and we have to do better at figuring it out.

    WHO says trials show malaria and HIV drugs don’t cut Covid-19 hospital deaths

    Hydroxychloroquine and lopinavir/ritonavir not found to help patients in hospital

    The World Health Organization (WHO) said on Saturday that it was discontinuing its trials of the malaria drug hydroxychloroquine and combination HIV drug lopinavir/ritonavir for patients in hospital with Covid-19 after they failed to reduce mortality.

    The setback came as WHO also reported more than 200,000 new cases globally of the disease for the first time in a single day. The US accounted for 53,213 of the total 212,326 new cases recorded on Friday, the WHO said.

    Hydroxychloroquine, also known by its brand name, Plaquenil, is a drug used to treat malaria. It is a less toxic version of chloroquine, another malaria drug, which itself is related to quinine, an ingredient in tonic water.

    Related: Oxford offers best hope for Covid-19 vaccine this year, MPs told

    Continue reading…

    Oxford offers best hope for Covid-19 vaccine this year, MPs told

    University is leading rivals but first drugs may not work fully, says vaccine taskforce chair

    Oxford University is leading the world in developing a vaccine against Covid-19 and offers the best chance of having something protective against the virus as we go into winter, MPs have been told.

    Kate Bingham, chair of the UK vaccine taskforce, said she expected to have a vaccine “early next year” from one or more of the candidates, although it was possible the first vaccines might only “help alleviate the symptoms” so that people have a less serious bout of disease, rather than fully protecting them.

    Related: ‘I felt guilty’: volunteer on signing up for Oxford Covid-19 vaccine trial

    Related: The Lancet’s editor: ‘The UK’s response to coronavirus is the greatest science policy failure for a generation’

    Continue reading…

    Coronavirus Vaccine Update, July 7

    More vaccine news to catch up on – previous updates and specific topic posts on this subject were on June 15, on June 11, on May 26, on May 18 (with two other posts), on May 14, on May 1, on April 23, and on April 15 (author’s note: yikes). Keep in mind that some of those posts were updated after their original publication data as well.

    Here’s the latest on the ones I’ve covered before and with new efforts added. There are now so many of these running that unless the program is especially noteworthy I’ll only touch on the ones that are in trials right now, or about to start soon. And I’m going to arrange them by vaccine class – the April 15 background post goes into some more detail on these, but I’ll start each group off with a short scientific summary. Neither the order in which these different mechanisms are presented nor the order in which companies are listed within them is meant to reflect any horserace handicapping on my part.

    Viral Vectors:

    This class uses some other infectious virus, but with its original genetic material removed. In its place goes genetic instructions to make coronavirus proteins, and when your infected cells do that, it will set off an immune response. Note that this is different than being infected with a “real” virus, whose instructions are (naturally enough) to produce more virus, which go off and infect more cells. No, in this case each viral particle that you’re injected with will be able to infect one cell, and that’s it. An advantage of this approach is that it should appear to your immune system like a pretty realistic viral attack, and set off a full range of responses. A disadvantage is that this technique (as far as I can tell) has only once been used in human therapy (the Ebola vaccine, see below – update: edited this section to reflect this) – a lot of people have been working on it over the years, but things have now accelerated. Another disadvantage is that (depending on which virus you pick as a vector) some of your patients may already have antibodies to that one. That can mean that your attempt to repurpose it might crash and burn as the carefully designed vector gets attacked by antibodies and eaten by immune cells before it can even do its work. It also means that booster shots would have an uphill battle, since the antibodies from that first dose will be waiting for the second one. Antibodies to the viral payload: good. Antibodies to the viral vector itself: not so much.

    Oxford/AstraZeneca: ChAdOx1-nCov19/AZD122: This is one of the frontrunning candidates in human trials (the WHO agrees), and it’s recently started dosing in South Africa and Brazil as well as the ongoing trials in the UK, etc. We’re going to be seeing a lot of that jump-around-the world pattern, tracking the places that have significant outbreaks in order to get the best statistics. That means that the organizations behind each candidate either have to have substantial resources themselves, or partner with those who do (pharma, the WHO, groups such as CEPI and the Gates Foundation, etc.) I don’t know when the next report of human data will be on this one, but it will be very closely watched indeed – see the May 18 post for the reaction to the last big data drop, which had some observers (not all) worried about the vaccine’s effectiveness. This one tries to get around the pre-existing antibody problem by using an adenovirus from chimpanzees (the “Ch” in the name).

    CanSino/AMMS: their Ad5-nCov, we find out this morning, has been approved for use in the Chinese military “after clinical trials proved it was safe and showed some efficacy”. That’s probably how I would put it, too – the company reported on the Phase I data a few weeks ago, and one of the notable features was that about half the patients that they dosed, in all age cohorts, had pre-existing antibodies to the vector. That’s adenovirus-5, as the name implies, and it’s a pretty common human pathogen. This one was widely used earlier (back to the 1980s) in the viral-vector field (which encompasses both vaccines and gene therapy) and a great deal is known about its behavior in humans, but the existing immune response has been a problem every step of the way. Ad5 is also considered a good choice if you want your payloads delivered to the liver and not much of anywhere else – it tends to concentrate there, and it wouldn’t surprise me if a lot of the coronavirus protein production with the CanSino vaccine is taking place in that tissue. At any rate, an executive with the company has said that their Phase II results will be published very soon, while not missing a chance to take a shot at Moderna for not doing the same (see below), so it’s going to be very interesting to dig through those. Update: apparently the company is looking at a booster-shot regimen, and the same article quotes a Canadian hospital as saying that they are preparing to help with Phase III trials “in the fall”. How well booster shots will work with an Ad5 vector remains to be seen.

    Johnson & Johnson (Janssen): J&J, on the other hand, is working with a different adenovirus platform, Ad26. That’s a much rarer strain, and very few people have pre-existing antibodies to it. They’ve been investing in this for years now, and the coronavirus epidemic has, as it has for so many other areas, accelerated things past anything that was contemplated before. This is the time to mention, though, that it’s not just the pre-existing response that can be a problem – if you raise too vigorous a response to the new viral vector you can cause trouble, too (and, as mentioned, perhaps wipe out the chances to ever use that particular vector for anything again). No big announcements since the company said that they were speeding up human trials to first dosing in July.

    Gamaleya Research Institute: Those previous entries are a good lead-up to this one, because the Russian GRI vaccine is a mixture of Ad5 and Ad26 vectors. To be honest, I’m not sure of the thinking behind giving both, but it will be an interesting comparison with the Chinese and J&J efforts, for sure. This work made headlines not long ago when the head of the institute let it be known that he and other workers there had actually injected themselves with their own candidate vaccine (!) This was not, he said, an attempt to prove safety, but rather a means to protect the staff while they were working with the coronavirus itself. One would suspect that the Russian language, with its rich stockpile of phrases, would have a metaphor similar to the English “putting the cart before the horse”, wouldn’t it? At any rate, this one has gone into human dosing in Russia.

    Reithera: This Rome-based company is taking a similar approach to the Oxford group, in that they have a gorilla-infecting coronavirus platform that should be immunologically novel in a human population. Data are scarce, although the company has said that they expect to go into human trials “this summer”, and some stories on them say July.

    Altimmune: Here’s another adenovirus vector, but administered via a different route. They’re going intranasal, and thus hoping to bring in a mucosal immune response as well. Since this seems to be the same platform as their earlier Nasovax influenza vaccine program, I will assume that this is also an Ad5 vector. This one is still listed as “preclinical” on the company’s web site, with such studies taking place partly at the University of Alabama-Birmingham. It’s good to see another technique being applied here; we’re going to need all the shots on goal that we can get.

    Merck/Iavi: Now here’s a non-adenovirus vector. Merck’s partnership with nonprofit Iavi is around vesicular stomatitis virus (VSV), which is what was successful in the development of the Ebola vaccine. In that case, the gene for the VSV glycoprotein was replaced by one for the Ebola protein, and I would assume that something similar will be done to swap in the coronavirus spike protein here. Merck is expected to use the same Vero cell line production for this that they used for making the Ebola vaccine and for their rotavirus vaccine. That last one isn’t a VSV vector, but rather a group of mixed bovine-human rotavirus strains – but for all of these you need cells to serve as factories to crank out viral particles for you. I have seen no projected date for first-in-human dosing for this one, though

    Merck/Themis: In another non-adenovirus move, Merck had been collaborating with Themis on using attenuated measles virus as a therapeutic, platform, and about a month ago they announced that they were buying them outright. The attenuated measles vaccine (see below for attenuated viruses in general) has a very good safety record and has long been considered an attractive candidate for repurposing, and now we’re going to find out how that works rather before we thought we would. The plan is for this to go into patients sometime later this year.

    Vaxart: Now, these folks I had not heard much until the other day, when they popped up with a surprise press release saying that their vaccine candidate had been selected as part of the government’s “Operation Warp Speed” for a challenge test in primates. They have a platform developing oral vaccines – an adenovirus vector delivered in a coated tablet to get past the stomach and into the small intestine. (There’s an immediately obvious difference this route and the injectables in ease of storage and administration, which might be quite advantageous). This “mucosal immunity” technique will be familiar to many via its use in the oral polio vaccine, and the differences between it and the immune response generated by injection are quite complex. Vaxart hopes to go into Phase I later this year, and it will be very interesting to see what happens in the primate study and in humans. This route could turn out to be noticeably better or noticeably worse than other the efforts in the category, or might even end up as an adjunct to another vaccination route. I’m very glad that we have a completely different approach being looked at. (Update: corrected and moved the category on this one; I’d initially thought they were using just recombinant proteins).

     

    Genetic Vaccines:

    These take DNA or RNA coding for coronavirus proteins and inject that directly into the bloodstream. “Directly” isn’t quite the right word, though – for these things to work, they have to be formulated and modified to survive destruction in the blood, to be taken up through cell membranes, and to be used for protein production once they’re inside. There have been extensive experiments in animal models over the years, but this is another category where no existing human vaccine uses the technology (yet!) Advantages include fast development and (possibly) ease of manufacture, depending on how exotic the final form turns out to be, and lack of an existing immune response to the vaccine itself (as seen with some of the viral vectors above). The big disadvantage is, well, once again no one has taken these things into humans yet. And another one is that some of these may need to be stored at not even the usual cold-chain conditions (which are enough of a logistical problem, thanks, particularly outside the industrialized countries) but even colder than that to keep them stable (for example) – an underappreciated problem, perhaps, that we’ll have to keep an eye on. Others have been shown to be stable without cold chain storage, so there’s clearly a wide variation.

    Moderna: mRNA1273: this one, the leading mRNA vaccine candidate has been getting a lot of the coronavirus vaccine headlines, of course. They’re still heading for Phase III in July, and have signed up with Catalent (who are also working with J&J) for support in vaccine production, labeling, and distribution for that effort. This in addition to their own production work and the deal that they’ve already signed with Lonza in Europe. The company’s CEO said earlier this week that the best-case timeline had them with efficacy data before Thanksgiving, and yeah, I believe that would be the “everything goes flawlessly the first time through” situation. What we haven’t seen are many more details about how the vaccine has been performing so far. All we have is that small mid-May press release, and it’s been a while, hasn’t it? At some point, there’s going to be a dumptruck of data that will have to be released on this one, and until then we’re all just sort of tapping our collective feet. Update: well, it turns out that Moderna’s Phase III will be delayed a couple of of weeks – and it appears from this story that one reason is that the company has been arguing with the NIH and the FDA over how that trial should be run. As of July 7, their Phase I data have yet to be published.

    Pfizer/BioNTech: Not much news here, but we definitely will be getting some. This effort started out with four different mRNA approaches, and there’s no word on if they’ve narrowed things down yet. Pfizer’s CEO Albert Bourla said recently that they’re sticking to a strict policy of not commenting on their vaccine results until they’re published in a journal. He also emphasized that they are not part of the government’s “Operation Warp Speed” effort, saying “We don’t take the money because we don’t need the money”, and believes that doing so would just slow down the company’s own efforts. They’re also planning for about 30,000 patients in their eventual Phase III trial, with about 100 sites (US and international). The number of drug companies that can organize (and pay for) something like that with cash-on-hand can be easily counted on your fingers, and Pfizer is certainly one of them. The company has also said that their best-cast timeline has a possible emergency use authorization in October (!), which will also require everything to ring the bells exactly on time. Not everyone believes that’s possible, but hey, we’ll find out pretty damn soon, won’t we? Update: initial Phase I data are out the first of their four candidates, and look good so far.

    Inovio: this DNA vaccine candidate (INO-4800) is getting messy. The company had sued their manufacturing partner, VGXI, claiming that they were in breach of contract and holding up Inovio’s program because they could not fulfill their targets for delivery. A judge has just ruled against Inovio’s request to force disclosure of VGXI’s proprietary manufacturing techniques. For my part, I was already out of sympathy with Inovio after their announced early on in the pandemic that they had produced a vaccine in about three hours, when what he was actually talking about – as people who know any molecular biology whatsoever realized instantly – was a candidate construct for a possible vaccine. That brought on shareholder lawsuits, as the shares were whacked back and forth like a tennis ball between enthusiastic dice-rolling long investors and you-gotta-be-kidding-me short-sellers. I should note that the company has a stock market following that is need of therapy all by itself. Anyway, at this stage, a serious vaccine player should be talking about where they’re going to round up all the glass vials, where the sterile production lines are, how they’re going to handle the logistics for tens of thousands of clinical trial doses, and so on. Not off hammering on their contractual partners in the Montgomery County Court of Common Pleas.

    CureVac: hey, remember these guys? Back in March, there was a flare of a story about how the US had allegedly tried to buy up the company (or the rights to any mRNA vaccine they produced), with sourcing of the news to irate members of the German government. There hasn’t been anything quite that lively around them since, but they recently got a 300 million Euro investment from the German government (who now own 23% of the company). They have continued to state that they expect to go into Phase I human trials before the end of June, which means that they have about 28 hours to go (Central European Time), as I write this.

    Imperial College: this is another mRNA candidate, but it’s a self-amplifying one, like one of the four Pfizer/BioNTech variations – these are the only two that I know of using this technique. The vaccine went into human volunteers just a few days ago. The way these things work is to deliver messenger RNA that codes not only for the antigen protein of interest, but for an RNA polymerase enzyme (there’s a useful one that’s been borrow from alphaviruses) that will turn around and make more copies of the mRNA itself. The idea is that you can then dose with much smaller amounts of material, since it’s going to go out and make more of itself anyway.

    Sanofi/Translate: this one is still scheduled to go into human trials in December. Sanofi has recently expanded their collaboration with Translate in this area, but I haven’t been able to track down details on the vaccine itself. There are an awful lot of ways to deal with the problem mentioned in the intro to this section, though, and I would expect this to be a different run at them than the other mRNA players have taken. Given that we have no idea how these things are going to perform in human subjects, a diversity of opinion is no bad thing.

    Genexine: this South Korean company’s DNA vaccine, GX-19, has started human dosing. These folks and Inovio seem to be the front-running DNA vaccine players for now; everyone else in this category is RNA. I would assume that none of this testing is going to be done in Korea itself, though, since COVID-19 levels are so low there (and good for them).

    AMMS/Abogen/Walvax: this is the first mRNA coronavirus vaccine in China, and was recently approved for human trials there. An interesting feature is that it’s said to be stable at room temperature for up to a week – rather surprising for an mRNA construct, but something to keep an eye on.

     

    Recombinant protein vaccines

    Here we get to a technique that really is used for human vaccines. The previous two categories force your own cells to make viral antigen proteins, but here you’re making them industrially and just injecting them directly. The advantage can be that such protein production can be accomplished in many different ways and is already done on a large scale. That said, every new protein is a new project, with its own idiosyncrasies. A disadvantage is that this technique sometimes does not produce enough of a robust immune response by itself (at reasonable doses of protein, anyway), and needs added “adjuvants” as part of the vaccine formulation. These are substances that increase immunologic reaction – through mechanisms that honestly have not always been so well understood over the years (more here) and you’ll see these in the entries below.

    Novavax: The company has been raising significant amounts of money as they push on with their recombinant vaccine (a Spike protein produced in an Sf9 insect cell system). Otherwise, there’s very little news – now everyone waits to see their Phase I results! Update: the company has published preclinical results in baboons and mice. And they have received up to 1.6 billion in funding from the US government, bringing their vaccine candidate into the “Operation Warp Speed” portfolio.

    Clover Biopharmaceuticals: These folks are also teaming up with GSK to use their adjuvant, as well as testing their recombinant glycoprotein with another adjuvant from Dynavax. Dosing of these trial arms has already started; they were the second effort in the recombinant protein space to go into humans after Novavax.

    Sanofi/GSK: This one, a recombinant version of the Spike protein along with GSK’s own adjuvant, has also had its timeline pushed up. Dosing was scheduled to start in December, but’s now slated for September, with rollout in mid-2021 if everything works. The GSK adjuvant is the one used in their shingles vaccine, and even before the pandemic the company had planned to make this the centerpiece of their vaccine programs. It’s a mixture of a bacterial lipid from a strain of Salmonella and an extract of the Chilean soapbark tree. “Saponin” compounds of that sort have long been known as adjuvants, but this one really seems to ring the bells. I certainly noticed a reaction when I got the shingles vaccine myself (particularly the second dose).

    Zhifei Biological Products: Basically, all I know about this one is that it’s just been approved to go into human trials. There’s a lot of stuff going on in China – some of it (like CanSino’s) being well published, and some of it almost totally in the dark.

    Queensland/CFL/GSK: Back at the end of April, the team at the University of Queensland announced preclinical results on antibody response to their vaccine candidate. They’re also looking at adjuvants from both GSK and Dynavax, and have partnered with several other companies for production and logistics so far. From what I can see, they’re recruiting patients now to start dosing next month. I’m not sure what the coronavirus situation is in Queensland itself, though – where will the majority of dosing be done?

    Stabilitech: Here’s another small company working on oral vaccines, in this case with recombinant proteins (from what I can see). Their web site seem to claim to have formulations that have been through animal dosing, and says that they are ready to start human clinical trials “pending secured funding”. With all the money sloshing around in this area, I would have to assume that they have knocked on some doors, so we’ll see if this goes anywhere.

    Zydus Cadila: (update) this Indian company has now received authorization from the government to move their first vaccine candidate (ZyCov-D) into human trials. They’re talking up a very aggressive timeline; we’ll see how that goes. They are also, according to that interview, working on some other vaccine platforms against the coronavirus, and I’ll update those as more information becomes available.

     

    Attenuated Virus Vaccines:

    This is another well-precedented vaccination technique. It involves producing a weakened form of the actual infectious virus, one that is not capable of causing damage but can still set off the immune system. There are several ways to do this, and it’s a bit of an art form involving taking the virus through a huge number of replications in living cells as you select for variants that are less and less harmful. An advantage is that such vaccines can be quite effective at raising a response – ideally, the immune system reacts exactly as it would to the real pathogen, except you avoid all the getting-sick part. A disadvantage is that part about it being an art form: balancing the lack of harm with immunogenicity is not something that can always be achieved. Some viruses have a wider window for this sort of thing than others, and it’s not easy (or possible, really) to know if this is a feasible pathway up front. That may well be one reason why (at the moment) I know of no candidate vaccines for this coronavirus that are using this method.

     

    Inactivated Virus Vaccines:

    This is also one that’s also been used in medical practice for many years, and it’s another inactivation step beyond the attenuated viruses. Heat or chemical agents are used to damage the virus to the point that it can no longer infect cells at all, but the plan is for there to be enough of the viral material left unaltered to still raise an immune response. Not the most high-tech approach, but it can definitely work. Many times, though, vaccines of this don’t provide enough of a response in a single shot, so you may be looking at a booster vaccine schedule. Interestingly, the Chinese groups seem to have this field to themselves; I’m not aware of any inactivated-virus vaccine for the pandemic that’s in serious development anywhere else.

    SinoVac: When last heard from, the company had released positive Phase II data – well, some data. The full report on the trial is not out yet, but two weeks ago they issued a statement saying that over 90% of the participants had neutralizing antibodies at 14 days after dosing. That’s good news, but you’d want to see a lot more detail, such as actual antibody titers, and it hasn’t shown up yet (although SinoVac says it’s coming). Their Phase III trial will be starting shortly in Brazil – which given the epidemic situation there at the moment seems like (sadly) a good choice of venue. More on this one when more data show up. Update: dosing in Brazilian volunteers started July 6.

    SinoPharm/Wuhan Institute of Biological Products: This is the one that’s already being given to employees of Chinese state-owned companies who are traveling to high-risk areas overseas, so hey, why bother with clinical trial results? Well, anyway, the organization has announced that antibody titers were “high” in the initial trials, and the the seroconversion rates (at 28 days) were a flat 100%. One would like to see a full paper on these data, but I don’t know when (or if) that will ever show up; SinPharm seems to like to announce these things on Weibo and move on. The Phase III trials will take place in the United Arab Emirates, (and likely other locations as well?)

    SinoPharm/Beijing Institute: This is the other SinoPharm vaccine, and just today the company has announced that it also passed safety trials and generated neutralizing antibodies. But this was another Weibo posting, so that’s all we have. I also have no clear idea about the differences between this one and the Wuhan-originated vaccine – all I know is that they’re both some form of inactivated coronavirus.

    Institute of Medical Biology (China): Last week there was an announcement that this one had moved into Phase II testing, but we don’t know much more. There was a Phase I trial in May (China Daily link) with 200 people, whose results (as far as I can tell) have not been reported, either. Nor do we know anything about the method used to inactivate the virus in this candidate (just like the other two, actually).

    Bharat Biotech: (update) this Indian company has also just received the go-ahead to take their inactivated-virus candidate Covaxin into human trials. This is not without controversy: the Indian Council on Medical Research apparently communicated a timeline to hospitals taking part in the study that is completely unrealistic. How unrealistic? How about a launch by August 15? Which is India’s Independence Day, by what is no doubt a coincidence? This does not inspire confidence.

     

    Virus-Like Particles

    Here’s yet another category, which can be thought of as a “stripped virus”. A VLP has most or all of the surface proteins of the real virus, but doesn’t have the genetic payload inside, and therefore cannot replicate. But the immune response that develops to the surface antigens is still available. This technique is already used for vaccines against HPV and Hepatitis B, so it’s proven that it can work well. You have several options for preparing such VLPs, mixing and matching material from the natural virus (or more than one natural virus) and recombinant proteins.

    Mitsubishi-Tanabe/Medicago: this is one of the companies that is producing recombinant proteins in tobacco leaves. This idea has been around a while, because the plant can produce reasonable yields of well-folded proteins that can have different glycosylation states than the ones produced by other platforms. As that last link shows, though, uptake of this technology has not been as quick as people once expected – improvements in the more traditional platforms (and the long experience with them) make this a difficult market to crack. But vaccines are a good place to be, because the plant-derived proteins may in fact be more immunogenic because of those glycosylation patterns. Medicago has announced that they are going into human trials with a plant-derived virus-like-particle coronavirus vaccine before August.

     

    OK, sheesh. There’s the state of the business as of today. I hope to use this post as a standing reference point for a little while to come, so I will be coming back in to update it as more news shows up. Right now we’re at an awkward age for vaccine development against this pathogen. Not all of these approaches are going to work, or at least not well enough to be useful. And we don’t have enough data on any of them to even start to guess which those might be. We can’t even do Phase II data comparisons, and the crucial Phase III data don’t even exist yet. So we’re going to be hanging in this limbo of “lots of things going, not sure about any of them yet” for quite a while. It’s going to get exhausting – what’s that, you say it’s kind of exhausting already? Hah – just you wait. . .

    Demand for flu vaccine soars as countries plan for second Covid-19 wave

    Manufacturers warn they will struggle to meet demand as governments seek to ease pressure on health services

    Fears of a second wave of coronavirus have sparked a global scramble for influenza shots from countries that hope to vaccinate great swathes of the population to reduce pressure on their health services.

    Health officials in the UK are considering whether to offer flu shots to everyone as part of planning for a resurgence of coronavirus in the autumn, but with other countries hitting on the same strategy, demand for flu vaccines has soared.

    Continue reading…

    The Lancet’s editor: ‘The UK’s response to coronavirus is the greatest science policy failure for a generation’

    Richard Horton does not hold back in his criticism of the UK’s response to the pandemic and the medical establishment’s part in backing fatal government decisions

    There is a school of thought that says now is not the time to criticise the government and its scientific advisers about the way they have handled the Covid-19 pandemic. Wait until all the facts are known and the crisis has subsided, goes this thinking, and then we can analyse the performance of those involved. It’s safe to say that Richard Horton, the editor of the influential medical journal the Lancet, is not part of this school.

    An outspoken critic of what he sees as the medical science establishment’s acquiescence to government, he has written a book that he calls a “reckoning” for the “missed opportunities and appalling misjudgments” here and abroad that have led to “the avoidable deaths of tens of thousands of citizens”. 

    In being shielded, he has learned the true significance of key workers… ‘they are making society work’

    Related: UK failures over Covid-19 will increase death toll, says leading doctor

    Whitty is in the middle of viral storm… it’s debatable whether he’d increase public confidence by acknowledging he got it wrong

    Continue reading…

    FLU-PRO©: InFLUenza Patient-Reported Outcome

    Access the on-demand webinar now https://bit.ly/FLU-PRO The FLU-PRO is a self-administered patient-reported outcome measure (PRO) to quantify symptom severity in influenza and influenza-like illness. The instrument was developed by a team of academic investigators spanning multiple sites across many countries under the direction of Dr. John H. Powers of George Washington University and the University […]

    The post FLU-PRO©: InFLUenza Patient-Reported Outcome appeared first on PharmaVOICE.

    Healthcare Headlines: November 2019

    <h2 class="heading-medium">Medicare Shared Savings ACOs Generated $1.7b In Savings In 2018
    </h2>
    <p>CMS announced that the 2018 Medicare Shared Savings Program generated $1.7 billion in total savings. It also reported that ACOs in the shared savings and risk-based models saw reductions in per-enrollee spending. ACOs that took on downside risk generated more savings than ACOs that did not. See the full report for more on how ACOs are trending.&nbsp;<a href="https://www.healthleadersmedia.com/finance/medicare-shared-savings-acos-generated-17b-savings-2018" target="_blank" aria-label="Read more about Medicare Shared Savings ACOs Generated $1.7b In Savings In 2018">Read more</a></p>
    <h2 class="heading-medium">Number Of Certified Physician Assistants Surging
    </h2>
    <p>The U.S. Bureau of Labor Statistics projects 31% growth in the PA profession from 2018 to 2028, which the federal agency characterizes as "much faster than average" compared to other occupations. With the anticipated physician shortage, many think that physician assistant participation in clinical care teams is the solution. Check out the full analysis for more on the shifting role of PAs.&nbsp;<a href="https://www.healthleadersmedia.com/welcome-ad?toURL=/clinical-care/number-certified-physician-assistants-surging" target="_blank" aria-label="Read more about Number Of Certified Physician Assistants Surging">Read more</a></p>
    <h2 class="heading-medium">CDC Updates Guidelines To Prevent Infections In Health Care Personnel
    </h2>
    <p>The Centers for Disease Control and Prevention released an <a href="https://www.cdc.gov/infectioncontrol/guidelines/healthcare-personnel/exec-summary.html" target="_blank">update</a>&nbsp;to its 1998 guidelines to prevent and control infection in the health care workplace. While the guidelines are intended for health care leaders and staff who address workplace health and safety, the guidelines themselves apply to a broader range of health care settings than before. Read the full guidelines for more on ways to prevent infections in your setting.&nbsp;<a href="https://www.aha.org/news/headline/2019-10-21-cdc-updates-guidelines-prevent-infections-health-care-personnel" target="_blank" aria-label="Read more about CDC Updates Guidelines To Prevent Infections In Health Care Personnel">Read more</a></p>
    <h2 class="heading-medium">More ACOs Taking On Downside Risk, Analysis Finds
    </h2>
    <p>Research shows that ACOs participating in the Medicare Shared Savings Program are increasingly moving toward downside financial risk through value-based contracts. The percentage participating in downside risk programs has grown from 2% the first performance year of the MSSP (2012) to approximately 30%. Check out the full article for more on these trends and the implications of downside risk.&nbsp;<a href="https://www.healthaffairs.org/do/10.1377/hblog20191020.962600/full/" target="_blank" aria-label="Read more about More ACOs Taking On Downside Risk, Analysis Finds">Read more</a></p>
    <h2 class="heading-medium">60% Of Younger Patients Will Switch Healthcare Providers Over A Poor Digital Experience: Survey
    </h2>
    <p>Half of consumers say they are frustrated about their provider&rsquo;s lack of adoption of digital administrative processes, such as online bill pay, access to insurance information and digital pre-appointment forms, according to a recent survey. What&rsquo;s more striking is that many patients are willing to ditch their healthcare providers for their slow adoption of modern technology &ndash; 41% said they would stop going while 1 in 5 said they had already stopped or switched providers over a poor digital experience. Read the full article to avoid these pitfalls.&nbsp;<a href="https://www.fiercehealthcare.com/tech/60-younger-patients-will-switch-healthcare-providers-over-a-poor-digital-experience-survey" target="_blank" aria-label="Read more about 60% Of Younger Patients Will Switch Healthcare Providers Over A Poor Digital Experience: Survey">Read more</a></p>
    <h2 class="heading-medium">Rapid Expansion Of Telehealth Comes With New Challenges
    </h2>
    <p>The growth of telehealth is being met with regulatory risk that is largely due to the interplay between state regulations and federal policies, and the fact that state regulations widely vary from one to the next. See the full text to learn more about how these challenges, especially those related to reimbursement, are inhibiting the full potential of these new delivery methods.&nbsp;<a href="https://www.statnews.com/2019/10/21/telehealth-rapid-expansion-offers-challenges/" target="_blank" aria-label="Read more about Rapid Expansion Of Telehealth Comes With New Challenges">Read more</a></p>
    <h2 class="heading-medium">Knock Pressure Injury Rates Down To Zero: 5 Ways
    </h2>
    <p>In 2018, the Dermal Defense Team at Temple University Hospital set out to achieve zero Stage 3 and Stage 4 pressure injuries developed by patients after a hospital admission. Through education, risk assessment, and other prevention protocols, the goal was met. Learn the 5 strategies they used to achieve success in preventing pressure injuries.&nbsp;<a href="https://www.psqh.com/news/knock-pressure-injury-rates-down-to-zero/" target="_blank" aria-label="Read more about Knock Pressure Injury Rates Down To Zero: 5 Ways">Read more</a></p>