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Author: Jean-Claude Muller, 穆卓Executive Editor at BtoBioInnovation  jcm9144@gmail.com

SPECIAL REPORT #36

US FDA grants EUA to Pfizer/BioNTech COVID-19 vaccine

The second part of the week was also been highly intense on the COVID-19 front.

Just 24 hours after the Vaccine and Related Biological Products Advisory Committee (VRBPAC) had voted, 17-4 with one abstaining, that the benefits of BNT162b, Pfizer and BioNTech’s COVID-19 vaccine, outweighs its risks, the U.S. FDA issued an Emergency Use Authorisation (EUA) for the vaccine. This EUA, which is not an approval, sets the stage to start the vaccination programme across the various states. Shipments are expected to start immediately and should reach nursing homes allowing elderly subjects to be vaccinated as soon as administrators will collect the waivers from residents and their families.

The VRBP Advisory Committee conviened for eight and a half hours and debated mainly on safety issues and on how to handle long-term follow up studies. In his introductory remarks a FDA representative reminded the panel of the definition of an EUA and gave additional explanations. Under section 564 of the Federal Food, Drug and Cosmetic Act, (FD&C Act) an “UEA may be granted when there are no adequate, approved or available alternatives”. An EUA is not an approval, and several COVID-19 could receive an EUA as long as none of them is approved and/or as long as there is not enough supply to vaccinate the designated population by the CDC (Centres for Disease Control and Prevention).

The main issues raised by the VRBP Advisory Committee were:

– potential lack in enrollment of diversity subjects needed to show that the vaccine was safe and effective in a wide range of ethnicity.

– potential issues related with administration of the vaccine to people with a history of allergic reactions, in particular after the two anaphylactic reactions seen in the U.K.

– concerns about authorising subjects 16 or 17 years old in the final wording. Several panelists believed they should be excluded from the label.

– how to handle subjects, currently in the placebo arm follow-up study, after an EUA would be granted. In other words, should there still be a placebo arm in future studies with the Pfizer vaccine and should subjects currently in the placebo arm be offered the vaccine?

In order to transform an EUA into a full Biological Licensing Application (BLA), the FDA requests more data and in particular a follow-up of at least six months for a new vaccine. Pfizer is expected to present a full BLA in late April.

The VRBP Advisory Committee appointed to review Moderna’s mRNA vaccines is still set for Friday December 19, and analysts forecast that it will issue a similar vote to the one the Pfizer-BioNtech application received.

On Friday December 11, Sanofi and GlaxoSmithKline announced that their partnered COVID-19 vaccine development will be delayed after a phase 1/2 found a low immune response in elderly subjects receiving the investigational vaccine. This adjuvanted recombinant protein-based vaccine triggered adequate response in adults aged 18 to 49 years old but a low immune response in older adults likely due to an “insufficient concentration of antigen”. This clear setback for two of the world leaders in the vaccine field has several consequences:

• The companies will have to start a new phase 2 study, expected to start in February 2021, with an improved antigen/adjuvant formulation, based on a recent positive preclinical study in non-human primates.
• If this phase 2 study is positive, Sanofi and GSK could launch a phase 3 study in the second quarter of 2021 with a possible regulatory submission in late 2021. Consequently the potential availability of supply of the vaccine will be moving from the anticipated mid-2021 to the end of 2021 and possibly early 2022.
• By then, several other vaccines may already have received their EUAs and according to the U.S. FDA definition (see above), Sanofi and GSK may have to apply right away for a BLA and not for an EUA thus adding another six months to get approval.
• It is therefore very likely that several health authorities will request Sanofi and GSK to test their improved formulation against an already authorised COVID-19 vaccine and possibly request a three arm phase 3 study (investigational vaccine – approved vaccine- placebo)
• The expected one billion doses supply by Sanofi and GSK, in 2021, will need to be provided by another manufacturers which will undoubtedly trigger shortage of vaccine all over 2021.

Moncef Slaoui, the co-leader of the U.S government Operation Warp Speed expressed confidence that other vaccines would also be successful. J&J has already enrolled 35,000 subjects in its pivotal U.S. trial which is set to enrolling 40,000 volunteers down from the 60,000 in the original plan. This seems not to be the case with AstraZeneca with only 17,000 volunteers when the FDA was requesting a minimum of 30,000 trial participants for an EUA filing. The U.S. pivotal trial with the AstraZeneca/Oxford vaccine has been on hold for 47 days after a British participant had developed neurological disorders consistent with transverses myelitis which AstraZeneca failed to disclose immediately to the FDA on September 8 during a conference call, according to the New York Time.

Late yesterday evening, AstraZeneca and Gamaleya Institute in Moscow have disclosed a surprising approach namely the study of the combination of the AstraZeneca adenovirus vaccine with the Sputnik V vaccine in order to check if there is an increase of efficacy by giving an initial dose of one vaccine followed by a booster dose of the other. A similar project combining the AstraZeneca vaccines followed by a booster dose of the Pfizer vaccine is also considered to be starting in the U.K. soon.

A study performed by Science suggests now that the Biogen Conference, attended by 175 people in late February in Boston, is likely to have seed between 205,000 and 330,000 infections around the world including up to 1.6% of all U.S. cases. A previous study from the same team had suggested that the conference triggered up to 20,000 infections in the greater Boston area. After the Biogen Conference, 99 of 175 participants fell ill and many had flown back to home states and home countries. Using DNA sequencing a complete reconstruction of the evolutionary tree has been performed. The study for example found that 71,540 cases in Florida had a link to the Biogen Conference.

Paris December 12, 2020

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