7 dec Episode 92 News and Views on COVID vaccines

Mon, 12/07/2020 - 14:48

Episode 92 News and views on COVID vaccines:

Dear colleagues,


This episode is a bit “lighter” than the previous one.  I summarize the reflections on the fast developments in the COVID vaccine field over the last month, mainly based on editorials and comments in Nature and Science-related journals.


  1. COVID-19 vaccines buoy hope (Nat Rev Drug Discovery 4 Dec): summarizes the results that were released in the press:
  • Pfizer-BioNTech mRNA: 95 % efficacy = 170 infections with only 8 in active vaccine arm
  • Moderna mRNA: 94 % efficacy= 196 infections with 11 in active arm. No severe disease in active vaccine arm.
  • AstraZeneca Chimp Adenovirus vector: 131 confirmed cases with 19 in one of the vaccine arms. Overall efficacy = 70 %, but 90 % in a subset of participants that only received half “prime” dose.
  • Russian Gamaleya Sputnik V Adenovirus 5 + 26 claims 91 % efficacy, based on 39 confirmed cases of SARS-CoV-2. 


  1. The challenges of COVID vaccination  (Nature 26 Nov 2020) and The UK has approved a COVID vaccine — here’s what scientists now want to know(Nature 3 Dec 2020).  
  • Lack of transparency about the data: only press releases, no formal publications.
  • It seems that only AstraZeneca was testing the participants systematically on SARS-CoV-2 By PCR regardless of symptoms, while the others only tested when symptoms occurred. 
  • Hence the question: is the vaccine protecting only against symptomatic infection or also against transmission and severe disease?
  • To put it in a different way: it is not excluded that a vaccine induces partial and a bit retarded immunity with a very mild upper respiratory infection but solid protection  against severe (i.e. lower respiratory tract) infection. If this is the case, onwards transmission is still possible and very vulnerable subjects (e.g. very old people with comorbidities)  might still be susceptible and get ill…  
  • Hence the question: What is the efficacy in high risk groups (elderly, obese, diabetics …)? (Only a small proportion of the participants were older than 65 and it is unclear whether people with comorbidities were included).
  • Data in children; pregnant women?
  • What is the commitment of different actors to make vaccines available in LMIC?


  1. Temperature concerns (Science 16 Nov 2020)

mRNA vaccines in lipid nanoparticles generally require freezing (Moderna -20; Pfizer -70)


  • CureVac develops a more “compact” mRNA vaccine that could be stored in a refrigerator
  • Freeze-drying to store at 4 °C?


  1. Questions about the AstraZeneca trial(s) (Wired 26 Nov 2020). In this paper, serious questions are asked about the set-up and the reporting, because of several “unorthodox” elements:
  • AstraZeneca has set-up several trials (UK, Brazil, US) with different populations, different doses, different controls. 
  • The US trial was halted for a long time, because of safety concern.
  • They reported on a subset of the results in UK and Brazil, apparently leaving out some parts and it is not explained why
  • The “strongest” protection (of 90 %) was obtained in a subset of the Brazilian study, where a “mistake” was made (only half of the first dose was administered).  

Clearly, we need more transparency!


  1. How COVID vaccines are being divvied up around the world (Nature 30 Nov 2020):
  • Capacity for 2021:  Astra-Zeneca, Pfizer-BioNTech and Moderna together could provide 5.3 billion doses (enough for 2.6-3.1 billion people) + Gamaleya (Russian) enough for 500 million outside Russia.
  • AstraZeneca committed to make the vaccine available at cost price (= 3-4 USDà during the pandemic and maintain this price for LMIC , while price is 5-10 X more for mRNA (Pfizer, Moderna), who intend to make profit. 
  • EU + other rich countries (Canada, US, Australia, Japan, Swiss, Israel…)  have secured half of those vaccines, while representing only 13 % of world population.
  • Expansion of ongoing production + 6 other candidate vaccines would provide another 10 billion doses    
  • India has secured more than 2 billion doses of vaccine, in part by leveraging access to the manufacturing capabilities of the Serum Institute of India in Pune, the world’s largest vaccine maker.
  • 189 LMIC  seem to be relying on contributions from COVAX, a joint fund for equitable distribution of COVID-19 vaccines led by Gavi, a funder of vaccines for low-income countries based in Geneva, Switzerland, the World Health Organization, and the Coalition for Epidemic Preparedness Innovations (CEPI) in Oslo. It has secured an estimated 700 million vaccine doses so far and wants to provide 2 billion by the end of 2021, with the aim of providing coverage to at least 20% of the population of participating countries.


  1. The dilemmas of emergency approval (Nature 3 Dec 2020):
  • After emergency approval, participants in the placebo arm will likely request the vaccine, which will complicate the evaluation of long-term efficacy and safety, because the control group will disappear.
  • Even participants in other trials might quit to receive an approved vaccine.

→ Monitoring efficacy and safety in high risk group (without real  placebo control) might be the only viable option.

  • It will be more complicated to test new vaccines: “placebo controls” might be replaced by “approved vaccine controls”: and the new vaccine should then prove not just efficacy and safety, but immediately “superiority”.


  1. The ethical aspects are worked out further by David Wendler from NIH in:  Trial ethics once we have an efficacious vaccine (Science 3 Dec 2020).

7.1.  If a vaccine candidate is found to be safe and efficacious in a placebo-controlled trial, should the researchers continue that trial as designed or provide the placebo group with the vaccine?

- Usually FDA requests results of more than 1 phase 3 trial before approving for marketing.  This is not the case here, because FDA may grant Emergency Use Authorization, based on incomplete results of a single trial and before FDA marketing approval.  

- The authors, however, disagree that it would be per se unethical to continue the double blind trial, because a trial is distinct from clinical care and it is perfectly OK according to trial guidelines “to expose participants in clinical trials, including vaccine trials, to some risks to collect socially valuable data that cannot be obtained in a less risky way”.

- The “social value” to continue the double blind is that it creates more confidence in the result, because of longer follow-up for both (duration of) efficacy and occurrence of side-effects.

- The risk to participants, however, in the setting of few effective treatments and potentially strained hospital systems, receiving placebo for an extended period rather than a safe and efficacious vaccine can pose substantial risks.

- There is a formal obligation to inform participants about  results that might influence their willingness to stay in the trial or leave it.  

- Therefore, individuals at low risk of severe disease could stay in the blinded trial, whereas high risk participants should be unblinded and either offered the vaccine within a redesigned study or given the opportunity to seek the vaccine outside the trial.

7.2. Should researchers continue to test other vaccine candidates using placebo-controlled trials?   

- Clearly, even if a few candidates show efficacy and safety, there may be room for other candidates to test: might be more effective, generate longer-lasting immunity, work better in certain subpopulations, provide greater protection against severe disease, or prevent infection better and they might be less costly, requiring less difficult storage conditions etc…

- New candidates will have to be tested NOT against placebo, but against proven vaccine →this will require larger sample size and extended duration.


  1. An optimistic note by Denis Burton: Towards superhuman immunity (Nat Med 30 Nov 2020).

The authors remind us that some vaccines induce less longstanding immunity than natural infection, but there are several examples where vaccination induces stronger and longer protection than the infection. In the bacterial world: tetanus and Hemophilus Influenzae type B (when protein-conjugated polysaccharides are used), but also in the viral world: varicella vaccine is better at preventing shingles than natural infection and (tetra- or nona-valent) Human Papilloma virus-like particles induce longer lasting immunity than individual HPV serotypes 

My conclusions: Like all of us, I’m very happy with the prospect of getting vaccinated unexpectedly soon against COVID, because considering the world from my study room only gets a bit boring. Since I worked on mRNA myself, I’d prefer such a vaccine;  if possible the upcoming CureVac one, since I visited them 10 years ago in Tübingen and I trust these scientists most. 

But what worries me is….

  • The lack of transparency by all the producers is very annoying and in my view counterproductive, because it gives arguments to the antivaxxers, that, as an honest scientists, we cannot counter, as long as we cannot see and judge the data.
  • The lack of ethical consistency by the same producers: they swore holy oats that they would share information, work together, make the vaccines available to everybody in the world etc.  But what we see today looks more like games of power, prestige and (financial) interests amongst companies, individual states and “unions” (like the EU and the US), while international organizations (like WHO and COVAC) as well as LMIC are left behind.   
  • While COVD did not improve socio-economic relations, it has resulted in profound changes of our scientific practice:
    • We publish, read, discuss and quote pre-prints much more than peer-reviewed work, which is worrisome: there is no time for critical reflection.  
    • Even more importantly, it will become very difficult to pursue the quest for the best possible COVID vaccine (optimal balance between efficacy, safety, cost and availability), since vaccine trials will become even more complicated and costly than they already are now….