23 July Vaccines and human challenges part 1

1. Encouraging results in phase ½ trials.  There seem to be 4 forerunners now: 2 RNA vaccines (Moderna = US and BioNTech = German) and 2 Adeno with inserted S genetic code (Chinese Ad5 and Oxford ChimpAdenoOx1), presented in the same order in attachment. 

• All 4 prototype vaccines elicited high titers of anti-receptor binding domain (RBD) antibodies and very reasonable neutralizing activity, comparable to convalescent sera.  The Chinese Ad5 applied only 1 injection, which may explain lower final titers than the Oxford and the RNA vaccines.
• The three latter studies (but not RNA Moderna) evaluated T cell responses: which showed good Interferon-gamma responses. The BioNTech RNA was evaluated more deeply for T cell responses: both CD4 and CD8 T cell responses were found with a clearly type 1 profile (IFN-g, TNF-a, IL-1, IL12 but no IL4 or IL5).
• With regard to persistence, it is less clear for the Chinese Ad5, since responses have only been recorded until day 28.  Moderna RNA shows a small decline in Ab responses between day 43 and 57; for BioNTech RNA some responses seem to decline between day 29 and 43; for Oxford Adeno  most responses at day 56 are still at the highest level.
• The Adeno vaccines seem to have quite some side effects, which were dose-limiting and could partly be prevented by paracetamol.

In summary: these results are promising.  There are a few caveats and perspectives:

• Ad5 is not an ideal vector as many people have already antibodies and those increase with age, which could hamper the efficacy. Remember the fiasco of the STEP trial (HIV vaccine, based on Ad5, which rather showed enhanced infection in those with pre-existing Ad5 antibodies.  In that respect the RNA and Chip Adeno are better.
• In view of the observed waning of (neut) antibodies after natural infection, it will be important to investigate how stable antibodies (and T cell responses) are on the long run.
• Therefore, prime-boost with RNA and ChimpAdeno might be a future option.

However, we should not forget about the Chinese inactivated vaccine candidate, which was already announced in a preprint of April in bioRxiv.  Now the same results have been published in Science.  In this case challenge studies in non-human primates have already been done.         

2. Human challenges in phase 3? 

A colleague dew my attention for the WHO paper on “Eight key criteria for  for the ethical acceptability of COVID-19 human challenge studies” dated 6 May 2020. In addition I found 3 “opinion” papers from US, UK, Australian and Singapore’s researchers, all arguing that this is the best way forward.  In fact, they echo the criteria from WHO.  It is obvious that such studies should be done on young healthy individuals, preferentially living in an environment, where there is a “background risk” on COVID (but nowadays that could be the entire planet Earth), under optimal research conditions, with informed consent etc….

An obvious advantage is that this could speed up the process, although, as pointed out by Eylal in Fig 1 p.3, successful protection after challenge should still be followed by large scale phase 2, before licensing and    

In my opinion, the above candidates are not yet ready: first animal challenge studies should be done and the likelihood of antibody-mediated enhancement should be excluded, which would require repeated challenge.

Obviously, things may become much easier, if a very efficacious and specific anti-COVID drug becomes available soon….