13 Dec Episode 94 Deeper analysis of phase 2 trials of COVID vaccines: knows and unknows

Sun, 12/13/2020 - 20:09

Dear colleagues,

Based on a request, I interrupted my search for innovative vaccines and turned to safety and immunogenicity of the vaccines that are in phase 3 or already being rolled out, based on published evidence in phase 1 and 2 studies. see Table in annex and papers at  

It is not easy to compare different candidate vaccines or even understand the details of the set-up of phase 2 trials in each vaccine and there is no consistency in reporting. The numbers in the table are sometimes “deduced/inferred”, because it was difficult to find exact comparable data. 

For immunogenicity, I focused on the percentage of subjects who had neutralizing antibodies in a classical neutralization test with live virus. All vaccines that were tested in 2 doses reached 100 % for this parameter, but that does not mean that they are equivalent, as the neutralization tests differ in technical details and the titers cannot directly be compared. In some cases a comparison is made with neutralization by a number of convalescent plasma, but that is also very relative and depends on which plasmas were chosen.   In other words: standardization is completely lacking!

For safety, the reporting was also very different. I just tried to understand what percentage of participants showed any side effect, or any local side effect or fever (as the most objective systemic side effect). My interpretation is that the overall order of side effects is Adeno > mRNA > inactivated, but that is a personal impression more than a scientific fact.

Some remarks:

  • As I already wrote before, I’m rather impressed by the good results of these two inactivated (Chinese) vaccines.  The preclinical work on these two has been very extensive and transparent as well.  Besides the biohazard during production, the only conceptual weakness is that no T cell responses have been studied. 
  • All Adenoviruses seem rather reactogenic, especially at high doses (1011 pfu or more). 
    • It looks as if the development of Cansino Ad 5 was interrupted, because only a single dose is used and the announced study with two doses has not been published.
    • The data for the Russian vaccine are based on small groups of rather young people that were not randomized.  Not very professional.
    • For the Janssen Ad 26 vaccine, only “blinded” safety data are given. It is very difficult to understand what they mean. 
  • For mRNA vaccines, it is annoying that Pfizer is not specific about which placebo they used in the  control group and Moderna even doesn’t mention a placebo group at all. 
  • Only Janssen (Ad26) and Moderna (mRNA1273) have included a separate group of older subjects in their phase 2. The relatively good news is that in those studies older individuals showed a final immunogenicity equivalent to the younger groups, but it builds up slower.  Also reactogenicity (side effects) tends to be lower in older subjects.  Older people with underlying conditions were, however, excluded and that is of course the most important part of the population to protect. For the other vaccines we lack info on effects in older subjects and that is really a concern.  

To be honest, I feel very frustrated as a scientist-MD, with a strong conviction about the importance  of vaccines and preventive medicine in general.  Amongst the plethora of COVID literature, the 8 or 9 papers I quote here is about all there really is on published clinical data and they are certainly not as clear and convincing as they should be. 

It is not surprising that the general public will be critical about the use of these rather new concepts, developed so quickly and in such a poorly transparent fashion. Nevertheless there is a lot of  preliminary work done in experimental cancer, HIV and even clinical EBOLA vaccination with these types of vaccines. From that literature, we know that:

  • mRNA has a very good safety track record, but we should note that the side effects are rather linked to the liponanoparticles than to mRNA.  A local inflammatory response in the injection site (muscle), with attraction of myeloid cells (including neutrophils, monocytes and dendritic cells is needed for their immogenicity (see Ref 9).
  • Both human and chimp adenoviruses have been used as vector in EBOLA vaccination, with promising results (Ref 10)
  • A human Adenovirus type 5 used as a preventive HIV vaccine, however, had paradoxical effects: it did not protect against HIV infection and the population with pre-existing immunity against Ad5 had even an higher chance on transmission.  Clearly, the Cansino and the Sputnik V vaccine should therefore be considered with caution (Ref 11).   

People will ask us all kind of questions that I have no answer to, for instance:

- How safe will the various COVID vaccines be on a population level, including in people who have had COVID (without knowing), in elderly, in youngsters, in people with allergic conditions, with co-morbidities and all others who have not or marginally been represented in the various clinical trial phases?    

-  Are the companies asking a “fair price”?  And related: how accessible will these ‘fancy” vaccines be in low-and-middle-income countries?

- Are the “simple” inactivated vaccines not equivalent or even superior to the fancy ones we will get, if you take into account efficacy, safety and price?

My question to all of you: should we not demand that all the data, submitted for regulatory approval by Pfizer, Moderna and others, be published in Open Access, within days after approval is obtained.  How else can we as honest scientists and medical doctors convince the population to get vaccinated?  Should we write a letter to Lancet  to this effect?

But let’s not get cynical. As a distraction, I collected some “COVID cartoons” from the internet. See them in attachment and smile….

Best wishes,




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