30 Jan COVIDOLOGY 106 Reflections on breaking variant and vaccine news

Sat, 01/30/2021 - 10:22

Dear colleagues,

Yesterday we have been bombarded by news about new vaccines: approval of Astra Zeneca by EMA and positive results from AD26 (Janssen) and protein-based Novavax.  Unfortunately, all this news has not been accompanied by scientific publications and, at least in my mind, many questions remain. Since new year the big question is how good vaccines will protect us against the new variants (UK, South-Africa and Brazilian).  Therefore, I will first summarize the literature of the past week on the variants and discuss the emerging vaccines afterwards.

Par 1 How resistant are the new variants? (see slides)

    1. The paper by Sadine Cele (Ep 106-1 and slides 2-3) shows a dramatic decrease of sensitivity of the South-African variant for convalescent sera from the 1st wave.  This study is well done and is the  only one that uses whole virus.  No doubt: the variant is an escape mutant and it is likely that it will result in re-infections.
    2. The paper by Kai Wu (Ep 106-2 slides 4-5) uses sera from Moderna vaccinated subjects and shows that they neutralize the “Mink mutant” well, there is a small decrease for the UK variant, but a full log decrease for the South-African variant.
    3. The paper by Wang (Ep 106-3 slides 6-10) is the most insightful.  It first analyzes the position of the various mutations of the UK and SA variant, showing that some of them are in the receptor-binding domain and others in the N-terminal domain, which includes an “antigenic supersite”: both sites are known to be important as targets for neutralizing antibodies (slide 6).  
  • In slides 7 and 8 the relative resistance to convalescent sera is analyzed: 2-4 fold forb  the UK variant and 10-35 fold towards the SA variant.  For the latter the mutations in D215G and 242-244 deletions in the NTD supersite plus the E484K in the RBD are important determinants.
  • In slide 9 and 10, the resistance to Pfizer and Moderna sera shows again that the UK variant remains sensitive (only 2 X less), but that the SA variant is more resistant (almost 1 log).  For the latter, the E484K is crucial.

The latter two studies have been done by pseudoviruses: replicating the envelope of a VSV or HIV reporter virus by the spike of SARS-CoV-2.  This is of course a nice system, but it is more sensitive to neutralizing antibodies than real virus. In other words: the resistance of the “real” variant viruses to convalescent or vaccinated sera might be more pronounced, which indeed is suggested in thye first paper (Cele).   

Slide 11 illustrates the molecular relationship between the mink, UK, SA and Brazilian variants.  It is to be expected that the Brazilian will indeed behave like the SA, because it shares several mutations, including the E484K.    So clearly, these mutants illustrate the concept of “convergent evolution”: similar patterns arising in various parts of the world as an “adaptation” (escape) of this “young and versatile” virus to its novel human host.  

Par 2 The “novel” vaccines

2.1. Astra-Zeneca.  This is the link to the statement by EMA: https://www.ema.europa.eu/en/news/ema-recommends-covid-19-vaccine-astrazeneca-authorisation-eu

My understanding is that the approval is based on the published data in the Lancet: the Brazilian part of the Voysey paper (Ep 106-4) and the Ramasamy paper (Ep 106-5), similar to the UK authorities? (Ep 106-6).  

To be honest, I get a headache of the Voysey paper,  because it has many issues: they changed the vaccine supplier, the way the dose was calculated, the dose was halved and the second dose postponed in an unplanned fashion (because of interruption of supply?)  And it seems to me that the crucial question about efficacy in elderly still rests on limited data.  (Comorbidities were sufficiently covered).

These are difficult times, but normally, as an evaluator, I would say to the company:” Interesting data, but please repeat you trial and do it properly this time: use the same batch of vaccine throughout, include at least 30 % of 65 + in your trial, use a standard dosing and timing (or include enough subjects to compare two or three schedules).

Although one of the studies (the major one?) was in Brazil, we have no idea whether the new Brazilian variant (P1) was already circulating at the time of the trial.  

 

Anyhow, we might know more once the full EMA file will be released “in a few days (?)”, as they state….

 

 2.2. Janssen: according to the press release by Johnson and Johnson (Ep 106-7) and in Nature Briefings (Ep 106-8), this looks better:

- The trial has been done in a consistent way with one dose

- Enough 65 + were included (over 13,000)

- They also claim that 95 % of the cases were due to the new SA variant.

- The level of protection against severe disease was 72% in the United States, 66% in Latin America and 57% in South Africa, 28 days post-vaccination.

 

I also include some of the preparatory papers (Ep 106-9 and EP 106-10), which show the thoroughness of their preparation.  But, of course, I would prefer to see the “real data” of phase 3, before making a final judgement.

 

2.3. Novavax: this is the first protein based S vaccine, which uses an interesting new adjuvant, enhancing the potency of the vaccine and stimulating the T cell response as well.  The pre-clinical studies were promising (Ep 106-12, 13, 14)  Although this vaccine was very potent (85%) to prevent disease in Britain, it was only 50 % effective in South-Africa, at the time that the variant was already dominant.  I did not see a breakdown according to age or comorbidities….

From these data (without insight in the phase 3), it is difficult to say whether this vaccine is equivalent or not to the Janssen Ad26….

 

Clearly, as of today, it looks as if the mRNA (Moderna and Pfizer vaccines) are clearly superior to the Ad vectors (A-Z, J§J) and protein Novavax, but:

  • There are no data on the efficacy of the mRNA vaccines on the new varints (they were in trial before these variants were circulating)
  • Protection against severe disease seems acceptable for all these vaccines
  • The vector and protein vaccines require less strict cold chains (no freezers).
  • We have no clear idea yet to what extent any of these vaccines can prevent infection and transmission….

Obviously, these are very preliminary thoughts.  Tomorrow there may be new insights.

If any of you has more or different info, please share!

Enjoy the WE!

Guido