22 June 2021 Episode 147 News on mRNA S pmrotein and inactivated vaccines

Dear all,

A quick update on COVID vaccinology

1. Disappointment over Curevac’s mRNA:  Ep 147-1,-2,-3: only 47 % effective.  The most probably explanation is their use of un-modified RNA (in contrast to Pfizer and Moderna), while the lipid nanoparticle is practically identical to Pfizer’s.  This unmodified RNA produced more side effects and therefore the chosen dose of 12 µg is below the Pfizer’s (30 µg) and Moderna (100 µg).   

Clearly, the modification, applied by Pfizer and Moderna, relates to the use of slightly biochemically altered nucleotides, which induce less type 1 interferon and stabilize the mRNA.  We and others have shown in the past that the induction of type 1 IFN by un-modified mRNA can indeed lower the immune responses.  

2. Confirmation of good results for Novavax protein vaccine: 

• Ep 147-4: The trial in US and Mexico showed 90 % efficacy against symptomatic COVID.  Earlier trial in UK was equally positive with a slight reduction in activity against the alpha (British) VOC.  However, the efficacy sank to 49 % in South-Africa, because of the beta VOC.   
• Ep 147-5: this beta VOC issue is being addressed by a beta-variant version, which in homologous and heterologous prime-boost, shows promising results in mouse and primate models.
• Although some US scientists consider it as a “me too” product, as compared to Pfizer and Moderna vaccines I feel it has two advantages over mRNA vaccines:
  • It can be stored at 4°C
  • It is NOT a nucleic acid, nor a virus, but a more “common” protein vaccine type, similar to generally well-accepted vaccines against hepatitis B and papilloma virus (cervix cancer-causing virus)

Therefore, it could overcome practical freezer problems as well as vaccine hesitancy in much of the “Global South” ….at least if it is affordable

3. Mixed news on inactivated virus vaccines

Ep 147-6: Favorable results in United Arab Emirates: two classical Alum-formulated and beta-propiolactone inactivated vaccines from China National Biotec Group were tested and showed 73 % (WIV04 vaccine ) and 78 %  (HBO2) efficacy against symptomatic COVID, with (as compared to mRNA and Adeno vaccines) rather mild side effects.  The authors admit several limitations:

• Mainly young healthy men were included: few women, no pregnant women, few people > 60, no info on co-morbidities
• Hence very few severe cases (only 2 in placebo and none in vaccinated groups)
• No systematic info on asymptomatic infections
• No info on variants, but trial was conducted before VOC were circulating.
• (The latter point may explain that a similar vaccine was “only” 50 % efficacious in Brazil, at a time when the gamma VOC was already circulating).

Ep 147-7: The limitations and questions asked in the previous paper are echoed in a Nature comment, containing a nice comprehensive table with the date from various, mainly inactivated Chinese vaccines.

Ep 147-8: Ciao and other Chinese investigators present results on antibody specificity and function, elicited by the inactivated CoronaVac as compared to a protein RBD subunit (receptor binding domain) vaccine.  They suggest that 3 doses of the RBD vaccine may elicit superior antibodies against the beta (South-African) variant in a pseudovirus neutralization test, as compared to CoronaVac and convalescent patients (recovered from wild-type infection?) Obviously, this interesting and rather unexpected observation needs to be confirmed in a clinical trial.

Ep 147-9:  Ragan et al propose a novel inactivation method, based on “photochemicals” (riboflavin or Vit B2), in combination with UV light, which is supposed to be more gentle to proteins, as compared to “chemical” inactivation (such as formaldehyde or beta-propiolactone (the latter used in all presently available inactivated SARS-CoV-2 vaccines).  They rather convincingly show that it works fine in protecting the very susceptible Syrian hamsters from SARS-CoV-2 and COVID, but unfortunately, a comparison with beta-propiolactone is not provided…

Ep 147-10: a preprint tries to evaluate the effect of rapid roll-out of mainly Coronavac (77%) and Astra-Zeneca (16 %) on mortality of person of 80+ in Brazil, while the gamma P1 VOC was rampant.  The coverage with 1 dose is shown in Fig 4 p.7: about 50 % by week 5-6 and almost 90 % week 7-8.  Fig 1 (p. 5) and Fig 3 (p. 6) show a rather spectacular decline in mortality, with an estimated 13,800 “saved lives” in this age group.

Clearly, this is a very rough approach, but it suggests at least that “suboptimal” vaccines, such as inactivated and Adeno’s, can be very useful indeed !!!! 

Ep 147-11: Another short preprint, clearly suggesting that antibodies from people vaccinated with Covaxin (the Indian inactivated vaccine with a Th1-promoting adjuvant) maintain rather robust neutralizing activity against the delta variant.

Some conclusions:

1. Nucleotide modifications seems key to the success of the mRNA vaccines.
2. An S protein vaccine may be a good alternative to mRNA and Adeno-based vaccines
3. Although, as compared to Pfizer and Moderna mRNA,  inactivated COVID vaccines generally performed less well in clinical trials, they may be very useful in rapidly containing the worst effects of COVID epidemics, particularly in low and middle income countries, which lack the resources and logistics to rapidly deploy the “delicate” mRNA vaccines (requiring a strict -20 or -80 cold chain).

Best wishes,

Guido