COVID: mRNA vaccine works in nonhuman primates

A recent vaccine efficacy trial in nonhuman primates found an impressive immunologic and protective benefit (see covid vaccine mRNA primates nejm2020 in dropbox, or DOI: 10.1056/NEJMoa2024671) 

 

Details: 

-- 12 male and 12 female Indian-origin rhesus macaques, vaccinated with either 10µg or 100µg of mRNA-1273 vaccine or placebo, at week 0 and at week 4 

-- all animals were then challenged with 7.6×10⁵ plaque forming units of SARS-CoV-2 virus (a typical number found in infected people), with a combination of intratracheal and intranasal inoculations with the virus

-- PCR was used to quantify viral RNA, and a subgenomic RNA was used to quantify replicating RNA in bronchoalveolar lavage (BAL) fluid and nasal swab specimens 

-- histopathology was also done on lung tissue specimens 

 

Results (will give broader results, not the detailed immunologic changes; see the article for those details): 

-- neutralizing antibody levels from the vaccine, expressed as the live-virus reciprocal 50% inhibitory dilution geometric mean titers:  

    -- 10µg group: 501, a titer 12 times as high as found in human convalescent-phase serum 

    -- 100µg group 3481, a titer 84 times as high as found in human convalescent-phase serum 

    -- and, there were robust antibody responses with potent neutralizing capacity targeting both the receptor binding domain and the N-terminal subdomains

-- T cell responses: 

    -- CD4 Th1 responses (involved with cell-mediated immune response) were noted in 4 weeks after the 2^nd vaccination in 4 of 8 animals in the 10µg group and 7 of 7 in the 100µg group, and the level of responses was higher in the 100µg group 

    -- CD4 Th2 responses (involved with humoral immune response) were undetectable in both vaccine groups 

    -- CD8 T cell responses were low to undetectable after vaccination in both vaccine groups

-- viral replication was not detectable in the BAL fluid by day 2 in 7 of 8 animals in both vaccine groups, though was detectable in all the control animals. And the viral loads were significantly less in the vaccinated animals 

-- no viral replication was detectable in the nose of any of the 8 animals in the 100µg dose group by day 2 after challenge, vs 5 of 8 animals in the 10µg group and 6 of 8 in the control group 

    -- however by day 4, 2 of the animals in the 10µg group and one of the 8 in the 100µg group did have low levels of RNA detected in the nose 

-- limited inflammation, or detectable viral genome or antigen, was noted in lungs of animals in either vaccine group, though in the control group there was moderate to severe inflammation in the small airways and adjacent alveolar interstitia; they also had occasional inflammatory cell infiltrates in the alveolar spaces and the alveolar capillary septa were moderately thickened 

 

Commentary: 

-- the majority of vaccines being developed are focusing on the trimeric SARS-CoV-2 spike protein (the one that binds to the ACE2 receptor and triggers virus cell membrane fusion) 

-- nonhuman primates have the advantage of being more similar to humans than other animal species, to have similar B cell and T cell repertoires, and to allow for the use of clinically relevant vaccine doses for humans. In addition they have similar replication sites and some of the features of human viral infection (though, “nonhuman primates have transient viral replication in the upper and lower airways and mild inflammation in the lung that resolves within 14 days” [i.e., their response to the virus is pretty different from what happens in people] 

-- this study found that these nonhuman primates had a vaccine-induced robust SARS-CoV-2 neutralizing activity, rapid protection in the upper and lower airways from early infection, and essentially no pathologic changes in the lung. by limiting viral replication in both the lower and upper airways, there should be vaccine-induced prevention of both Covid-19 disease and transmission of the virus. And the vaccine hit a few different viral targets, making it more likely to withstand some genetic changes in the virus

 

--one of the major concerns about this vaccine is the use of the mRNA approach, which effectively steers cells into making an antibody to attack the SARS-CoV-2 virus.  There is a bit of unease (at least to me) about manipulating the genetic cellular functions, for a few reasons:

    --they cite 3 studies that “RNA vaccines encoding viral antigens have been shown to be safe and immunogenic in several clinical trials”:

        -- the first is the pre-publication, pre-peer reviewed interim report of a phase 1/2 study in 45 adults aged 18-55 yo looking only at the 7 days after the injections, finding mostly injection site reactions (https://www.medrxiv.org/content/10.1101/2020.06.30.20142570v1.full.pdf ). this study used a different mRNA vaccine (BNT162b1)

        --the second is a preclinical assessment of an mRNA vaccine against H10N8 and H7N9 flu viruses, with an assessment up to 43 days in only 31 subjects  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5475249/ ), also not finding significant major adverse reactions

        --the third is the NEJM article on safety in 45 people given their mRNA-1273 vaccine, though they only report what seems to be the immediate adverse effects right after the 1^st then the 2^nd injections (timeframe not so clear)

    --and an earlier blog (aided and abetted by Jon Pincus) points out the limited data on safety: see http://gmodestmedblogs.blogspot.com/2020/05/covid-more-on-moderna-vaccine.html

    --so, safety is really a primary concern. the current mRNA vaccine is scheduled for large clinical trials, with 30,000 subjects (see https://www.nih.gov/news-events/news-releases/phase-3-clinical-trial-investigational-vaccine-covid-19-begins and https://www.fiercebiotech.com/biotech/moderna-finalizes-design-phase-3-covid-19-vaccine-trial-ahead-july-start ). and, we really do need a large study to show vaccine efficacy, but also one looking at longer term adverse effects (especially with a brand-new, never really tested type of vaccine in humans) to really know the adverse effects

    --for a more detailed historical assessment of the development of these vaccines see  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906799/ 

    --one specific concern i have is whether the mRNA vaccine, leading to specific cellular protein development, may be diverting or undercutting some other important functions/protein development by these cells??

 

Limitations of the study:

-- the study was done in nonhuman primates; they clearly do not reflect the true pathophysiology found in humans (eg the differences noted above in macaques' pulmonary response to SARS-CoV-2)

-- and this was a small sudy wih few animals and observing only very short-term benefits and risks. are the benefits sustainable and risks minimal longerterm??

so, an intriguing study. good immunologic response and decreased infectivity after vaccination. There are very clear pluses to the mRNA vaccines, including the easier ability to express complex proteins including monoclonal antibodies, much faster development, much easier/faster ability to tweak the proteins produced, and much faster to manufacture in large quantity and at  low cost (though we shall see what the company will charge, despite huge US taxpayer support to the company to the tune of $483 million...). But, these mRNA vaccines are new and have never been really tested in humans, with unknown safety issues (some of which might manifest themselves in only a small % of people and maybe only after a prolonged time). the upcoming study of 30,000 people should be able to give at least some of the answers on efficacy and safety

but, i do find it perplexing, disingenuous, highly misleading and borderline fraudulent to comment in the body of the article that these mRNA vaccines are safe "in several clinical trials", yet there is miniscule evidence based on a few handfuls of people for short-term adverse effects and zero assessment of any longer adverse effects. [and the only reason i looked at the actual cited references was because i was unaware of any significant human safety data...]

geoff

 

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