COVID: ?escape mutant virus

 i will send out several blogs in the next few days on the B.1.1.7 variant, but will start with this ominous one:

A new pre-print, pre-peer review article found that a new mutation of the UK B.1.1.7 variant may “escape” vaccine protection (see covid escape mutant UK medRxiv2021 in dropbox, or https://www.medrxiv.org/content/10.1101/2021.01.19.21249840v2 ). the point of this study is that the B.1.1.7 variant of SARS-CoV-2 is pretty universal and rapidly gaining ground worldwide. And there continue to be ongoing mutations. This study focused on the neutralizing antibody potential produced by vaccination on several of these newer mutations.

 

Details: 

-- 23 people who had received the Pfizer mRNA vaccine (BNT162b2), a full-length trimerised S protein of the SARS-CoV-2 virus, were studied after a single immunization

-- median age 82, 30% female 

-- they assessed neutralizing antibody responses using pseudo-viruses expressing the wild type Spike protein, or 8 mutations that they found in the B.1.1.7 Spike protein, analyzing the IgG titers to the N protein, S, and S RBD (receptor binding domain)

-- initial IgG titers for spike and RBD were much higher than in healthy controls and similar to convalescent plasma from recovered individuals, though with a 100-fold variation in the vaccinated people 

 

Results: 

-- neutralizing titers against: 

    -- the wild type pseudo-viruses (ie mimicking the wild SARS-CoV-2 virus, the regular old one): varied from <1:4 to 3449 

    -- B.1.1.7 variant: neutralizing titers reduced the titer 3.85-fold over the wild-type virus (similar reductions found in sera of convalescent Covid patients)

        -- titers were also reduced with monoclonal antibodies targeting the N-terminal domain (9 of 10), the RBM (5 of 29), but not the neutralizing monoclonal antibodies binding outside the RBM (receptor binding motif, part of the receptor binding domain RBD) 

    -- 8 mutations in the S protein (including N501Y), all with D614G, in 15 individuals finding in 10 of them that there was further reduced efficacy of antibodies against the B.1.1.7 mutant (fold change >3, with the highest change was about 6-fold).  but in 7 who recovered from actual infection, only 2 had sera with reduced potency against B.1.1.7 (ie, those who did recover from infection mostly did have demonstrable effectiveness of neutralizing antibodies)

    -- there is a recently identified E484K mutation of the B.1.1.7 SARS-CoV-2 virus that in the laboratory seems to escape neutralization by most of the NTD-specific antibodies (N-terminal domain) tested and by some of the RBM-specific antibodies

        -- this E484K mutation (from 5 individuals): further increased loss of neutralizing activity by vaccine-elicited antibodies, beyond the reduction conferred by the B.1.1.7 mutations alone; about a 7-fold decrease from their figure, with confidence intervals between 4-9 [on this graph, the 50% serum neutralization titer was 3-fold for B.1.1.7 itself with CI 2-4]

 

Commentary: 

-- the SARS-CoV-2 is a relatively stable virus compared to many (influenza, HIV), and only has 1 to 2 mutations on average per month 

-- as a perspective, the neutralization geometric mean tighter for the Pfizer vaccine is almost 3 times higher than that from convalescent plasma from infected patients (1536 vs 602 U/ml)

    -- this study found similar responses in this group to wild type pseudovirus used in the neutralization assay

-- this study suggests increasing viral resistance with B.1.1.7 and further increasing with some subsequent modifications now being found in the population 

-- other studies have found 100-fold neutralization loss against the N501Y mutant

-- the study also suggests that these may be ”escape mutants”,  which happens with other viruses as well, meaning that they escape being covered by vaccines that had worked previously 

 

--the E484K mutations have been reported in the B.351 (from South Africa) and the P.1 (from Brazil) lineages (see https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/scientific-brief-emerging-variants.html ) 

-- and, as in this study, E484K is reported in the B.1.1.7 variant in the UK and seems to have a high impact on the level of neutralizing antibodies from post-vaccine or post-covid infection serum, especially in the setting of the additional N501Y and K417N mutations

 

Limitations: 

-- the big one is whether how the laboratory-determined neutralizing antibody responses correlates with clinical vaccine effectiveness. And, even which of the neutralizing antibody responses (?or combination, perhaps from non-S antibodies) are the most consistent with clinical vaccine effectiveness. neutralizing antibodies do however seem to confer protection in non-human primates (though no correlation between T cell responses and protection). 

    -- for example, it is unclear exactly what the role of the N-terminal domain (NTD) is in conferring resistance

    -- and, “escape mutants” are only an issue if the virus actually mutates enough to escape vaccine coverage or immunity resulting from prior infections 

-- study had a small sample size evaluated, limiting the generalizability of the findings in terms of the larger population 

-- the study involved people 3 weeks after the first dose of the Pfizer vaccine. would there have been differences after the second dose? other studies with 2 doses of mRNA vaccines did not find different results for B.1.1.7 variant after a first dose

-- i use the term "wild" or "regular old" SARS-CoV-2 virus above to connote the initial virus. of course, this virus has mutated extensively, as noted above with 1-2 mutations/month, and is therefore actually a very different virus from one area to another, and one person to another. but we need some comparison with the vaccine-susceptible old strain, albeit it is all a moving target...

 

So, this is concerning but not unexpected news. There are bound to be mutations that do escape vaccine coverage, now or sometime in the future, and they will proliferate in the setting of both prior SARS-CoV-2 infections as well as immunization: this will effectively negate the prior immunity against SARS-CoV-2, providing a selection bias for the escapees. the above study highlights this issue. A few issues here: 

-- the B.1.1.7 variant is an important one because it is more transmissible and clinically worse than the regular old virus, hence is spreading very quickly (more in the next few blogs)

-- we need to accelerate vaccination programs in order to decrease the population load of SARS-CoV-2 virus, to decrease the probability of developing these more aggressive variants (and the B.1.1.7 variant at this point seems to be covered by the vaccine)

-- we will undoubtedly need modifications of current vaccines to cover some of these current or future variants that are escape mutants (sounds like a grade B sequel to X-Men); fortunately tweaking the vaccines is not so difficult with current technology, but there will always be a lag in scaling up production sufficiently to cover the population

-- this is also the background which reinforces the continuing need for masks, distancing, avoiding indoor contacts, etc to protect both the individual and those around them, even if vaccinated

-- at this point there are no clear variants that we know of that are escaping the vaccine or prior immunity, so my sense is that this is the calm before the storm: ie, if patients need to have procedures done, medical testing done, teeth cleaning, visits to their local store, hang out with their friends at a restaurant (but appropriately distanced), etc, now is about as good a time as any…. 

 

geoff

 

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