Thread by @Williams_T_C

could a non-segmented RNA virus rapidly evolve to evade a polyclonal immune response, rendering a vaccine ineffective?

I think if you'd asked the average RNA virus researcher a year ago, the answer would have been no

but then again, 2020 wasn't an average year ... 🧵1/n

what has been shown is that if you grow a virus in culture in the presence of a *monoclonal* antibody (mAb)

you will select for mutations that render the virus resistant to that mAb

this has been shown in the lab for measles, polio, and RSV sciencedirect.com/science/articl… 2/n

and also clinically for HIV doi.org/10.1056/NEJMoa… @NEJM and RSV doi.org/10.1093/cid/ci… @IDSAInfo 3/n

Suptavumab is a long lasting mAb to antigenic site V of the RSV F protein

in a large clinical trial it turned out to be highly effective in protecting from RSV A, but not RSV B, infection, due to 2 point mutations in the RSV B strain circulating during the trial 4/n

there are other viral vaccines based on recombinant proteins where escape mutants have been documented

for the hepatitis B vaccine, the antibody response to the vaccine focuses on a stretch of 25 amino acids. Hep B strains with mutations in this stretch have been found in 5/n

vaccinated individuals doi.org/10.4161/hv.343… (however the clinical significance of these remains unclear) 6/n

for the HPV vaccine, the L1 protein used is genotype specific

this is why vaccines which include the 16 and 18 genotype L1 protein do not protect against genotypes 6 and 11 7/n

(and incidentally, why Australia, which chose to introduce 6 and 11 from the start, has seen an almost total eradication in genital warts in young people since introduction of the quadrivalent vaccine bmj.com/content/346/bm…) 8/n

so what about SARS-CoV-2?

Spike (the vaccine target) is a trimer, with each component consisting of S1 and S2 units nature.com/articles/s4158…

the human immune response is concentrated on just 2 sections of S1, the NTD (N-terminal domain) and RBD (receptor binding domain) 9/n

as with other viruses, if you grow SARS-CoV-2 in the presence of a monoclonal antibody, the virus will mutate to evade these elifesciences.org/articles/61312 10/n

what has been shown now for the first time in an elegant paper by @e_andreano, @McLellan_Lab & colleagues @biorxivpreprint is that if you grow SARS-CoV-2 in the presence
of a *polyclonal* human convalescent plasma biorxiv.org/content/10.110… 11/n

the virus can with just 3 mutations (in this case, deletion and insertion in two of the NTD loops and an E484K substitution in the RBD) escape from neutralisation by that plasma @mugecevik @devisridhar @ProfCalumSemple 12/n

they then tested whether samples from 20 convalescent patients also showed reduced neutralising activity against this mutant

here is the key point of this paper: *all patient samples* showed an at least 2-fold reduction in this neutralising activity 13/n

reassuringly though:

"not all plasma and mAbs tested were equally affected by the three mutations suggesting that natural immunity to infection can target additional epitopes that
can still neutralize the PT188-EM variant" 14/n

less reassuringly & contrary to what has been found in other viruses they examined whether the escape mutant had decreased fitness

this didn't appear to be the case

suggesting mutations that rendered virus less likely to be neutralised did not make it less transmissible 15/n

what are the implications of this?
1) The results are surprising: normally the presence of just 2 mAbs is sufficient to prevent the evolution of escape mutants- here the virus has mutated under pressure from a (presumably) higher number of polyclonal antibodies @arambaut 16/n

2) The mutations (in the NTD and RBD) observed in this laboratory escape mutant are not dissimilar to those seen in strain VOC 202012/01 virological.org/t/preliminary-… 17/n

3) Studies are needed to examine whether VOC 202012/01 can also escape neutralisation by convalescent sera @PHE_uk 18/n

4) The longer SARS-CoV-2 is in circulation, and the greater the number of people infected, the more of a chance escape mutants will have to form, and imperil the unprecedented efforts put into vaccine development

#ZeroCovid

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