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Review 1: "An emerging SARS-CoV-2 mutant evading cellular immunity and increasing viral infectivity"

Published onApr 14, 2022
Review 1: "An emerging SARS-CoV-2 mutant evading cellular immunity and increasing viral infectivity"
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key-enterThis Pub is a Review of
An emerging SARS-CoV-2 mutant evading cellular immunity and increasing viral infectivity

SummaryDuring the current SARS-CoV-2 pandemic that is devastating the modern societies worldwide, many variants that naturally acquire multiple mutations have emerged. Emerging mutations can affect viral properties such as infectivity and immune resistance. Although the sensitivity of naturally occurring SARS-CoV-2 variants to humoral immunity has recently been investigated, that to human leukocyte antigen (HLA)-restricted cellular immunity remains unaddressed. Here we demonstrate that two recently emerging mutants in the receptor binding domain of the SARS-CoV-2 spike protein, L452R (in B.1.427/429) and Y453F (in B.1.298), can escape from the HLA-24-restricted cellular immunity. These mutations reinforce the affinity to viral receptor ACE2, and notably, the L452R mutation increases protein stability, viral infectivity, and potentially promotes viral replication. Our data suggest that the HLA-restricted cellular immunity potentially affects the evolution of viral phenotypes, and the escape from cellular immunity can be a further threat of the SARS-CoV-2 pandemic.Graphical Abstract

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.



While it is true that both L452R and Y453F mutations individually increase affinity to ACE2, it remains to be established whether this translates into increased viral replication or increased transmissivity among humans, so the authors’ conclusions are a little bit too alarming.

While to date SARS-CoV-2 has many examples of dramatic convergent evolution in the SARS-CoV-2 genome in general and in Spike protein in particular (e.g. E484K), Y453F has been identified to date only in the B.1.298 strain (also known as “Cluster V”) in mink farmworkers in Denmark and Netherlands (the two countries with the highest engage in mink fur factories), suggesting limited fitness from this mutation. Accordingly, and luckily enough, the B.1.298 hotspot has been easily contained by health authorities’ efforts, and it is considered extinct since Summer 2020. Hence, this strain should not be considered as “recently emerging”. To date what is known about the Y453+ B.1.298 strain is slightly reduced sensitivity to neutralization by the monoclonal antibodies etesevimab and casirivimab 1 : no in vivo efficacy data are available since vaccines and monoclonal was not available at the time the strain circulated. The authors focus on cellular immunity, which, while not fundamental as a frontline defense on nasopharyngeal mucosae, is extremely relevant to preventing severe disease. The finding that the mutation impairs antigen presentation by the common HLA class I allele A24 is new and relevant, but many more epitopes in the Spike and other SARS-CoV-2 antigens are likely conserved enough to maintain the cellular response to protective levels overall.

The situation is instead very different for the close L452R mutations, whose prevalence is increasing worldwide, both in the cited in B.1.427/429 clade and in many more clades (e.g. A.21, A.2.4, B.1.1.10, B.1.1.130, the scaring Indian variant B.1.617 2, and C.16; a single B.1.74 strain harbors the L452Q mutation 3). Such convergent evolution suggests increased fitness over ancestral strains. Again, the immune escape of the L452R-containing epitope could be easily compensated by cellular immunity against different epitopes within the SARS-CoV-2 proteome and/or from humoral immunity (despite evidence of resistance to etesevimab 4, bamlanivimab 5 and regdanvimab  4). Accordingly, the in vitro efficacy of mRNA vaccine-elicited sera against B.1.427/429 is only modestly reduced4.

In conclusion, while the cellular immune response to SARS-CoV-2 (and in particular, its HLA restriction) remains a poorly investigated field (largely due to the poorly scalable technologies) and the authors should be lauded for their effort, both the title and the conclusions seems too dramatic. The title should be modified: “An emerging SARS-CoV-2 mutant” should be changed into “An emerging SARS-CoV-2 mutation”, while “evading cellular immunity and increasing viral infectivity” seems poorly supported by evidence.


1.         Yao W, Wang Y, Ma D, et al. Spike mutations decrease SARS-CoV-2 sensitivity to neutralizing antibodies but not ACE2-Ig in vitro. 2021: 2021.01.27.428353.

2.         Cherian S, Potdar V, Jadhav S, et al. Convergent evolution of SARS-CoV-2 spike mutations, L452R, E484Q and P681R, in the second wave of COVID-19 in Maharashtra, India. 2021: 2021.04.22.440932.

3.         Tchesnokova V, Kulakesara H, Larson L, et al. Acquisition of the L452R mutation in the ACE2-binding interface of Spike protein triggers recent massive expansion of SARS-Cov-2 variants. 2021: 2021.02.22.432189.

4.         McCallum M, Bassi J, De Marco A, et al. SARS-CoV-2 immune evasion by variant B.1.427/B.1.429. 2021: 2021.03.31.437925.

5.         Starr TN, Greaney AJ, Dingens AS, Bloom JD. Complete map of SARS-CoV-2 RBD mutations that escape the monoclonal antibody LY-CoV555 and its cocktail with LY-CoV016. Cel Reports Medicine 2021; 2(4): 100255.

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