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Review 2: "Enhanced Recombination Among SARS-CoV-2 Omicron Variants Contributes to Viral Immune Escape"

This manuscript investigates the prevalence of recombination events in multiple SARS-CoV-2 lineages. Reviewers find the claim that Omicron has higher recombination rates than other lineages to be under-supported by the analysis and find the study potentially informative.

Published onDec 01, 2022
Review 2: "Enhanced Recombination Among SARS-CoV-2 Omicron Variants Contributes to Viral Immune Escape"
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key-enterThis Pub is a Review of
Enhanced Recombination Among SARS-CoV-2 Omicron Variants Contributes to Viral Immune Escape

ABSTRACTSARS-CoV-2 virus evolution occurs as a result of antigenic drift and shift. Although antigenic drift has been extensively studied, antigenic shift, which for SARS-CoV-2 occurs through genetic recombination, has been examined scarcely. To gain a better understanding of the emergence and prevalence of recombinant SARS-CoV-2 lineages through time and space, we analyzed SARS-CoV-2 genome sequences from public databases. Our study revealed an extraordinary increase in the emergence of SARS-CoV-2 recombinant lineages during the Omicron wave, particularly in Northern America and Europe. This phenomenon was independent of sequencing density or genetic diversity of circulating SARS-CoV-2 strains. In SARS-CoV-2 genomes, recombination breakpoints were found to be more concentrated in the 3’ UTR followed by ORF1a. Additionally, we noted enrichment of certain amino acids in the spike protein of recombinant lineages, which have been reported to confer immune escape from neutralizing antibodies, increase ACE2 receptor binding, and enhance viral transmission in some cases. Overall, we report an important and timely observation of accelerated recombination in the currently circulating Omicron variants and explore their potential contribution to viral fitness, particularly immune escape.

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.



The evolution of the SARS-CoV-2 sequence has often been thought to be due to errors in RNA replication.  Another possible mechanism is RNA recombination.  This has rarely been discussed in the literature so far.  This manuscript reports the analysis of complete SARS-CoV-2 genomic sequences in public domains and reports the detection of recombinant lineages.  Furthermore, if the recombinants acquire certain amino acid sequences that can render the virus resistant to immune selection, they will lead to the predominance of certain recombinants.  These are interesting new findings relevant to SARS-CoV-2.   However, the interpretation of this data has to be more meticulous.

Coronavirus recombination was best studied in a murine coronavirus, mouse hepatitis virus (MHV) (1).  It occurs at a very high frequency (2)  and occurs at multiple sites, some of which result in altered neutralizing and neuropathogenic properties of the virus.  Interestingly, recombination occurs readily at a hypervariable region as well as  5’-and 3’-ends of the viral genome (3-5).  All these works are relevant to the findings presented in this manuscript.  Unfortunately, the authors apparently did not do a thorough literature search.

The findings presented in this manuscript are, in general, consistent with the idea that recombination played a role in virus evolution.  However, the suggestion that certain Omicron recombinants which dominated in certain geographical regions have higher recombination rates may not necessarily be true. Some Omicron mutants are known to have enhanced multiplication ability or growth advantages, which confuse the true recombination rate.

It will be more useful if the authors discuss the nature of the crossover sites in these recombinants.

Lastly, some of the figures are hard to read.

References cited:

  1. Lai et al (J. Virol.  449-456. 1985)

  2. Makino et al. (J. Virol. 57:728-737, 1986)

  3. Makino et al (PNAS 6567-6571, 1987)

  4. Keck J.G. et al: (Virology 156:331-341, 1987)

  5. Banner L,R. (Virology  175:548-555, 1990)


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