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Review 1: "SARS-CoV-2 Omicron BA.2.12.1, BA.4, and BA.5 Subvariants Evolved to Extend Antibody Evasion"

Published onAug 02, 2022
Review 1: "SARS-CoV-2 Omicron BA.2.12.1, BA.4, and BA.5 Subvariants Evolved to Extend Antibody Evasion"
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key-enterThis Pub is a Review of
SARS-CoV-2 Omicron BA.2.12.1, BA.4, and BA.5 subvariants evolved to extend antibody evasion
SARS-CoV-2 Omicron BA.2.12.1, BA.4, and BA.5 subvariants evolved to extend antibody evasion

Abstract The Omicron subvariant BA.2 accounts for a large majority of the SARS-CoV-2 infection worldwide today1. However, its recent descendants BA.2.12.1 and BA.4/5 have surged dramatically to become dominant in the United States and South Africa, respectively2,3. That these novel Omicron subvariants carry additional mutations in their spike proteins raises concerns that they may further evade neutralizing antibodies, thereby further compromising the efficacy of our COVID-19 vaccines and therapeutic monoclonals. We now report findings from a systematic antigenic analysis of these surging Omicron subvariants. BA.2.12.1 is only modestly (1.8-fold) more resistant to sera from vaccinated and boosted individuals than BA.2. On the other hand, BA.4/5 is substantially (4.2-fold) more resistant and thus more likely to lead to vaccine breakthrough infections. Mutation at spike residue L452 found in both BA.2.12.1 and BA.4/5 facilitates escape from some antibodies directed to the so-called Class 2 and Class 3 regions of the receptor-binding domain (RBD)4. The F486V mutation found in BA.4/5 facilitates escape from certain Class 1 and Class 2 antibodies to the RBD but compromises the spike affinity for the cellular receptor ACE2. The R493Q reversion mutation, however, restores receptor affinity and consequently the fitness of BA.4/5. Among therapeutic antibodies authorized for clinical use, only bebtelovimab (LY-COV1404) retains full potency against both BA.2.12.1 and BA.4/5. The Omicron lineage of SARS-CoV-2 continues to evolve, successively yielding subvariants that are not only more transmissible but also more evasive to antibodies.

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.



The rapid evolution of SARS-CoV-2 presents a problem for the effectiveness of therapeutic monoclonal antibodies and vaccines. The evolutionary jump made by the Omicron variant that introduced a large number of mutations into the viral spike protein, resulted in resistance of the virus to several of the monoclonal antibodies and decreased the protection afforded by vaccination. The emergence of new Omicron subvariants, particularly BA.4/5, has again raised this issue. Wang et al. show that the most recent Omicron subvariant BA.4/5 is more resistant to neutralization by some of the anti-spike protein monoclonal antibodies including those used to treat COVID-19 and are more resistant to the antibodies elicited by the mRNA vaccines even after boosting. Only one of the monoclonal antibodies approved for clinical use, Bebletovimab, remains highly effective against the new variants.

These are important findings. The study provides accurate data on neutralization by over 20 different mAbs, using both VSV-pseudotyped virus and live virus assays. The study also analyzes the individual spike protein mutated amino acids to identify those that contribute to the resistance and measures the affinity of the variant spike proteins for ACE-2, demonstrating their high affinity for the receptor. Interestingly, a mutation that increases neutralization resistance decreases ACE-2 affinity but is compensated for by another mutation that increases affinity. The study is thorough, and in combination with the spike protein structural images, provides insight at the atomic level of how the mutations disrupt antibody binding.

It is important to keep in mind that it is difficult to draw conclusions from lab studies about how the increased neutralization resistance will affect monoclonal antibody therapy or the frequency of vaccine breakthroughs. The 1.8-fold resistance of BA.2.12.1 to the sera of vaccinated individuals is termed by the authors “moderate” while the 4.2-fold resistance to BA.4/5 is termed “substantial”. The authors believe that this will, in fact, translate to an increased frequency of vaccine breakthrough. While they are probably correct, it’s hard to know, as the correlates of protection are not yet well understood. In addition, vaccination induces a T cell response which may help to maintain protection against the variants in spite of the decrease in antibody effectiveness. The T cell response will need to be investigated in other studies. As the authors note, the virus continues to evolve to increase transmissability and evade immune responses. It will be important to tailor monoclonal antibodies and vaccines to the new variants as they appear.

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