Neutralization Escape by SARS-CoV-2 Omicron Subvariants BA.2.12.1, BA.4, and BA.5

Neutralization Escape by SARS-CoV-2 Omicron Subvariants BA.2.12.1, BA.4, and BA.5

To the publisher:

Omicron subvariant mutations and neutralizing antibody responses.

Panel A shows the lineage of mutations that have been identified in the omicron subvariants BA.1, BA.2, BA.2.12.1, and BA.4 or BA.5 of SARS-CoV-2, compared to the reference WA1. /2020 isolated. BA.4 and BA.5 have identical spike protein sequences and have therefore been grouped together. FP indicates fusion peptide, HR1 heptad repeat 1, HR2 heptad repeat 2, NTD N-terminal domain, RBD receptor binding domain, RBM receptor binding motif, SD1 subdomain 1 and SD2 subdomain 2. Panel B shows neutralizing antibody titers as determined by luciferase-based pseudovirus neutralization assays in samples obtained from 27 participants 6 months after receiving the two-dose BNT162b2 messenger RNA vaccine series and 2 weeks after the third dose (reinforcement). Panel C shows neutralizing antibody titers in participants who had been infected with the BA.1 or BA.2 subvariant. All infected participants had been vaccinated except 1 participant who had a negative neutralizing antibody titer. In 9 participants, two or three time points after infection are shown. Neutralizing antibody titers were measured against the reference isolate SARS-CoV-2 WA1/2020 and the omicron subvariants BA.1, BA.2, BA.2.12.1, and BA.4 or BA.5. In Panels B and C, medians (black bars) are displayed numerically and factor differences with respect to other subvariates are indicated; the dashed horizontal line indicates the lower detection limit of the assay.

In recent months, multiple lineages of the omicron variant (B.1.1.529) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged,1 with subvariants BA.1 and BA.2 showing substantial escape of neutralizing antibodies.2-5 The BA.2.12.1 subvariant is now the dominant strain in the United States, and BA.4 and BA.5 are dominant in South Africa (Figure 1A). The BA.4 and BA.5 subvariants have identical spike protein sequences.

We evaluated neutralizing antibody titers against the SARS-CoV-2 reference isolate WA1/2020 along with the omicron subvariants BA.1, BA.2, BA.2.12.1, and BA.4 or BA.5 in 27 participants who had been vaccinated and boosted with the messenger RNA vaccine BNT162b2 (Pfizer–BioNTech) and in 27 participants who had been infected with the BA.1 or BA.2 subvariant a median of 29 days earlier (range, 2 to 113) (Tables S1 and S2 in the Supplemental Appendix, available with the full text of this letter at NEJM.org). In the vaccine cohort, participants were excluded if they had a history of SARS-CoV-2 infection or a positive nucleocapsid serology test or had received another coronavirus disease 2019 (Covid-19) vaccine. or an immunosuppressive drug.

Six months after the initial two immunizations with BNT162b2, the median neutralizing antibody pseudovirus titer was 124 against WA1/2020 but less than 20 against all omicron subvariants tested (Figure 1B). Two weeks after administration of the booster dose, the median neutralizing antibody titer increased substantially, to 5783 against isolate WA1/2020, 900 against subvariant BA.1, 829 against subvariant BA.2, 410 against BA .2.12.1 subvariant, and 275 against subvariant BA.4 or BA.5. These data show that, compared to the response against isolate WA1/2020, the neutralizing antibody titer was lower by a factor of 6.4 against BA.1, by a factor of 7.0 against BA.2, by a factor of 7.0 against BA.2. factor of 14.1 against BA. 2.12.1, and by a factor of 21.0 against BA.4 or BA.5. In addition, compared with the median neutralizing antibody titer against the BA.1 subvariant, the median titer was lower by a factor of 2.2 against the BA.2.12.1 subvariant and by a factor of 3.3 against BA. .4 or BA. 5 subvariant.

Among the participants who had been infected with the BA.1 or BA.2 subvariant of omicron, all but one had been vaccinated against Covid-19. Due to variation in sampling after the onset of infection, some samples may not reflect peak neutralizing antibody titers (Table S2). Among participants with a history of Covid-19, the median neutralizing antibody titer was 11,050 against isolate WA1/2020, 1,740 against subvariant BA.1, 1,910 against subvariant BA.2, 1,150 against subvariant BA. 2.12.1, and 590 against subvariant BA.4 or BA.5 (Figure 1C). These data show that, compared to isolate WA1/2020, the median neutralizing antibody titer was lower by a factor of 6.4 against BA.1, by a factor of 5.8 against BA.2, by a factor of 9.6 against BA.2.12. 1, and by a factor of 18.7 compared to BA.4 or BA.5. In addition, compared to the median titers against the BA.1 subvariant, the median titer was lower by a factor of 1.5 against the BA.2.12.1 subvariant and by a factor of 2.9 against the BA.2.12.1 subvariant. the BA.4 or BA.5 subvariant.

These data show that subvariants BA.2.12.1, BA.4 and BA.5 substantially escape neutralizing antibodies induced by both vaccination and infection. In addition, neutralizing antibody titers against the BA.4 or BA.5 subvariant and (to a lesser extent) against the BA.2.12.1 subvariant were lower than the titers against the BA.1 and BA.2 subvariants, which suggests that the SARS-omicron variant of CoV-2 has continued to evolve with increasing neutralization escape. These findings provide immunological context for current spikes caused by BA.2.12.1, BA.4, and BA.5 subvariants in populations with high frequencies of BA.1 or BA.2 vaccination and infection.

Nicole P. Hachmann, B.S.
Jessica Miller, Bachelor of Science
Airis Y. Collier, MD
John D. Ventura, Ph.D.
Jingyou Yu, Ph.D.
Marjorie Rowe, Bachelor of Science
Esther A. Bond, MSN
Olivia Powers, Bachelor of Science
Nehalee Surve, MS
Kevin Hall, Bachelor of Science
Dan H. Barouch, MD, Ph.D.
Beth Israel Deaconess Medical Center, Boston, MA
[email protected]

Supported by a grant (CA260476) from the National Institutes of Health (NIH), for the Massachusetts Consortium for Pathogen Preparednessand for him Ragon Institute. Dr. Barouch is supported by the musk foundation. Dr. Collier is supported by the Scientific Reproductive Development Program of the National Institute of Child Health and Human Development Eunice Kennedy Shriverby a grant (HD000849) from the Burroughs Wellcome Fund, and by a grant (AI69309) from the NIH.

Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

This letter was published on June 22, 2022 on NEJM.org.

  1. 1. Viana R., moyo s, Amoako DG, et al. Rapid epidemic expansion of the omicron variant SARS-CoV-2 in southern Africa. Nature 2022;603:679686.

  2. two. the, jackson l, Khoury DS, et al. Omicron largely but incompletely escapes Pfizer BNT162b2 neutralization. Nature 2022;602:654656.

  3. 3. liu l, IketaniS, guo-y, et al. Surprising antibody evasion manifested by the omicron variant of SARS-CoV-2. Nature 2022;602:676681.

  4. Four. yu j, Collier AY, Rowe M, et al. Neutralization of SARS-CoV-2 omicron BA.1 and BA.2 variants. N English J Med 2022;386:15791580.

  5. 5. IketaniS, liu l, guo-y, et al. Antibody-evading properties of omicron SARS-CoV-2 sublineages. Nature 2022;604:553556.

Leave a Comment

Your email address will not be published.