Neutralization evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4 and BA.5 | NEJM

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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 insulate. BA.4 and BA.5 have identical spike protein sequences and have therefore been grouped together. FP designates the fusion peptide, the heptad HR1 repeat 1, the heptad HR2 repeat 2, the N-terminal domain NTD, the receptor binding domain RBD, the receptor binding motif RBM, the subdomain SD1 1 and the 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 receipt of the messenger RNA vaccine series BNT162b2 at two doses and 2 weeks after the third dose (booster). 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 for one participant who had a negative neutralizing antibody titer. In 9 participants, two or three time points after infection are indicated. Neutralizing antibody titers were measured against reference isolate SARS-CoV-2 WA1/2020 and omicron subvariants BA.1, BA.2, BA.2.12.1 and BA.4 or BA .5. In panels B and C, the medians (black bars) are presented numerically and the factor differences with respect to the other subvariants are indicated; the dotted horizontal line indicates the lower detection limit for the test.

In recent months, several 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 leakage 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 assessed neutralizing antibody titers against the reference isolate WA1/2020 of SARS-CoV-2 as well as 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 BNT162b2 messenger RNA vaccine (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 Supplementary Appendix, available with the full text of this letter on NEJM.org). In the vaccinated cohort, participants were excluded if they had a history of SARS-CoV-2 infection or a positive nucleocapsid serology test result or if they had received another vaccine against the disease to coronavirus 2019 (Covid-19) or an immunosuppressive drug.

Six months after the first two BNT162b2 immunizations, the median pseudovirus neutralizing antibody titer was 124 against WA1/2020 but less than 20 against all omicron subvariants tested (Figure 1B). Two weeks after the booster dose, the median neutralizing antibody titer increased significantly, to 5783 against the WA1/2020 isolate, 900 against the BA.1 subvariant, 829 against the BA subvariant .2, 410 against the BA.2.12.1 sub-variant, and 275 against the BA.4 or BA.5 sub-variant. 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 14.1 against BA. 2.12.1, and by a factor of 21.0 compared to BA.4 or BA.5. In addition, compared to the median titer of neutralizing antibodies against subvariant BA.1, the median titer was lower by a factor of 2.2 against subvariant BA.2.12.1 and by a factor of 3, 3 against BA.4 or BA. 5 subvariant.

Of the participants who had been infected with omicron subvariant BA.1 or BA.2, all but one had been vaccinated against Covid-19. Due to variation in sampling after 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 the WA1/2020 isolate, 1,740 against the BA.1 subvariant, 1,910 against the BA subvariant. 2, 1,150 against the BA.2.12.1 subvariant, and 590 against the BA.4 or BA.5 subvariant (Figure 1C). These data show that compared to the WA1/2020 isolate, the median neutralizing antibody titre was lower by a factor of 6.4 against BA.1, by a factor of 5.8 against BA.2, by a factor 9.6 against BA.2.12. 1, and by a factor of 18.7 against BA.4 or BA.5. Moreover, 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 subvariant. -BA.4 or BA.5 variant.

These data show that the BA.2.12.1, BA.4 and BA.5 subvariants 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 subvariants and BA.2, suggesting that the SARS -CoV-2 omicron variant continued to evolve with increasing neutralization escape. These findings provide immunological context for the current outbreaks caused by BA.2.12.1, BA.4, and BA.5 subvariants in populations with high frequency of BA.1 or BA.2 vaccination and infection.

Nicole P. Hachmann, BS
Jessica Miller, BS
Air-ris Y. Collier, MD
John D. Ventura, Ph.D.
Jingyou Yu, Ph.D.
Marjorie Rowe, BS
Esther A. Bondzie, MSN
Olivia Powers, BS
Nehalee Surve, MS
Kevin Hall, BS
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), by the Massachusetts Consortium for Pathogen Preparednessand speak Ragon Institute. Dr Barouch is supported by the Musk Foundation. Dr. Collier is supported by the Reproductive Scientists Development Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Developmentby a grant (HD000849) from the Burroughs Wellcome Fund, and by a grant (AI69309) from the NIH.

The disclosure forms provided by the authors are available with the full text of this letter on NEJM.org.

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

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  2. 2. Cele S, Jackson L., Khoury DS, et al. Omicron largely but incompletely escapes Pfizer BNT162b2 neutralization. Nature 2022;602:654656.

  3. 3. Liu L., Iketani S, Guo Y, et al. Striking antibody evasion exhibited by the omicron variant of SARS-CoV-2. Nature 2022;602:676681.

  4. 4. YuJ, AY necklace, 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. Iketani S, Liu L., Guo Y, et al. Antibody evasion properties of SARS-CoV-2 omicron sublines. Nature 2022;604:553556.

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