Neutron SARS-CoV-2 Subvariate Neutron Leakage BA.2.12.1, BA.4 and BA.5

Neutron SARS-CoV-2 Subvariate Neutron Leakage BA.2.12.1, BA.4 and BA.5

In the editor:

Omicron subvariante mutations and neutralizing antibody responses.

Panel A shows the lineage of mutations that have been identified in the omicron BA.1, BA.2, BA.2.12.1, and BA.4 or BA.5 subvariants of SARS-CoV-2, compared to 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, N-terminal NTD domain, RBD receptor binding domain, RBM receptor binding domain, subdomain SD1 1, and subdomain SD2 2. Panel B shows the 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 (booster) dose. Panel C shows neutralizing antibody titers in participants who had been infected with subvariant BA.1 or BA.2. All infected participants had been vaccinated except one 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 with 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, the averages (black bars) are shown numerically and the factor differences with respect to other subvariants are indicated; the dashed horizontal line indicates the lower limit of detection of the assay.

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

Neutralizing antibody titers against SARS-CoV-2 reference isolate WA1 / 2020 were evaluated together 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 reinforced with the BNT162b2 messenger RNA vaccine (Pfizer – BioNTech) and in 27 participants who had been infected with subvariant BA.1 or BA.2 an average of 29 days before (range, 2 to 113) (Tables S1 and S2 in the Supplementary 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 result in the serological analysis of the nucleocapsid or if they had received another vaccine against coronavirus disease 2019 ( Covid-19) or an immunosuppressive drug.

Six months after the initial two immunizations of BNT162b2, the mean titer of neutralizing antibody pseudoviruses 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 mean titer of neutralizing antibodies increased substantially, to 5783 against the isolated WA1 / 2020, 900 against the subvariant BA.1, 829 against the 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 the WA1 / 2020 isolate, the titer of neutralizing antibodies 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 against BA.4 or BA.5. In addition, compared to the mean titer of neutralizing antibodies against subvariant BA.1, the mean titer was lower by a factor of 2.2 against subvariant BA.2.12.1 and by a factor of 3.3 against the BA.4 or BA. 5 subvariant.

Among participants who had become infected with omicron subvariant BA.1 or BA.2, all but one had been vaccinated against Covid-19. Due to the variation in sampling after the onset of infection, some samples may not reflect the maximum neutralizing antibody titers (Table S2). Among participants with a history of Covid-19, the mean titer of neutralizing antibodies was 11,050 against the isolated WA1 / 2020, 1,740 against the subvariant BA.1, 1910 against the subvariant BA.2, 1150 against the subvariant BA .2.12.1, and 590 against subvariant BA.4 or BA.5 (Figure 1C). These data show that, compared to the WA1 / 2020 isolate, the mean titer of neutralizing antibodies was lower by a factor of 6.4 against BA.1, by a factor of 5.8 against BA.2, in a factor of 9.6 against BA.2.12. 1, and by a factor of 18.7 against BA.4 or BA.5. In addition, compared to the average titles against the BA.1 subvariant, the average title 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 subvariant. .4 or BA.5.

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

Nicole P. Hachmann, BS
Jessica Miller, BS
Ai-ris Y. Collier, MD
John D. Ventura, Ph.D.
Jingyou Yu, Ph.D.
Marjorie Rowe, BS
Esther A. Bond, 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]

With the support of a grant (CA260476) from the National Institutes of Health (NIH), pel Massachusetts Consortium for Pathogen Preparationand for the Ragó Institute. Dr. Barouch has the support of the Musk Foundation. Dr. Collier is supported by the Reproductive Scientists Development Program Eunice Kennedy Shriver National Institute of Child Health and Human Developmentfor a grant (HD000849) from the Burroughs Wellcome Fund, and for a grant (AI69309) from the NIH.

The 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.

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  2. 2. The S, Jackson L, Khoury DS, et al. Omicron largely but incompletely escapes the neutralization of Pfizer BNT162b2. Nature 2022602:654656.

  3. 3. Liu L, Iketani S, Guo Y, et al. The amazing antibody evasion manifested by the omicron variant of SARS-CoV-2. Nature 2022602:676681.

  4. 4. Yu J, Necklace AY, Rowe M, et al. Neutralization of SARS-CoV-2 omicron variants BA.1 and BA.2. N Engl J Med 2022386:15791580.

  5. 5. Iketani S, Liu L, Guo Y, et al. Antibody evasion properties of SARS-CoV-2 omicron underlines. Nature 2022604:553556.

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