Neutralizing potency of COVID‐19 vaccines against the SARS‐CoV‐2 Omicron (B.1.1.529) variant

The recently emerged SARS-CoV-2 Omicron variant encodes 37 amino acid substitutions in the spike protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody-based therapeutics. Here we show that the Omicron RBD binds to human ACE2 with enhanced affinity, relative to the Wuhan-Hu-1 RBD, and binds to mouse ACE2. Marked reductions in neutralizing activity were observed against Omicron compared to the ancestral pseudovirus in plasma from convalescent individuals and from individuals who had been vaccinated against SARS-CoV-2, but this loss was less pronounced after a third dose of vaccine. Most monoclonal antibodies that are directed against the receptor-binding motif lost in vitro neutralizing activity against Omicron, with only 3 out of 29 monoclonal antibodies retaining unaltered potency, including the ACE2-mimicking S2K146 antibody1. Furthermore, a fraction of broadly neutralizing sarbecovirus monoclonal antibodies neutralized Omicron through recognition of antigenic sites outside the receptor-binding motif, including sotrovimab2, S2X2593 and S2H974. The magnitude of Omicron-mediated immune evasion marks a major antigenic shift in SARS-CoV-2. Broadly neutralizing monoclonal antibodies that recognize RBD epitopes that are conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers.

To the Editor: On November 26, 2021, the World Health Organization (WHO) named the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first detected in South Africa, as a variant of concern. 1 By November 29, 2021, three days after the announcement by the WHO, cases of infection with the omicron variant had already been detected in many other countries. Whether the BNT162b2 vaccine (Pfizer–BioNTech), which was previously shown to have 95% efficacy against coronavirus disease 2019 (Covid-19), 2,3 will effectively neutralize infection with the omicron variant is unclear. We compared neutralization of omicron-infected cells in serum samples obtained from participants who had received two doses of vaccine with neutralization in samples obtained from participants who had received three doses. Microneutralization assays with wild-type virus and B.1.351 (beta), B.1.617.2 (delta), and omicron variant isolates were performed with the use of serum samples obtained from two groups of 20 health care workers. One group comprised participants who had received two doses of the BNT162b2 vaccine (mean, 165.6 days since receipt of the second dose), and the second group comprised those who had received three vaccine doses (mean, 25 days since receipt of the third dose) (Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). Significance was assessed with the use of a Wilcoxon matched-pairs signed-rank test. Receipt of three vaccine doses led to better neutralization of the wild-type virus and the three variants than receipt of two vaccine doses (Figure 1). The geometric mean titers of the wild-type virus and the beta, delta, and omicron variants were 16.56, 1.27, 8.00, and 1.11, respectively, after receipt of the second vaccine dose and 891.4, 152.2, 430.5, and 107.6, respectively, after receipt of the third dose. A significantly lower neutralization efficiency of the BNT162b2 vaccine against all the tested variants of concern (beta, delta, and omicron) than against the wild-type virus was observed in samples obtained from participants who had received two doses than in those obtained from participants who had received three doses (Figure 1B and 1D). The lower neutralization efficiency against the beta and omicron variants than against the wild-type virus was similar in samples obtained from participants who had received two doses and in those obtained from participants who had received three doses. The third dose of the BNT162b2 vaccine efficiently neutralized infection with the omicron variant (geometric mean titer, 1.11 after the second dose vs. 107.6 after the third dose) (Figure 1A and 1C). We analyzed the neutralization efficiency of the BNT162b2 vaccine against wild-type SARS-CoV-2 and the beta, delta, and omicron variants of concern. Limitations of the study include the small cohort tested and the fact that the test was only an in vitro assay. Nevertheless, we found low neutralization efficiency with two doses of the BNT162b2 vaccine against the wild-type virus and the delta variant, assessed more than 5 months after receipt of the second dose, and no neutralization efficiency against the omicron variant. The importance of a third vaccine dose is clear, owing to the higher neutralization efficiency (by a factor of 100) against the omicron variant after the third dose than after the second dose; however, even with three vaccine doses, neutralization against the omicron variant was lower (by a factor of 4) than that against the delta variant. The durability of the effect of the third dose of vaccine against Covid-19 is yet to be determined.

ABSTRACT The emerging new VOC B.1.1.529 (Omicron) variant has raised serious concerns due to multiple mutations, reported significant immune escape, and unprecedented rapid spreading speed. Currently, studies describing the neutralization ability of different homologous and heterologous booster vaccination against Omicron are still lacking. In this study, we explored the immunogenicity of COVID-19 breakthrough patients, BBIBP-CorV homologous booster group and BBIBP-CorV/ZF2001 heterologous booster group against SARS-CoV-2 pseudotypes corresponding to the prototype, Beta, Delta, and the emergent Omicron variant. Notably, at 14 days post two-dose inactivated vaccines, pVNT titre increased to 67.4 GMTs against prototype, 8.85 against Beta and 35.07 against Delta, while neutralization activity against Omicron was below the lower limit of quantitation in 80% of the samples. At day 14 post BBIBP-CorV homologous booster vaccination, GMTs of pVNT significantly increased to 285.6, 215.7, 250.8, 48.73 against prototype, Beta, Delta, and Omicron, while at day 14 post ZF2001 heterologous booster vaccination, GMTs of pVNT significantly increased to 1436.00, 789.6, 1501.00, 95.86, respectively. Post booster vaccination, 100% samples showed positive neutralization activity against Omicron, albeit illustrated a significant reduction (5.86- to 14.98-fold) of pVNT against Omicron compared to prototype at 14 days after the homologous or heterologous vaccine boosters. Overall, our study demonstrates that vaccine-induced immune protection might more likely be escaped by Omicron compared to prototypes and other VOCs. After two doses of inactivated whole-virion vaccines as the “priming” shot, a third heterologous protein subunit vaccine and a homologous inactivated vaccine booster could improve neutralization against Omicron.