Memory B cell repertoire from triple vaccinees

Omicron (B.1.1.529), the most highly mutated variant of SARS-CoV-2 to date, is highly resistant to neutralizing antibodies, raising concerns about the efficacy of antibody therapies and vaccines1, 2. Here, we investigated whether sera from people who received two or three doses of inactivated SARS-CoV-2 vaccine could neutralize authentic Omicron.

Neutralizing antibody seroconversion rates were 3.3% (2 of 60) and 95% (57 of 60) for people who received 2 and 3 doses of vaccine, respectively. For recipients of three vaccine doses, the geometric mean neutralizing antibody titer for Omicron was 16.5 times lower than for the ancestral virus (254).

We isolated 323 memory B cell-derived human monoclonal antibodies from triplicate vaccinees, half of which recognized the receptor-binding domain, and showed that a subset (24 of 163) potently neutralized all SARS variants of concern. -CoV-2, including Omicron. Therapeutic treatments with representative broadly neutralizing monoclonal antibodies were highly protective against infection of mice with SARS-CoV-2 Beta (B.1.351) and Omicron.

Atomic structures of the Omicron spike protein in complex with three classes of antibodies that were active against the five variants of concern defined binding and neutralization determinants and revealed a key antibody escape site, G446S, which confers greater resistance to a class of antibodies that bind to the right shoulder of the receptor binding domain by altering the local conformation at the binding interface.

Our results rationalize the use of three-dose immunization schedules and suggest that the fundamental epitopes revealed by these largely ultrapotent antibodies are rational targets for a universal sarbecovirus vaccine.

The ongoing evolution and emergence of SARS-CoV-2 variants has heightened concerns about the efficacy of monoclonal antibody-based therapies and vaccines3,4,5, posing challenges for control of the global pandemic. These variants have been classified as variants of interest (VOI) or variants of concern (VOC) by the World Health Organization (WHO).

The more recently identified Omicron variant, referred to as a new COV, has led to an increase in COVID-19 cases in South Africa and is now spreading globally6. Omicron is the most highly mutated variant to emerge to date, with over 30 mutations in its spike (S) protein, 15 of which occur in the receptor binding domain (RBD). Additionally, there are three small deletions and a three-residue insertion in the N-terminal domain (NTD) of the S1 subunit (Fig. 1a).

The pattern of some of these alterations, similar to those noted in previous VOCs, such as Δ69–70 in Alpha (B.1.1.7), N501Y in Alpha, Beta, and Gamma (P.1), and P681H in Alpha and Delta (B.1.617.2), are associated with increased transmissibility, while many substitutions, including G142D/Δ143–145, ins214EPE, K417N, T478K, E484A, Q493R, and N501Y, are closely related to resistance to neutralizing antibodies and vaccine-induced humoral antibodies. immunity