Imprinted antibody responses against SARS-CoV-2 Omicron sublineages

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages carry distinct spike mutations resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters elicit plasma-neutralizing antibodies against Omicron BA.1, BA.2, BA.2.12.1, and BA.4/5, and that breakthrough infections, but not vaccination alone, induce neutralizing antibodies in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1, BA.2, and BA.4/5 receptor-binding domains, whereas Omicron primary infections elicit B cells of narrow specificity up to 6 months after infection. Although most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant–neutralizing antibody that is a strong candidate for clinical development. Description Defending against Omicron The Omicron BA.1 lineage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2021 and quickly became dominant, in part because of a large number of mutations that allowed escape from existing antibodies. New infection waves have come from other Omicron sublineages. Park et al. found that either a vaccination booster or a breakthrough infection elicits neutralization activity against the Omicron variants, but only a breakthrough infection induces an antibody response in the nasal mucosa, which might give better protection against transmission. Testing a panel of antibodies, the authors showed that the antibody S2X324 potently neutralizes all SARS-CoV-2 variants tested, making it a candidate for therapeutic development. A cryo–electron microscopy structure shows how this antibody accommodates Omicron-specific mutations to block binding of the viral spike protein to the human ACE2 receptor across the variants. —VV Vaccine boosters or breakthrough infections elicit plasma-neutralizing activity against Omicron variants.