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.

Automated summary

SARS-CoV-2 Omicron sublineages have spike mutations that allow them to evade antibodies from previous infection or vaccination. Hybrid immunity or booster shots can generate neutralizing antibodies against Omicron variants, and breakthrough infections lead to the production of neutralizing antibodies in the nasal mucosa. Antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases show cross-reactivity with different receptor-binding domains, while primary Omicron infections elicit B cells with narrow specificity. A highly potent pan-variant-neutralizing antibody has been identified as a potential candidate for clinical development.