Preferential boosting of SARS-CoV-2 Omicron lineage-specific immune responses by monovalent XBB.1.5 vaccination

Ongoing escape from pre-existing antibodies by severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2) necessitates yearly coronavirus disease 2019 (COVID-19) vaccine updates. Monovalent variant-specific booster vaccines for at-risk populations aim to re-direct antibody responses towards antigenically distinct variants. However, multiple past exposures to the ancestral SARS-CoV-2 spike (S) protein through vaccination and infection could hinder the de novo induction of variant-specific immune responses.

Here, we profiled SARS-CoV-2-specific antibody, T- and B-cell responses in healthcare workers up to 6 months after monovalent XBB.1.5 vaccination.

Neutralizing antibodies targeting Omicron subvariants circulating at the time of vaccination were preferentially boosted by vaccination but remained lower than those neutralizing the ancestral strain. Similar responses were observed for antibodies that mediate functionality through antibody-dependent cellular cytotoxicity, although these responses were more promiscuous. Broadly S-reactive B-cells were recalled by vaccination, with limited de novo induction of XBB.1.5-specific B-cell clones. B-cells targeting the receptor binding domain of circulating Omicron subvariants were favored, and T-cell responses cross-reacted with all SARS-CoV-2 variants that were assessed.

Combined, this comprehensive immune profiling demonstrates that despite evidence of imprinted antibody responses targeting ancestral S, monovalent booster vaccination skews the immune response to Omicron lineage recognition.