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 for at-risk populations. Monovalent variant-specific booster vaccines, such as those for XBB.1.5, JN.1, and LP.8.1, aim to re-direct immune responses towards antigenically distinct variants; However, immune imprinting by multiple exposures to the ancestral SARS-CoV-2 spike (S) protein can hinder the de novo induction of these immune responses. Here, we profiled the SARS-CoV-2-specific immune response in healthcare workers up to 6 months after monovalent XBB.1.5 vaccination. Memory T– and B-cell responses, and antibodies were boosted up to 6 months post-vaccination. Neutralizing antibodies targeting Omicron subvariants circulating at the time of vaccination were preferentially boosted by vaccination but remained lower than those targeting the ancestral strain. Similar responses were seen for antibodies that mediate functionality through antibody-dependent cellular cytotoxicity, although these responses were more promiscuous. Broadly S-reactive B-cells were recalled with limited de novo induction of XBB.1.5-specific clones. Omicron RBD-directed B-cells targeting circulating subvariants were selected, and T-cell responses cross-reacted with all SARS-CoV-2 variants at 6 months post-vaccination. Combined, this comprehensive immune profiling demonstrates that despite evidence of imprinting, monovalent booster vaccination skews the immune response to Omicron lineage recognition.