Background: Variant-adapted vaccines are recommended in vulnerable populations to address the waning immunity and the emergence of immune-escaping SARS-CoV-2 variants, yet data about immune responses to such vaccines in people living with HIV (PLWH) are limited. We therefore aimed to assess long-term immune responses to an original-BA.4/5 mRNA booster in this population.

Methods: In this prospective longitudinal study, PLWH receiving either an original-BA.4/5 bivalent booster or an original monovalent booster and HIV-negative healthcare workers (HCWs) receiving a bivalent booster were enrolled and sampled before (T0), 1 month (T1), and 4-9 months (T2) after the vaccine administration. SARS-CoV-2-specific T and B cells, RBD-binding antibodies, and RBD-blocking antibodies against both wild type (WT) and omicron BA.4/5 virus were determined.

Results: The bivalent booster is able to transiently increase both humoral and polyfunctional T cell responses in PLWH, with humoral responses comparable to those observed in HCWs. While T cell responses are cross-reactive against viral variants and stable over time, humoral immunity is imprinted to the ancestral virus and wanes quickly. Furthermore, whilst previous SARS-CoV-2 infection does not affect the trajectory of vaccine-elicited immune responses, markers of HIV-related T cell dysfunction are associated with lower antibody peak responses and higher antibody waning. Lastly, the bivalent booster was superior to the monovalent one in inducing BA.4/5-reactive RBD-blocking antibodies.

Conclusions: The original-BA.4/5 bivalent booster is highly immunogenic in PLWH and superior to the monovalent one in inducing humoral responses against the BA.4/5 virus, although HIV-related T cell dysfunction markers are associated with blunted and less durable antibody immunity.