ABSTRACT
Background: Limited data exist regarding the immune benefits of fourth COVID-19 vaccine doses in people with HIV (PWH) receiving antiretroviral therapy (ART), particularly given that most have now experienced SARS-CoV-2 infection. We measured the effect of fourth doses on SARS-CoV-2 neutralization in 63 PWH, including 19 SARS-CoV-2-naive and 44 SARS-CoV-2-experienced participants. Method(s): Wild-type (WT)-, Omicron-BA.5 and Omicron-BQ.1-specific neutralization activities were longitudinally quantified using live virus assays up to one month post-fourth vaccine dose. Multiple linear regression was used to investigate the relationship between sociodemographic, health and vaccinerelated variables and SARS-CoV-2 neutralization. Result(s): Participants (54 male;9 female) received monovalent (44%) or bivalent (56%) mRNA fourth doses. In COVID-19-naive PWH, a fourth dose enhanced WT- and BA.5-specific neutralization modestly above three-dose levels (p=0.1). In COVID-19-experienced PWH, a fourth dose enhanced WT neutralization modestly (p=0.1) and BA.5 neutralization significantly (p=0.002). Consistent with the humoral benefits of 'hybrid' immunity, the highest neutralization was observed in COVID-19-experienced PWH after a fourth dose. Of note, PWH with Omicron-era infections exhibited higher WT-specific (p=0.04), but comparable BA.5- or BQ.1-specific neutralization, compared to PWH with pre-Omicron-era infections. Overall, BA.5 neutralization was significantly lower than WT in all participants regardless of COVID-19 experience, and BQ.1 neutralization was significantly lower than BA.5 (all p< 0.0001). In multivariable analyses, fourth dose valency did not significantly affect neutralization magnitude, nor did sex, age nor CD4+ T-cell count (neither recent nor nadir). Rather, an mRNA-1273 fourth dose (versus a BNT162b2 one) was the strongest correlate of WT-specific neutralization, while prior COVID-19, regardless of infection era, was the strongest correlate of BA.5 and BQ.1-specific neutralization post-fourth dose. Conclusion(s): Fourth COVID-19 vaccine doses, irrespective of valency, benefit PWH regardless of prior SARS-CoV-2 infection, but the highest neutralization of Omicron-BA.5 and BQ.1 variants post-fourth dose occurred in PWH with hybrid immunity. These results support existing recommendations that all adults receive a fourth immunization within 6 months of their third vaccine dose (or their most recent SARS-CoV-2 infection). (Figure Presented).