Introduction People living with HIV (PLWH) can exhibit impaired immune responses to vaccines. Accumulating evidence indicates that PLWH, particularly those receiving antiretroviral therapy, mount strong antibody responses to COVID-19 vaccination, but fewer studies have examined cellular immune responses to vaccination. We measured SARS-CoV-2 spike-specific CD4+ and CD8+ T cell responses generated by two and three doses of COVID-19 vaccine in PLWH receiving antiretroviral therapy, compared to control participants without HIV. We also quantified T cell responses after post-vaccine breakthrough infection, and receipt of fourth vaccine doses, in a subset of PLWH.

Methods We quantified CD4+ and CD8+ T cells reactive to overlapping peptides spanning the ancestral SARS-CoV-2 spike protein in 50 PLWH and 87 controls without HIV, using an activation induced marker (AIM) assay. All participants remained SARS-CoV-2 naïve until at least one month after their third vaccine dose. SARS-CoV-2 infection was determined by seroconversion to nucleocapsid (N) antigen, which occurred in 21 PLWH and 38 controls post-third dose. Multivariable regression analyses were used to investigate relationships between sociodemographic, health and vaccine-related variables and vaccine-induced T cell responses, as well as breakthrough infection risk.

Results A third vaccine dose boosted spike-specific CD4+ and CD8+ T cell frequencies significantly above those measured after the second dose (all p<0.0001). Median T cell frequencies did not differ between PLWH and controls after the second dose (p>0.1), but CD8+ T cell responses were modestly lower in PLWH after the third dose (p=0.02), an observation that remained significant after adjustment for sociodemographic, health and vaccine-related variables (p=0.045). In PLWH who experienced breakthrough infection, median T cell frequencies increased even higher than those observed after three vaccine doses (p<0.03), and CD8+ T cell responses in this group remained higher even after a fourth vaccine dose (p=0.03). In multivariable analysis, the only factor associated with increased breakthrough infection risk was younger age, consistent with the rapid increases in SARS-CoV-2 seropositivity among younger adults in Canada after the initial appearance of the Omicron variant.

Conclusion PLWH receiving antiretroviral therapy mount strong T cell responses to COVID-19 vaccines that can be enhanced by booster doses or breakthrough infection.

The authors have declared no competing interest.

This work was supported by the Public Health Agency of Canada through a COVID-19 Immunology Task Force COVID-19 Hot Spots Award (2020-HQ-000120 to MGR, ZLB, MAB). Additional funding was received from the Canadian Institutes for Health Research (GA2-177713 to MAB), the Coronavirus Variants Rapid Response Network (FRN-175622 to MAB), the Canada Foundation for Innovation through Exceptional Opportunities Fund COVID-19 awards (to MAB, MLD, ZLB). FMM was supported by fellowships from the Canadian Institutes of Health Research (CIHR) Canadian HIV Trials Network and Michael Smith Health Research BC (MSHR-BC). FHO was supported by a Ph.D. fellowship from the Sub-Saharan African Network for TB-HIV Research Excellence (SANTHE), a DELTAS Africa Initiative (grant DEL-15-006). The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS) Alliance for Accelerating Excellence in Science in Africa (AESA) and supported by the New Partnership for Africa Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust [grant 107752/Z/15/Z] and the UK government. MCD was supported by a CIHR CGS-M award. MLD and ZLB hold Scholar Awards from MSHR-BC.

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The datasets analysed in this study are available from the corresponding author upon reasonable request. Data have also been deposited into the COVID-19 Immunology Task Force (CITF) data bank, available online at: https://portal.citf.mcgill.ca.