Heterogeneity of baseline immune activation and SARS-CoV-2 vaccine responses in people with HIV: a multicenter prospective study.

OBJECTIVE: To determine whether baseline immune activation and inflammation contribute to heterogeneity in SARS-CoV-2 vaccine-induced immunity in antiretroviral therapy (ART)-treated people with HIV (PWH) compared to HIV-negative controls. METHODS: In this multicenter prospective study, 159 ART-treated PWH from two cohorts and 56 HIV-negative controls were enrolled. The two PWH cohorts differed in immunovirological control: one showed sustained viral suppression and CD4+ T-cell recovery, the other persistent CD4+ T-cell lymphopenia despite ART, sometimes with residual viremia. Baseline plasma levels of 20 cytokines, chemokines and soluble endothelial markers, were measured before SARS-CoV-2 mRNA vaccination. Post-vaccination anti-Spike IgG, neutralizing antibodies, and IFN-γ-producing T cells were quantified and correlated with baseline immune mediators. RESULTS: PWH had higher baseline levels of innate immune activation and endothelial inflammation markers than controls, particularly among immunological non-responders. Principal component analysis identified two inflammatory profile groups among PWH: one characterized by Th1/Th17-oriented cytokine profile, and the other with dominant monocyte activation and endothelial markers. Higher baseline inflammation in PWH was associated with reduced humoral vaccine responses and elevated ICAM-1 levels with decreased IFN-γ T-cell responses, irrespective of prior SARS-CoV-2 infection. In contrast, among HIV-negative participants with prior SARS-CoV-2 exposure, higher sCD14, IL-12p70, MCP-1, and E-selectin levels correlated with stronger humoral responses, whereas ICAM-1 was associated with increased IFN-γ T-cell responses. CONCLUSION: Baseline inflammatory and endothelial profiles may constitute additional determinants of SARS-CoV-2 vaccine-induced immune responses in PWH. The opposite associations observed in controls highlight the context-dependent immunological effects of these pathways across chronic immune dysfunction and immunocompetent states.