Background: The COVID-19 pandemic posed significant challenges worldwide, with SARS-CoV-2 vaccines critical in reducing morbidity and mortality. This study evaluates the immunogenicity and antibody persistence of the BNT162b2 vaccine in people living with HIV (PLWH). Methods: We monitored anti-SARS-CoV-2 Spike IgG concentration in a cohort of PLWH at five time points (T0–T4) using chemiluminescent microparticle immunoassays (CMIAs) at the baselined both during and after vaccination. In severely immunocompromised individuals, a boosting dose was recommended, and participants and IgG concentration were measured in the two subgroups (boosted and not boosted). Results: In total, 165 PLWH were included, and 83% were male with a median age of 55 years (IQR: 47–62). At T1, 161 participants (97.6%) showed seroconversion with a median of IgG values of 468.8 AU/mL (IQR: 200.4–774.3 AU/mL). By T2, all subjects maintained a positive result, with the median anti-SARS-CoV-2 Spike IgG concentration increasing to 6191.6 AU/mL (IQR: 3666.7–10,800.8 AU/mL). At T3, all participants kept their antibody levels above the positivity threshold with a median of 1694.3 AU/mL (IQR: 926.3–2966.4 AU/mL). At T4, those without a booster dose exhibited a marked decrease to a median of 649.1 AU/mL (IQR: 425.5–1299.8 AU/mL), whereas those with a booster experienced a significant increase to a median of 13,105.2 AU/mL (IQR: 9187.5–18,552.1 AU/mL). The immune response was negatively influenced by the presence of dyslipidaemia at T1 (aOR 4.75, 95% CI: 1.39–16.20) and diabetes at T3 (aOR 7.11, 95% CI: 1.10–46.1), while the use of protease inhibitors (aORs 0.06, 95% CI: 0.01–0.91) and being female (aOR 0.02, 95% CI: 0.01–0.32) at T3 were protective factors. Conclusions: The immunogenicity of the BNT162b2 vaccine in PLWH has been confirmed, with booster doses necessary to maintain high levels of anti-SARS-CoV-2 Spike IgG antibodies, especially in patients with comorbidities. These findings underline the importance of a personalized vaccination strategy in this population.
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