Pneumococcal vaccine hyporesponsiveness in people living with HIV: A narrative review of immunological mechanisms and insights from minimally invasive lymph node sampling

Despite highly effective antiretroviral therapy, people living with HIV (PLWH) remain at elevated risk for invasive pneumococcal disease. Clinical studies show that, even with high CD4⁺ counts, PLWH exhibit diminished serological responses and rapid antibody decline following pneumococcal vaccination, plausibly due to underlying immune dysfunction. Germinal centers (GCs), located within lymph nodes, are essential for generating high-affinity antibodies, but are structurally and functionally disrupted in PLWH. These local impairments, combined with systemic immune dysregulation, contribute to vaccine hyporesponsiveness in PLWH. This narrative review links immunological findings from experimental and in vivo studies to clinical pneumococcal vaccine trials, to investigate mechanisms that may be leveraged to strengthen vaccine-induced immunity in PLWH. We also highlight the application of fine needle aspiration (FNA) of the lymph node as a way to study pneumococcal vaccine hyporesponsiveness in the GC and provide potential direction to improve responses for next-generation pneumococcal conjugate vaccines in PLWH.