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

Abstract

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.

Keywords: Pneumococcal vaccination; germinal centers; lymph node fine-needle aspiration; people living with HIV; pneumococcal conjugate vaccine; pneumococcal polysaccharide vaccine.

Figure 1.

Differences in T cell-dependent (PCV) vs T cell-independent (PPV) pneumococcal vaccine responses in humans. This figure was created using BioRender software.

Figure 2.

Schematic overview of GC formation. 1) Early GC formation and clonal expansion occurring within weeks after initial contact with antigens. 2) Somatic hypermutation in the dark zone. 3) Selection in the light zone, B cells move into the light zone, where their modified B cell receptors are tested for improved antigen binding with help from T_fh cells and follicular dendritic cells. B cells with higher BCR affinity capture more antigen, receiving more T cell help, resulting in positive selection. B cells with unfavorable BCRs undergo apoptosis. 4) Recirculation and further mutation. Positively selected B cells undergo immunoglobulin class-switch recombination and are instructed to recirculate to the dark zone. In the dark zone, these B cells proliferate and undergo further SHM, generating higher affinity antibodies. 5) Final differentiation: antigen-selected B cells differentiate into memory B cell precursor cells and plasmablasts. This figure was created using BioRender software.

Figure 3.

Schematic overview of germinal center changes in PLWH. FDC = follicular dendritic cells. T_regs = T follicular regulatory cells. T_fh = T follicular helper cells. B_gc = germinal center B cells. This figure was created using BioRender software.

Figure 4.

GC and non-GC related immunological alterations in PLWH affecting vaccine responses. This figure was created using BioRender software.

Figure 5.

Detailed lymph node fine-needle aspiration procedure. This figure was created using BioRender software.