Lymphopenia is associated with broad host response aberrations in community-acquired pneumonia.

OBJECTIVES: Lymphopenia at hospital admission occurs in over one-third of patients with community-acquired pneumonia (CAP), yet its clinical relevance and pathophysiological implications remain underexplored. We evaluated outcomes and immune features of patients with lymphopenic CAP (L-CAP), a previously described immunophenotype characterized by admission lymphocyte count <0.724 × 109 cells/L. METHODS: Observational study in 149 patients admitted to a general ward for CAP. We measured 34 plasma biomarkers reflective of inflammation, endothelial cell responses, coagulation, and immune checkpoints. We characterized lymphocyte phenotypes in 29 patients using spectral flow cytometry. RESULTS: L-CAP occurred in 45 patients (30.2%) and was associated with prolonged time-to-clinical-stability (median 5 versus 3 days), also when we accounted for competing events for reaching clinical stability and adjusted for baseline covariates (subdistribution hazard ratio 0.63; 95% confidence interval 0.45-0.88). L-CAP patients demonstrated a proportional depletion of CD4 T follicular helper cells, CD4 T effector memory cells, naïve CD8 T cells and IgG+ B cells. Plasma biomarker analyses indicated increased activation of the cytokine network and the vascular endothelium in L-CAP. CONCLUSIONS: L-CAP patients have a protracted clinical recovery course and a more broadly dysregulated host response. These findings highlight the prognostic and pathophysiological relevance of admission lymphopenia in patients with CAP.

Protein/AS01B vaccination elicits stronger, more Th2-skewed antigen-specific human T follicular helper cell responses than heterologous viral vectors.

Interactions between B cells and CD4+ T follicular helper (Tfh) cells are key determinants of humoral responses. Using samples from clinical trials performed with the malaria vaccine candidate antigen Plasmodium falciparum merozoite protein (PfRH5), we compare the frequency, phenotype, and gene expression profiles of PfRH5-specific circulating Tfh (cTfh) cells elicited by two leading human vaccine delivery platforms: heterologous viral vector prime boost and protein with AS01B adjuvant. We demonstrate that the protein/AS01B platform induces a higher-magnitude antigen-specific cTfh cell response and that this correlates with peak anti-PfRH5 IgG concentrations, frequency of PfRH5-specific memory B cells, and antibody functionality. Furthermore, our data indicate a greater Th2/Tfh2 skew within the polyfunctional response elicited following vaccination with protein/AS01B as compared to a Th1/Tfh1 skew with viral vectors. These data highlight the impact of vaccine platform on the cTfh cell response driving humoral immunity, associating a high-magnitude, Th2-biased cTfh response with potent antibody production.