High-Dose Influenza Vaccination Partially Restores Impaired T Follicular Helper Cell Function in Aging and HIV 2309758

Abstract Introduction We have previously noted that flu vaccine responses decline with aging and further impaired in people with HIV (PWH), linked to chronic inflammation and impaired peripheral T follicular helper cell (pTfh) function. This study evaluated young (Y) and old (O) virally suppressed people with HIV (PWH) and people without HIV (PWoH) to determine whether high-dose (HD) vaccination could overcome pTfh defects. Methods Participants (mean age, n) included YPWH (33, n = 10), OPWH (65, n = 19), YPWoH (31, n = 10), and OPWoH (65, n = 19), who received a standard-dose (SD) influenza vaccine in one season followed by HD the next. PBMC at D0 and D14 were stimulated with A/H1N1 for 12h and stained (surface/ICS) to identify Activation Induced Markers (AIM) CD40L and CD69 in pTfh (CD45RO+CXCR5+ PD-1hi)) CD4+ T cells and intracellular cytokines by high-dimensional flow cytometry. Serum A/H1N1 and whole-vaccine (WV) HAI titers were measured at D0 and D28. Results With SD, A/H1N1 D28/D0 titer fold change (FC) was higher in PWoH than PWH. H1N1-induced AIM+ pTfh frequencies did not differ across groups at D0 or D14 post-SD vaccine. In AIM+ pTfh cells at D14, intracellular IL-21 was similar between groups, but IL-2 and TNF-α (deleterious for Ab production) were higher in O vs Y participants. In OPWH, TNF-α at D14 negatively correlated with WV titer FC (r=-0.78, p = 0.04). In YPWoH, ICOS expression increased and the Th2 marker CCR6 was reduced in AIM+ pTfh cells from D0 to D14. In YPWH, HD increased pTfh frequencies at D14 verse SD and correlated with WV (r = 0.64, p = 0.046) and H1N1 titer FC (r = 0.71, p = 0.002). HD vaccination lowered IFN-γ and IL-2 in AIM+ pTfh cells versus SD among Y participants, while O participants increased ICOS expression that correlated with WV (r = 0.74, p = 0.002) and H1N1 titer FC (r = 0.54, p = 0.036) in OPWH. Conclusion HD vaccination increased AIM+ pTfh frequency, enhanced ICOS expression and reduced pro-inflammatory cytokine production in pTfh with improved vaccine responses in aging individuals and PWH. Funding Source R01AG068110 to S. Pahwa and S. Pallikkuth (MPI) Topic Categories Immune Mechanisms of Human Disease (HUM)