HIV/aging contribute to inflammaging (chronic low-grade systemic inflammation) and immune senescence (accelerated aging of the immune system). Immune dysfunction, in the form of impaired antibody (Ab) responses to vaccines such as influenza (flu) vaccination, is observed in aging and HIV infection. Given the central role of IL-21 in Ab responses we hypothesized that administration of IL-21 as a flu vaccine adjuvant in aged, ART treated, SIV+ Rhesus Macaques (RM) would result in significant improvement in the quality of pTfh and B cell function alongside improved germinal center reactions, resulting in improved Ab responses to vaccination.
In this study flu vaccination was administered with (N=4) and without (N=4) subcutaneous IL-21 in a prime, boost, boost series at 3-month intervals to old ART treated, SIV+ (IV SIVmac239) RM. IL-21 was given (50µg/kg) on d-2, d0, d5 post each vaccine dose. Blood was collected on d0, d5, d14 and d42; and lymph node tissue was collected on d14 after each vaccine dose. Serum was analyzed for flu Ab titers, and PBMC with multicolor flow cytometry using panels for detailed phenotypic characterization of peripheral blood T follicular helper (pTfh) cells and CD4 memory populations.
In results analyzed to date, pre-prime H3N2 HAI titers of controls (mean=1:55) did not differ from IL-21 treated animals (mean=1:100). Titers increased significantly (p=0.0018) in IL-21 treated animals from 1:100 at baseline to 1:283 post boost 1 (PB1) and were significantly higher (P=<0.0001) than the PB1 control mean titer of 1:60 (Fig. 1A). We did not observe baseline differences in pTfh frequency between groups (Fig. 1A). IL-21 treated animals had significant (p=0.0118) expansion of pTfh, as measured by the fold change of pTfh frequency from day of Boost 1 (B1) to 14 days PB1, correlating with H3N2 HAI titers 14 days PB1 (R2=0.6978, P=0.0193, Fig. 1B). We also observed that the frequency of PD1+ pTfh cells was significantly higher (p=0.0188) in IL-21 treated animals (mean=27%) compared to controls (mean=16.7%) on the day of B1 and correlated with H3N2 HAI titers 14 days PB1 (R2=0.728, P=0.0146).
These findings suggest IL-21 has a significant adjuvant effect, improving flu vaccine titers in old, ART treated, SIV+ RM. As no baseline pTfh differences were observed, these results highlight that IL-21 may be directly or indirectly inducing a shift in pTfh cell kinetics and phenotype, warranting further investigation as a potential vaccine adjuvant.