T-follicular helper cell profiles differ by malaria antigen and for children compared to adults.

Circulating T-follicular helper (cT(FH)) cells have the potential to provide an additional correlate of protection against Plasmodium falciparum (Pf) as they are essential to promote B-cell production of long-lasting antibodies. Assessing the specificity of cT(FH) subsets to individual malaria antigens is vital to understanding the variation observed in antibody responses and identifying promising malaria vaccine candidates. Using spectral flow cytometry and unbiased clustering analysis, we assessed antigen-specific cT(FH) cell recall responses in vitro to malaria vaccine candidates Pf-schizont egress antigen-1 (PfSEA-1A) and Pf-glutamic acid-rich protein (PfGARP) within a cross-section of children and adults living in a malaria-holoendemic region of western Kenya. In children, a broad array of cT(FH) subsets (defined by cytokine and transcription factor expression) were reactive to both malaria antigens, PfSEA-1A and PfGARP, while adults had a narrow profile centering on cT(FH)17- and cT(FH)1/17-like subsets following stimulation with PfGARP only. Because T(FH)17 cells are involved in the maintenance of memory antibody responses within the context of parasitic infections, our results suggest that PfGARP might generate longer-lived antibody responses compared to PfSEA-1A. These findings have intriguing implications for evaluating malaria vaccine candidates as they highlight the importance of including cT(FH) profiles when assessing interdependent correlates of protective immunity.