Abstract
BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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.