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Summary 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., Graphical abstract, Highlights CD4 Tfh comparison in malaria vaccine trials using leading human vaccine platforms Protein/AS01B drives stronger antigen-specific Tfh responses than viral vectors Greater T(f)h2 skewing of antigen-specific CD4 T cells in protein/AS01B vaccinees Antigen-specific CD4 T(fh) cell parameters correlate with functional antibody, Nielsen et al. evaluate the induction of antigen-specific T follicular helper cell responses in human malaria vaccine trials using protein/adjuvant (AS01B) or heterologous viral vector platforms. They demonstrate that protein/AS01B drives a higher-magnitude polyfunctional response with greater skewing toward a Th2 phenotype, associated with superior production of neutralizing antibodies.