Abstract
The generation of protective humoral immunity after vaccination relies on the productive interaction between antigen-specific B cells and T follicular helper (Tfh) cells. Despite the central role of Tfh cells in vaccine responses, there is currently no validated way to enhance their differentiation in humans. From paired human lymph node and blood samples, we identify a population of circulating Tfh cells that are transcriptionally and clonally similar to germinal center Tfh cells. In a clinical trial of vaccine formulations, circulating Tfh cells were expanded in Tanzanian volunteers when an experimental malaria vaccine was adjuvanted in GLA-SE but not when formulated in Alum. The GLA-SE-formulated peptide was associated with an increase in the extrafollicular antibody response, long-lived antibody production, and the emergence of public TCRβ clonotypes in circulating Tfh cells. We demonstrate that altering vaccine adjuvants is a rational approach for enhancing Tfh cells in humans, thereby supporting the long-lived humoral immunity that is required for effective vaccines.
Highlights
Vaccination is one of the most powerful interventions for reducing the disability and death caused by infectious disease worldwide (Andre et al, 2008)
It is well established that there is a population of blood CXCR5+CD4+ cells that expands after vaccination (Bentebibel et al, 2013; He et al, 2013; Locci et al, 2013) and that these cTfh cells phenotypically and functionally resemble lymphoid tissue T follicular helper (Tfh) cells (Linterman and Hill, 2016)
Using HLA-DR tetramers in a subset of the volunteers with the appropriate HLA genotype (Yang et al, 2013), we were able to identify hemagglutinin (HA)-specific Inducible costimulator (ICOS)+CD38+CXCR5+PD-1+ cTfh cells 7 d after vaccination (Fig. S2, A–C). These data indicate that ICOS+CD38+CXCR5+PD-1+ cTfh cells could be a good biomarker of lymphoid tissue Tfh cells that support humoral immunity
Summary
Vaccination is one of the most powerful interventions for reducing the disability and death caused by infectious disease worldwide (Andre et al, 2008). Because Tfh cells are key determinants of the long-lived humoral immunity that arises from the GC, they represent an exciting therapeutic target through which vaccine strategies could be improved (Linterman and Hill, 2016). This is pertinent for malaria vaccine development, as clinical trials indicate that the development of long-lived antibody responses, in particular for the preerythrocytic and blood stages of infection, are essential for sustained protective immunity (Cockburn and Seder, 2018)
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