Protein/AS01B vaccination elicits stronger, more Th2-skewed antigen-specific human T follicular helper cell responses than heterologous viral vectors

Carolyn M Nielsen,Rebecca A Dabbs,Sarah E Silk,Jordan R Barrett,Isabela Pedroza-Pacheco,Todd Bradley,Kazutoyo Miura,Lea Barfod,Simon J Draper,Martino Bardelli,Susanne E Doeleman,Persephone Borrow,Yue Chen,Carole A Long,Ababacar Diouf,Angela M Minassian,Ane Ogbe,Barton F Haynes,Sean C Elias,Ruth Payne

doi:10.1016/j.xcrm.2021.100207

Abstract

SummaryInteractions 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.

Highlights

For many pathogens, protective immunity is conferred by antibodies
We focus on the impact of vaccine platform on the immune response elicited in humans by comparing 2 leading vaccine platforms that were used to deliver the same blood-stage P. falciparum malaria antigen RH5 (PfRH5) in Phase Ia trials: heterologous viral vectors and 3-dose full-length PfRH5 protein co-administered with the GlaxoSmithKline adjuvant AS01B
The frequency of circulating Tfh (cTfh) cells within the memory (CD45RAÀ) CD4+ T cell population was compared at baseline, 1 and 2 weeks after the first vaccination, and at day 63. cTfh cells were defined as either CXCR5+ or CXCR5+PD1+ cells within CD45RAÀCD4+ T cells (Figure S2), consistent with 2 commonly used approaches.[8,10,11,12,13,14,18,20,23,27]

Summary

Introduction

Protective immunity is conferred by antibodies. A successful vaccine is one that is capable of driving a B cell response that results in the production of sufficient circulating antibody to neutralize the pathogen and/ or block disease development in future infection. We focus on the impact of vaccine platform on the immune response elicited in humans by comparing 2 leading vaccine platforms that were used to deliver the same blood-stage P. falciparum malaria antigen RH5 (PfRH5) in Phase Ia trials: heterologous viral vectors (chimpanzee adenovirus serotype 63 prime, followed by modified vaccinia virus Ankara boost [ referred to as ChAd63-MVA]1) and 3-dose full-length PfRH5 protein co-administered with the GlaxoSmithKline adjuvant AS01B (protein/AS01B2). These 2 platforms have been used in vaccine development for a diverse range of diseases, including Ebola (heterologous viral vectors), pre-erythrocytic malaria (RTS,S/ Mosquirix), and shingles (Shingrix; both AS01; reviewed in O’Donnell and Marzi,[3] Laurens,[4] and Heinemann et al.[5]).

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Results

Discussion

Conclusion