CXCR3+ T Follicular Helper Cells Induced by Co-Administration of RTS,S/AS01B and Viral-Vectored Vaccines Are Associated With Reduced Immunogenicity and Efficacy Against Malaria.

Adrian V. S. Hill,Georgina Bowyer,Ripley W. Ballou,Navin Venkatraman,Tommy Rampling,Amy Grobbelaar,Danielle Morelle,Katie J. Ewer

doi:10.3389/fimmu.2018.01660

Adrian V. S. Hill, Georgina Bowyer

Open Access

https://doi.org/10.3389/fimmu.2018.01660

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Abstract

A malaria vaccine strategy targeting multiple lifecycle stages may be required to achieve a high level of efficacy. In two Phase IIa clinical trials, we tested immunogenicity and efficacy of RTS,S/AS01B administered alone, in a staggered regimen with viral-vectored vaccines or co-administered with viral-vectored vaccines. RTS,S/AS01B induces high titers of antibody against sporozoites and viral-vectored vaccines ChAd63 ME-TRAP and MVA ME-TRAP induce potent T cell responses against infected hepatocytes. By combining these two strategies, we aimed to improve efficacy by inducing immune responses targeting multiple parasite antigens. Vaccination with RTS,S/AS01B alone or in a staggered regimen with viral vectors produced strong immune responses and demonstrated high levels of protection against controlled human malaria infection. However, concomitant administration of these vaccines significantly reduced humoral immunogenicity and protective efficacy. Strong Th1-biased cytokine responses induced by MVA ME-TRAP were associated with a skew in circulating T follicular helper cells toward a CXCR3+ phenotype and a reduction in antibody quantity and quality. This study illustrates that while a multistage-targeting vaccine strategy could provide high-level efficacy, the regimen design will require careful optimization.

Highlights

Despite years of remarkable success in reducing malaria morbidity and mortality, progress appears to have stalled with 216 million new cases in 2016, 5 million more than 2015 [1]
Reduced Quantity and Quality of Antibody Responses When RTS,S/AS01B Is CoAdministered With Viral-Vectored Vaccines
Volunteers receiving RTS,S/AS01B alone (G1/2, R) Spearman r: −0.012, P = 0.96, RTS,S/AS01B co-administered with vectors (G3/4, R + V) Spearman r: 0.58, P = 0.0094 or RTS,S/AS01B and viral vectors given in a staggered regimen Spearman r: 0.06, P = 0.82

Summary

Introduction

Despite years of remarkable success in reducing malaria morbidity and mortality, progress appears to have stalled with 216 million new cases in 2016, 5 million more than 2015 [1]. An efficacious vaccine could be an essential tool to enable any further reduction in morbidity and mortality, and for the ultimate goal of eradication [2]. The most advanced vaccine candidate, RTS,S, has shown significant short-term protective efficacy and has completed testing in a large Phase III trial [3,4,5,6,7]. There remains a need to improve efficacy to achieve the goals laid out in the Malaria Vaccine Technology Roadmap [8]. It may be necessary to develop a vaccine regimen targeting multiple stages of the parasite lifecycle [9]. It is likely that for a multistage vaccine regimen to provide high-level efficacy, it will need to induce both potent T cell and antibody responses [9]

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