July 2018 | Volume 9 | Article 1660 1 ORIGINAL RESEARCH published: 25 July 2018 doi: 10.3389/fmmu.2018.01660 Frontiers in Immunology | www.frontiersin.org Edited by: Julius Clemence Hafalla, London School of Hygiene & Tropical Medicine, United Kingdom Reviewed by: Robin Stephens, The University of Texas Medical Branch at Galveston, United States Urszula Krzych, Walter Reed Army Institute of Research, United States Jason Scott Stumhofer, University of Arkansas for Medical Sciences, United States *Correspondence: Georgina Bowyer georgina.bowyer@ndm.ox.ac.uk Specialty section: This article was submitted to Vaccines and Molecular Therapeutics, a section of the journal Frontiers in Immunology Received: 10 May 2018 Accepted: 04 July 2018 Published: 25 July 2018 Citation: Bowyer G, Grobbelaar A, Rampling T, Venkatraman N, Morelle D, Ballou RW, Hill AVS and Ewer KJ (2018) CXCR3 + T Follicular Helper Cells Induced by Co-Administration of RTS,S/AS01B and Viral-Vectored Vaccines Are Associated With Reduced Immunogenicity and Effcacy Against Malaria. Front. Immunol. 9:1660. doi: 10.3389/fmmu.2018.01660 CXCR3 + T Follicular Helper Cells Induced by Co-Administration of RTS,S/AS01B and Viral-Vectored Vaccines Are Associated With Reduced Immunogenicity and Ef fcacy Against Malaria Georgina Bowyer 1 *, Amy Grobbelaar 1 , Tommy Rampling 1 , Navin Venkatraman 1 , Danielle Morelle 2 , Ripley W. Ballou 2 , Adrian V. S. Hill 1 and Katie J. Ewer 1 1 The Jenner Institute, University of Oxford, Oxford, United Kingdom, 2 GSK Vaccines, Rixensart, Belgium A malaria vaccine strategy targeting multiple lifecycle stages may be required to achieve a high level of effcacy. In two Phase IIa clinical trials, we tested immunogenicity and effcacy 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 effcacy 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 signifcantly reduced humoral immunogenicity and protective effcacy. 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 effcacy, the regimen design will require careful optimization. Keywords: malaria, vaccine, T follicular helper cell, antibody, effcacy, CXCR3, RTSS viral-vectored vaccines 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 efcacious vaccine could be an essential tool to enable any further reduction in morbidity and mortality, and for the ultimate goal of eradication (2). Te most advanced vaccine candidate, RTS,S, has shown signifcant short-term protective efcacy and has completed testing in a large Phase III trial (3–7). Abbreviations: ChAd, chimpanzee adenovirus; CHMI, controlled human malaria infection; CSP, circumsporozoite protein; cTf, circulating T follicular helper cell; GC, germinal center; ISI, inhibition of sporozoite invasion; ME, multi-epitope; MVA, modifed vaccinia virus Ankara; PBMCs, peripheral blood mononucleocytes; pfu, plaque-forming units; TRAP, thrombospon- din-related adhesive protein; VE, vaccine efcacy; VP, viral particles.