A delayed fractionated dose RTS,S AS01 vaccine regimen mediates protection via improved T follicular helper and B cell responses

Abstract
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Abstract

Malaria-071, a controlled human malaria infection trial, demonstrated that administration of three doses of RTS,S/AS01 malaria vaccine given at one month intervals was inferior to a delayed fractional dose (DFD) schedule (62.5% vs 86.7% protection respectively). To investigate the underlying immunologic mechanism, we analyzed the B and T peripheral follicular helper cell (pTfh) responses. Here we show that protection in both study arms was associated with early induction of functional IL-21-secreting circumsporozoite (CSP)-specific pTfh cells together with induction of CSP-specific memory B cell responses after the 2^nd dose that persisted after the 3^rd dose. Data integration of key immunologic measures identified a subset of non-protected individuals in the standard (STD) vaccine arm who lost prior protective B cell responses after receiving the 3^rd vaccine dose. We conclude that the DFD regimen favors persistence of functional B cells post 3^rd dose.

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All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 2, 3, 4 and 5

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Suresh Pallikkuth

Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, United States

Competing interests
No competing interests declared.
Sidhartha Chaudhury

Center for Enabling Capabilities, Walter Reed Army Institute of Research, Silver Spring, United States

Competing interests
No competing interests declared.
Pinyi Lu

Immunology & Vaccine Research, Biotechnology High Performance Computing Software Applications Institute (BHSAI), Maryland, United States

Competing interests
No competing interests declared.
Li Pan

Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, United States

Competing interests
No competing interests declared.
Erik Jongert

GSK Vaccine, Rixensart, Belgium

Competing interests
Erik Jongert, is an employee of GSK, and own shares of GSK.
Ulrike Wille-Reece

PATH's Malaria Vaccine Initiative, PATH's Malaria Vaccine Initiative, Washington DC, United States

Competing interests
No competing interests declared.
Savita Pahwa

Miami Center for AIDS Research, Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, United States

For correspondence
spahwa@med.miami.edu

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-4470-4216

Funding

PATH's Malaria Vaccine Initiative

Savita Pahwa

The funder contributed to conceptualization, data review and manuscript preparation.

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.