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

  1. Suresh Pallikkuth
  2. Sidhartha Chaudhury
  3. Pinyi Lu
  4. Li Pan
  5. Erik Jongert
  6. Ulrike Wille-Reece
  7. Savita Pahwa  Is a corresponding author
  1. University of Miami Miller School of Medicine, United States
  2. Walter Reed Army Institute of Research, United States
  3. Biotechnology High Performance Computing Software Applications Institute (BHSAI), United States
  4. GSK Vaccine, Belgium
  5. PATH's Malaria Vaccine Initiative, United States

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 2nd dose that persisted after the 3rd 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 3rd vaccine dose. We conclude that the DFD regimen favors persistence of functional B cells post 3rd dose.

Data availability

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

Article and author information

Author details

  1. Suresh Pallikkuth

    Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, United States
    Competing interests
    No competing interests declared.
  2. Sidhartha Chaudhury

    Center for Enabling Capabilities, Walter Reed Army Institute of Research, Silver Spring, United States
    Competing interests
    No competing interests declared.
  3. Pinyi Lu

    Immunology & Vaccine Research, Biotechnology High Performance Computing Software Applications Institute (BHSAI), Maryland, United States
    Competing interests
    No competing interests declared.
  4. Li Pan

    Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, United States
    Competing interests
    No competing interests declared.
  5. Erik Jongert

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

    PATH's Malaria Vaccine Initiative, PATH's Malaria Vaccine Initiative, Washington DC, United States
    Competing interests
    No competing interests declared.
  7. 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.
    ORCID icon "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.

Reviewing Editor

  1. Urszula Krzych, Walter Reed Army Institute of Research, United States

Publication history

  1. Received: September 15, 2019
  2. Accepted: April 14, 2020
  3. Accepted Manuscript published: April 28, 2020 (version 1)
  4. Accepted Manuscript updated: April 29, 2020 (version 2)
  5. Version of Record published: May 11, 2020 (version 3)

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.

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  1. Suresh Pallikkuth
  2. Sidhartha Chaudhury
  3. Pinyi Lu
  4. Li Pan
  5. Erik Jongert
  6. Ulrike Wille-Reece
  7. Savita Pahwa
(2020)
A delayed fractionated dose RTS,S AS01 vaccine regimen mediates protection via improved T follicular helper and B cell responses
eLife 9:e51889.
https://doi.org/10.7554/eLife.51889
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