1. Immunology and Inflammation
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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. Biotechnology HPC Software Applications Institute, U.S. Army Medical Research and Materiel Command, United States
  3. GSK Vaccine, Belgium
  4. PATH's Malaria Vaccine Initiative, United States
  5. University of Miami Miller School of Medicine, United States
Research Article
  • Cited 19
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Cite this article as: eLife 2020;9:e51889 doi: 10.7554/eLife.51889

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
    The authors declare that no competing interests exist.
  2. Sidhartha Chaudhury

    Telemedicine and Advanced Technology Research Center, Biotechnology HPC Software Applications Institute, U.S. Army Medical Research and Materiel Command, Maryland, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Pinyi Lu

    Telemedicine and Advanced Technology Research Center, Biotechnology HPC Software Applications Institute, U.S. Army Medical Research and Materiel Command, Maryland, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Li Pan

    Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Erik Jongert

    GSK Vaccine, Rixensart, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  6. Ulrike Wille-Reece

    PATH's Malaria Vaccine Initiative, PATH's Malaria Vaccine Initiative, Washington DC, United States
    Competing interests
    The authors declare that no competing interests exist.
  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
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4470-4216

Funding

Program for Appropriate Technology in Health

  • Savita Pahwa

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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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Further reading

    1. Immunology and Inflammation
    Takemichi Fukasawa et al.
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    Despite antigen affinity of B cells varying from cell to cell, functional analyses of antigen-reactive B cells on individual B cells are missing due to technical difficulties. Especially in the field of autoimmune diseases, promising pathogenic B cells have not been adequately studied to date because of its rarity. In this study, functions of autoantigen-reactive B cells in autoimmune disease were analyzed at the single-cell level. Since topoisomerase I is a distinct autoantigen, we targeted systemic sclerosis as autoimmune disease. Decreased and increased affinities for topoisomerase I of topoisomerase I-reactive B cells led to anti-inflammatory and pro-inflammatory cytokine production associated with the inhibition and development of fibrosis, which is the major symptom of systemic sclerosis. Furthermore, inhibition of pro-inflammatory cytokine production and increased affinity of topoisomerase I-reactive B cells suppressed fibrosis. These results indicate that autoantigen-reactive B cells contribute to the disease manifestations in autoimmune disease through their antigen affinity.

    1. Immunology and Inflammation
    Drew Wilfahrt et al.
    Research Article

    After antigenic activation, quiescent naive CD4+ T cells alter their metabolism to proliferate. This metabolic shift increases production of nucleotides, amino acids, fatty acids, and sterols. Here, we show that histone deacetylase 3 (HDAC3) is critical for activation of murine peripheral CD4+ T cells. HDAC3-deficient CD4+ T cells failed to proliferate and blast after in vitro TCR/CD28 stimulation. Upon T-cell activation, genes involved in cholesterol biosynthesis are upregulated while genes that promote cholesterol efflux are repressed. HDAC3-deficient CD4+ T cells had reduced levels of cellular cholesterol both before and after activation. HDAC3-deficient cells upregulate cholesterol synthesis appropriately after activation, but fail to repress cholesterol efflux; notably, they overexpress cholesterol efflux transporters ABCA1 and ABCG1. Repression of these genes is the primary function for HDAC3 in peripheral CD4+ T cells, as addition of exogenous cholesterol restored proliferative capacity. Collectively, these findings demonstrate HDAC3 is essential during CD4+ T-cell activation to repress cholesterol efflux.