1. Immunology and Inflammation

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
https://doi.org/10.7554/eLife.51889
Share this article
Cite this article
  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
  2. Download BibTeX
  3. Download .RIS

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

Version 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.

Metrics

  • 1,628
    views
  • 286
    downloads
  • 45
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.51889

Categories and tags

Research organism

Further reading

    1. Immunology and Inflammation

    Uremic toxin indoxyl sulfate induces trained immunity via the AhR-dependent arachidonic acid pathway in end-stage renal disease (ESRD)

    Hee Young Kim, Yeon Jun Kang ... Won-Woo Lee
    Research Article

    Trained immunity is the long-term functional reprogramming of innate immune cells, which results in altered responses toward a secondary challenge. Despite indoxyl sulfate (IS) being a potent stimulus associated with chronic kidney disease (CKD)-related inflammation, its impact on trained immunity has not been explored. Here, we demonstrate that IS induces trained immunity in monocytes via epigenetic and metabolic reprogramming, resulting in augmented cytokine production. Mechanistically, the aryl hydrocarbon receptor (AhR) contributes to IS-trained immunity by enhancing the expression of arachidonic acid (AA) metabolism-related genes such as arachidonate 5-lipoxygenase (ALOX5) and ALOX5 activating protein (ALOX5AP). Inhibition of AhR during IS training suppresses the induction of IS-trained immunity. Monocytes from end-stage renal disease (ESRD) patients have increased ALOX5 expression and after 6 days training, they exhibit enhanced TNF-α and IL-6 production to lipopolysaccharide (LPS). Furthermore, healthy control-derived monocytes trained with uremic sera from ESRD patients exhibit increased production of TNF-α and IL-6. Consistently, IS-trained mice and their splenic myeloid cells had increased production of TNF-α after in vivo and ex vivo LPS stimulation compared to that of control mice. These results provide insight into the role of IS in the induction of trained immunity, which is critical during inflammatory immune responses in CKD patients.

    1. Cancer Biology
    2. Immunology and Inflammation

    DHODH inhibition enhances the efficacy of immune checkpoint blockade by increasing cancer cell antigen presentation

    Nicholas J Mullen, Surendra K Shukla ... Pankaj K Singh
    Research Article

    Pyrimidine nucleotide biosynthesis is a druggable metabolic dependency of cancer cells, and chemotherapy agents targeting pyrimidine metabolism are the backbone of treatment for many cancers. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine biosynthesis pathway that can be targeted by clinically approved inhibitors. However, despite robust preclinical anticancer efficacy, DHODH inhibitors have shown limited single-agent activity in phase 1 and 2 clinical trials. Therefore, novel combination therapy strategies are necessary to realize the potential of these drugs. To search for therapeutic vulnerabilities induced by DHODH inhibition, we examined gene expression changes in cancer cells treated with the potent and selective DHODH inhibitor brequinar (BQ). This revealed that BQ treatment causes upregulation of antigen presentation pathway genes and cell surface MHC class I expression. Mechanistic studies showed that this effect is (1) strictly dependent on pyrimidine nucleotide depletion, (2) independent of canonical antigen presentation pathway transcriptional regulators, and (3) mediated by RNA polymerase II elongation control by positive transcription elongation factor B (P-TEFb). Furthermore, BQ showed impressive single-agent efficacy in the immunocompetent B16F10 melanoma model, and combination treatment with BQ and dual immune checkpoint blockade (anti-CTLA-4 plus anti-PD-1) significantly prolonged mouse survival compared to either therapy alone. Our results have important implications for the clinical development of DHODH inhibitors and provide a rationale for combination therapy with BQ and immune checkpoint blockade.

    1. Immunology and Inflammation

    ER-to-lysosome Ca2+ refilling followed by K+ efflux-coupled store-operated Ca2+ entry in inflammasome activation and metabolic inflammation

    Hyereen Kang, Seong Woo Choi ... Myung-Shik Lee
    Research Article

    We studied lysosomal Ca2+ in inflammasome. Lipopolysaccharide (LPS) + palmitic acid (PA) decreased lysosomal Ca2+ ([Ca2+]Lys) and increased [Ca2+]i through mitochondrial ROS, which was suppressed in Trpm2-KO macrophages. Inflammasome activation and metabolic inflammation in adipose tissue of high-fat diet (HFD)-fed mice were ameliorated by Trpm2 KO. ER→lysosome Ca2+ refilling occurred after lysosomal Ca2+ release whose blockade attenuated LPS + PA-induced inflammasome. Subsequently, store-operated Ca2+entry (SOCE) was activated whose inhibition suppressed inflammasome. SOCE was coupled with K+ efflux whose inhibition reduced ER Ca2+ content ([Ca2+]ER) and impaired [Ca2+]Lys recovery. LPS + PA activated KCa3.1 channel, a Ca2+-activated K+ channel. Inhibitors of KCa3.1 channel or Kcnn4 KO reduced [Ca2+]ER, attenuated increase of [Ca2+]i or inflammasome activation by LPS + PA, and ameliorated HFD-induced inflammasome or metabolic inflammation. Lysosomal Ca2+ release induced delayed JNK and ASC phosphorylation through CAMKII-ASK1. These results suggest a novel role of lysosomal Ca2+ release sustained by ER→lysosome Ca2+ refilling and K+ efflux through KCa3.1 channel in inflammasome activation and metabolic inflammation.