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Publications

Clinical Trial Journal Article Research Support, Non-U.S. Gov't Epublish 6 citations

PubMed: 37402153 DOI: 10.1172/JCI169676

Molecular correlates of vaccine-induced protection against typhoid fever.

J Clin Invest 133(16)

Authors: Henderson Zhu, Irina Chelysheva, Deborah L Cross, Luke Blackwell, Celina Jin, Malick M Gibani, Elizabeth Jones, Jennifer Hill, Johannes Trück, Dominic F Kelly, Christoph J Blohmke, Andrew J Pollard, Daniel O'Connor

Affiliations

  • Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
  • NIHR Oxford Biomedical Research Centre and Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.
  • Department of Infectious Disease, Imperial College London, St Mary's Campus, London, United Kingdom.
  • Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom. NIHR Oxford Biomedical Research Centre and Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.
  • Division of Immunology, University Children's Hospital Zurich, Zurich, Switzerland.

Abstract

BACKGROUNDTyphoid fever is caused by the Gram-negative bacterium Salmonella enterica serovar Typhi and poses a substantial public health burden worldwide. Vaccines have been developed based on the surface Vi-capsular polysaccharide of S. Typhi; these include a plain-polysaccharide-based vaccine, ViPS, and a glycoconjugate vaccine, ViTT. To understand immune responses to these vaccines and their vaccine-induced immunological protection, molecular signatures were analyzed using bioinformatic approaches.METHODSBulk RNA-Seq data were generated from blood samples obtained from adult human volunteers enrolled in a vaccine trial, who were then challenged with S. Typhi in a controlled human infection model (CHIM). These data were used to conduct differential gene expression analyses, gene set and modular analyses, B cell repertoire analyses, and time-course analyses at various post-vaccination and post-challenge time points between participants receiving ViTT, ViPS, or a control meningococcal vaccine.RESULTSTranscriptomic responses revealed strong differential molecular signatures between the 2 typhoid vaccines, mostly driven by the upregulation in humoral immune signatures, including selective usage of immunoglobulin heavy chain variable region (IGHV) genes and more polarized clonal expansions. We describe several molecular correlates of protection against S. Typhi infection, including clusters of B cell receptor (BCR) clonotypes associated with protection, with known binders of Vi-polysaccharide among these.CONCLUSIONThe study reports a series of contemporary analyses that reveal the transcriptomic signatures after vaccination and infectious challenge, while identifying molecular correlates of protection that may inform future vaccine design and assessment.TRIAL REGISTRATIONClinicalTrials.gov NCT02324751.

MeSH

Cells, Genes, Typhoid Fever, Vaccines, Polysaccharides, Vaccination, Infections

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