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Molecular correlates of vaccine-induced protection against typhoid fever
Henderson Zhu, … , Andrew J. Pollard, Daniel O’Connor
Henderson Zhu, … , Andrew J. Pollard, Daniel O’Connor
Published July 4, 2023
Citation Information: J Clin Invest. 2023;133(16):e169676. https://doi.org/10.1172/JCI169676.
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Clinical Research and Public Health Article has an altmetric score of 1

Molecular correlates of vaccine-induced protection against typhoid fever

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Abstract

BACKGROUND Typhoid 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.METHODS Bulk 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.RESULTS Transcriptomic 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.CONCLUSION The 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 REGISTRATION ClinicalTrials.gov NCT02324751.

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

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Figure 4

Clonal expansion in ViPS and ViTT participants at V7 with differential IGHV usage.

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Clonal expansion in ViPS and ViTT participants at V7 with differential I...
(A) Clonal expansion at V7 measured by clonal space homeostasis. Clonotype abundance of 50% is indicated by an orange dotted line. (B) Gini index at V7. Significance was determined by Mann-Whitney U test. (C and D) The Gini index at V7 correlates with ELISA and ELISPOT data. P values for R values were calculated using Spearman’s rank correlation test. P values for the Gini index and total IgG titers were calculated using the Mann-Whitney U test. Box plots show the median and IQR of the Gini index, Vi-specific IgG titers, and log Vi–specific IgG-secreting cell count for nTD (green) and TD (orange) participants. (C) The Gini index at V7 correlates with Vi-specific IgG titers at D0. (D) The Gini index at V7 correlates with log Vi–specific IgG-secreting cells at V7. Participants who received ViPS are denoted by a circle, and participants who received ViTT are denoted by a triangle. nTD participants are labeled in green and TD participants in orange. (E) Volcano plot shows the differential gene expression profile of nTD versus TD participants in both the ViTT and ViPS groups at V7. (F) IGHV usage across the time points for nTD and TD participants who received ViTT or ViPS. Mean IGHV usage of each IGHV gene represents the mean of the percentage of total BCR clonotypes utilizing the IGHV gene for each participant. IGHV with greater than 5% usage or greater than 1% increase from V0 to V7 are highlighted in color. (G) Average total BCR count in participants who expressed the BCR cluster.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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