Molecular correlates of vaccine-induced protection against typhoid fever
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
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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Clinical Research and Public Health

Molecular correlates of vaccine-induced protection against typhoid fever

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 6

Amino acid sequence conservation of BCR cluster 184.

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Amino acid sequence conservation of BCR cluster 184. (A) Expression of c...
(A) Expression of cluster 184 in ViTT and ViPS recipients at V7. (B) Logo plot highlighting probability and amino acid residue properties. (C) pLogo plot demonstrating that most amino acid residues are significantly outstanding from the background. Significance was determined by Mann–Whitney U test; the red lines indicate a significance level cutoff of P < 0.05. (D and E) Amino acid sequence conservation calculated by Clustal Omega (19) between (D) cluster 184 CDR H3 sequences alone and (E) cluster 184 CDR H3 sequences and known Vi-binding BCR CDR H3 sequences. Three example sequences for each are included for simplicity. An asterisk denotes positions that have a single, fully conserved residue; a colon denotes amino acids with strong similarity, which scores higher than 0.5 in the Gonnet PAM 250 matrix. Conservation is highlighted in crimson (*) and orange (:). (F) Unique BCR clonotypes in cluster 184 and 711 and the relative proximity to known Vi-binding BCR CDR H3 sequences at V0 and V7 for ViPS and ViTT participants. The number of unique BCR clonotypes was normalized by the number of participants for each time point.