Molecular correlates of vaccine-induced protection against typhoid fever
<p><strong>BACKGROUND.</strong> Typhoid fever is caused by the Gram-negative bacterium <i>Salmonella enterica</i> serovar Typhi and poses a substantial public health burden worldwide. Vaccines have been developed based on the surface Vi-capsular polysaccharide of <i&...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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American Society for Clinical Investigation
2023
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| _version_ | 1797110708607909888 |
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| author | Zhu, H Chelysheva, I Cross, DL Blackwell, L Jin, C Gibani, MM Jones, E Hill, J Trück, J Kelly, DF Blohmke, C Pollard, AJ O'Connor, D |
| author_facet | Zhu, H Chelysheva, I Cross, DL Blackwell, L Jin, C Gibani, MM Jones, E Hill, J Trück, J Kelly, DF Blohmke, C Pollard, AJ O'Connor, D |
| author_sort | Zhu, H |
| collection | OXFORD |
| description | <p><strong>BACKGROUND.</strong> Typhoid fever is caused by the Gram-negative bacterium <i>Salmonella enterica</i> serovar Typhi and poses a substantial public health burden worldwide. Vaccines have been developed based on the surface Vi-capsular polysaccharide of <i>S</i>. 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.</p>
<p><strong>METHODS.</strong> Bulk RNA-Seq data were generated from blood samples obtained from adult human volunteers enrolled in a vaccine trial, who were then challenged with <i>S</i>. 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.</p>
<p><strong>RESULTS.</strong> 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 (<i>IGHV</i>) genes and more polarized clonal expansions. We describe several molecular correlates of protection against <i>S</i>. Typhi infection, including clusters of B cell receptor (BCR) clonotypes associated with protection, with known binders of Vi-polysaccharide among these.</p>
<p><strong>CONCLUSION.</strong> 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.</p>
<p><strong>TRIAL REGISTRATION.</strong> ClinicalTrials.gov NCT02324751.</p> |
| first_indexed | 2024-03-07T07:58:38Z |
| format | Journal article |
| id | oxford-uuid:288fcd86-f7b0-4482-854f-a15490b8a9b4 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:58:38Z |
| publishDate | 2023 |
| publisher | American Society for Clinical Investigation |
| record_format | dspace |
| spelling | oxford-uuid:288fcd86-f7b0-4482-854f-a15490b8a9b42023-09-15T15:53:39ZMolecular correlates of vaccine-induced protection against typhoid feverJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:288fcd86-f7b0-4482-854f-a15490b8a9b4EnglishSymplectic ElementsAmerican Society for Clinical Investigation2023Zhu, HChelysheva, ICross, DLBlackwell, LJin, CGibani, MMJones, EHill, JTrück, JKelly, DFBlohmke, CPollard, AJO'Connor, D<p><strong>BACKGROUND.</strong> Typhoid fever is caused by the Gram-negative bacterium <i>Salmonella enterica</i> serovar Typhi and poses a substantial public health burden worldwide. Vaccines have been developed based on the surface Vi-capsular polysaccharide of <i>S</i>. 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.</p> <p><strong>METHODS.</strong> Bulk RNA-Seq data were generated from blood samples obtained from adult human volunteers enrolled in a vaccine trial, who were then challenged with <i>S</i>. 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.</p> <p><strong>RESULTS.</strong> 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 (<i>IGHV</i>) genes and more polarized clonal expansions. We describe several molecular correlates of protection against <i>S</i>. Typhi infection, including clusters of B cell receptor (BCR) clonotypes associated with protection, with known binders of Vi-polysaccharide among these.</p> <p><strong>CONCLUSION.</strong> 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.</p> <p><strong>TRIAL REGISTRATION.</strong> ClinicalTrials.gov NCT02324751.</p> |
| spellingShingle | Zhu, H Chelysheva, I Cross, DL Blackwell, L Jin, C Gibani, MM Jones, E Hill, J Trück, J Kelly, DF Blohmke, C Pollard, AJ O'Connor, D Molecular correlates of vaccine-induced protection against typhoid fever |
| title | Molecular correlates of vaccine-induced protection against typhoid fever |
| title_full | Molecular correlates of vaccine-induced protection against typhoid fever |
| title_fullStr | Molecular correlates of vaccine-induced protection against typhoid fever |
| title_full_unstemmed | Molecular correlates of vaccine-induced protection against typhoid fever |
| title_short | Molecular correlates of vaccine-induced protection against typhoid fever |
| title_sort | molecular correlates of vaccine induced protection against typhoid fever |
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