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Article ; Online: Host restriction, pathogenesis and chronic carriage of typhoidal Salmonella.

J Barton, Amber / Hill, Jennifer / J Blohmke, Christoph / J Pollard, Andrew

2021 Volume 45, Issue 5

Abstract: While conjugate vaccines against typhoid fever have recently been recommended by the World Health Organization for deployment, the lack of a vaccine against paratyphoid, multidrug resistance and chronic carriage all present challenges for the elimination ...

Abstract	While conjugate vaccines against typhoid fever have recently been recommended by the World Health Organization for deployment, the lack of a vaccine against paratyphoid, multidrug resistance and chronic carriage all present challenges for the elimination of enteric fever. In the past decade, the development of in vitro and human challenge models has resulted in major advances in our understanding of enteric fever pathogenesis. In this review, we summarise these advances, outlining mechanisms of host restriction, intestinal invasion, interactions with innate immunity and chronic carriage, and discuss how this knowledge may progress future vaccines and antimicrobials.
MeSH term(s)	Humans ; Salmonella ; Salmonella paratyphi A ; Salmonella typhi ; Typhoid Fever/prevention & control ; Typhoid-Paratyphoid Vaccines
Chemical Substances	Typhoid-Paratyphoid Vaccines
Language	English
Publishing date	2021-03-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	283740-7
ISSN	1574-6976 ; 0168-6445
ISSN (online)	1574-6976
ISSN	0168-6445
DOI	10.1093/femsre/fuab014
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Article ; Online: Early transcriptional responses to human enteric fever challenge.

Barton, Amber / Hill, Jennifer / O'Connor, Daniel / Jones, Claire / Jones, Elizabeth / Camara, Susana / Shrestha, Sonu / Jin, Celina / Gibani, Malick M / Dobinson, Hazel C / Waddington, Claire / Darton, Thomas C / Blohmke, Christoph J / Pollard, Andrew J

Infection and immunity

2023 Volume 91, Issue 10, Page(s) e0010823

Abstract: Enteric fever, caused by oral infection with ... ...

Abstract	Enteric fever, caused by oral infection with typhoidal
MeSH term(s)	Humans ; Typhoid Fever/prevention & control ; Salmonella typhi/genetics ; Typhoid-Paratyphoid Vaccines ; Vaccines, Attenuated ; Vaccination
Chemical Substances	Typhoid-Paratyphoid Vaccines ; Vaccines, Attenuated
Language	English
Publishing date	2023-09-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	218698-6
ISSN	1098-5522 ; 0019-9567
ISSN (online)	1098-5522
ISSN	0019-9567
DOI	10.1128/iai.00108-23
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Article ; Online: Molecular correlates of vaccine-induced protection against typhoid fever.

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

The Journal of clinical investigation

2023 Volume 133, Issue 16

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 ... ...

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 term(s)	Adult ; Humans ; Polysaccharides, Bacterial/genetics ; Receptors, Antigen, B-Cell ; Salmonella typhi/genetics ; Typhoid Fever/prevention & control ; Typhoid-Paratyphoid Vaccines/genetics ; Vaccination
Chemical Substances	Polysaccharides, Bacterial ; Receptors, Antigen, B-Cell ; Typhoid-Paratyphoid Vaccines
Language	English
Publishing date	2023-08-15
Publishing country	United States
Document type	Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI169676
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Article ; Online: The Current Status of Enteric Fever Diagnostics and Implications for Disease Control.

Baker, Stephen / Blohmke, Christoph J / Maes, Mailis / Johnston, Peter I / Darton, Thomas C

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

2020 Volume 71, Issue Suppl 2, Page(s) S64–S70

Abstract: Enteric (typhoid) fever remains a problem in low- and middle-income countries that lack the infrastructure to maintain sanitation and where inadequate diagnostic methods have restricted our ability to identify and control the disease more effectively. As ...

Abstract	Enteric (typhoid) fever remains a problem in low- and middle-income countries that lack the infrastructure to maintain sanitation and where inadequate diagnostic methods have restricted our ability to identify and control the disease more effectively. As we move into a period of potential disease elimination through the introduction of typhoid conjugate vaccine (TCV), we again need to reconsider the role of typhoid diagnostics in how they can aid in facilitating disease control. Recent technological advances, including serology, transcriptomics, and metabolomics, have provided new insights into how we can detect signatures of invasive Salmonella organisms interacting with the host during infection. Many of these new techniques exhibit potential that could be further explored with the aim of creating a new enteric fever diagnostic to work in conjunction with TCV. We need a sustained effort within the enteric fever field to accelerate, validate, and ultimately introduce 1 (or more) of these methods to facilitate the disease control initiative. The window of opportunity is still open, but we need to recognize the need for communication with other research areas and commercial organizations to assist in the progression of these diagnostic approaches. The elimination of enteric fever is now becoming a real possibility, but new diagnostics need to be part of the equation and factored into future calculations for disease control.
MeSH term(s)	Humans ; Salmonella typhi ; Sanitation ; Typhoid Fever/diagnosis ; Typhoid Fever/epidemiology ; Typhoid Fever/prevention & control ; Typhoid-Paratyphoid Vaccines ; Vaccines, Conjugate
Chemical Substances	Typhoid-Paratyphoid Vaccines ; Vaccines, Conjugate
Language	English
Publishing date	2020-05-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	1099781-7
ISSN	1537-6591 ; 1058-4838
ISSN (online)	1537-6591
ISSN	1058-4838
DOI	10.1093/cid/ciaa503
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Article ; Online: Genetic Susceptibility to Enteric Fever in Experimentally Challenged Human Volunteers.

Barton, Amber / Hill, Jennifer / Bibi, Sagida / Chen, Liye / Jones, Claire / Jones, Elizabeth / Camara, Susana / Shrestha, Sonu / Jin, Celina / Gibani, Malick M / Dobinson, Hazel / Waddington, Claire / Darton, Thomas C / Blohmke, Christoph J / Pollard, Andrew J

Infection and immunity

2022 Volume 90, Issue 4, Page(s) e0038921

Abstract: Infections with Salmonella enterica serovars Typhi and Paratyphi A cause an estimated 14 million cases of enteric fever annually. Here, the controlled nature of challenge studies is exploited to identify genetic variants associated with enteric fever ... ...

Abstract	Infections with Salmonella enterica serovars Typhi and Paratyphi A cause an estimated 14 million cases of enteric fever annually. Here, the controlled nature of challenge studies is exploited to identify genetic variants associated with enteric fever susceptibility. Human challenge participants were genotyped by Illumina OmniExpress-24 BeadChip array (
MeSH term(s)	Genetic Predisposition to Disease ; Healthy Volunteers ; Humans ; Paratyphoid Fever ; Salmonella enterica ; Salmonella paratyphi A ; Salmonella typhi ; Typhoid Fever/genetics
Language	English
Publishing date	2022-03-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218698-6
ISSN	1098-5522 ; 0019-9567
ISSN (online)	1098-5522
ISSN	0019-9567
DOI	10.1128/iai.00389-21
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Article ; Online: 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

The Journal of Clinical Investigation, Vol 133, Iss

2023 Volume 16

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 ... ...

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.
Keywords	Vaccines ; Medicine ; R
Subject code	616
Language	English
Publishing date	2023-08-01T00:00:00Z
Publisher	American Society for Clinical Investigation
Document type	Article ; Online
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Article: Transcriptomics in Human Challenge Models.

Barton, Amber J / Hill, Jennifer / Pollard, Andrew J / Blohmke, Christoph J

Frontiers in immunology

2017 Volume 8, Page(s) 1839

Abstract: Human challenge models, in which volunteers are experimentally infected with a pathogen of interest, provide the opportunity to directly identify both natural and vaccine-induced correlates of protection. In this review, we highlight how the application ... ...

Abstract	Human challenge models, in which volunteers are experimentally infected with a pathogen of interest, provide the opportunity to directly identify both natural and vaccine-induced correlates of protection. In this review, we highlight how the application of transcriptomics to human challenge studies allows for the identification of novel correlates and gives insight into the immunological pathways required to develop functional immunity. In malaria challenge trials for example, innate immune pathways appear to play a previously underappreciated role in conferring protective immunity. Transcriptomic analyses of samples obtained in human challenge studies can also deepen our understanding of the immune responses preceding symptom onset, allowing characterization of innate immunity and early gene signatures, which may influence disease outcome. Influenza challenge studies demonstrate that these gene signatures have diagnostic potential in the context of pandemics, in which presymptomatic diagnosis of at-risk individuals could allow early initiation of antiviral treatment and help limit transmission. Furthermore, gene expression analysis facilitates the identification of host factors contributing to disease susceptibility, such as
Language	English
Publishing date	2017
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2017.01839
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Article ; Online: Dissecting

Tondi, Serena / Clemente, Bruna / Esposito, Carmen / Sammicheli, Chiara / Tavarini, Simona / Martin, Laura B / Rossi, Omar / Micoli, Francesca / Bartolini, Erika / Brazzoli, Michela / Ulivieri, Cristina / Blohmke, Christoph J / Schiavetti, Francesca

Frontiers in cellular and infection microbiology

2022 Volume 12, Page(s) 767153

Abstract: Generalized Modules for Membrane Antigens (GMMA) are outer membrane exosomes purified from Gram-negative bacteria genetically mutated to increase blebbing and reduce risk of reactogenicity. This is commonly achieved through modification of the lipid A ... ...

Abstract	Generalized Modules for Membrane Antigens (GMMA) are outer membrane exosomes purified from Gram-negative bacteria genetically mutated to increase blebbing and reduce risk of reactogenicity. This is commonly achieved through modification of the lipid A portion of lipopolysaccharide. GMMA faithfully resemble the bacterial outer membrane surface, and therefore represent a powerful and flexible platform for vaccine development. Although GMMA-based vaccines have been demonstrated to induce a strong and functional antibody response in animals and humans maintaining an acceptable reactogenicity profile, the overall impact on immune cells and their mode of action are still poorly understood. To characterize the GMMA-induced immune response, we stimulated human peripheral blood mononuclear cells (hPBMCs) with GMMA from
MeSH term(s)	Animals ; Antigens, Bacterial ; Humans ; Immunity ; Leukocytes, Mononuclear ; Methylmethacrylates ; Shigella sonnei
Chemical Substances	Antigens, Bacterial ; Methylmethacrylates ; glyceryl methyl methacrylate
Language	English
Publishing date	2022-02-03
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2619676-1
ISSN	2235-2988 ; 2235-2988
ISSN (online)	2235-2988
ISSN	2235-2988
DOI	10.3389/fcimb.2022.767153
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Article ; Online: The use of systems biology and immunological big data to guide vaccine development.

Blohmke, Christoph J / O'Connor, Daniel / Pollard, Andrew J

Genome medicine

2015 Volume 7, Page(s) 114

Abstract: High-throughput technologies applied to the analysis of vaccine responses are likely to reveal the mechanisms responsible for vaccine-induced protection, aid understanding of vaccine safety and help accelerate vaccine development and clinical trials. ...

Abstract	High-throughput technologies applied to the analysis of vaccine responses are likely to reveal the mechanisms responsible for vaccine-induced protection, aid understanding of vaccine safety and help accelerate vaccine development and clinical trials.
MeSH term(s)	Biomedical Research ; Humans ; Systems Biology ; Vaccines
Chemical Substances	Vaccines
Language	English
Publishing date	2015-11-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2484394-5
ISSN	1756-994X ; 1756-994X
ISSN (online)	1756-994X
ISSN	1756-994X
DOI	10.1186/s13073-015-0236-1
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Article ; Online: Mucosal-Associated Invariant T cells exhibit distinct functional signatures associated with protection against typhoid fever.

Salerno-Gonçalves, Rosângela / Fresnay, Stephanie / Magder, Laurence / Darton, Thomas C / Waddington, Claire S / Blohmke, Christoph J / Angus, Brian / Levine, Myron M / Pollard, Andrew J / Sztein, Marcelo B

Cellular immunology

2022 Volume 378, Page(s) 104572

Abstract: We have previously demonstrated that Mucosal-Associated Invariant T (MAIT) cells secrete multiple cytokines after exposure to Salmonella enterica serovar Typhi (S. Typhi), the causative agent of typhoid fever in humans. However, whether cytokine ... ...

Abstract	We have previously demonstrated that Mucosal-Associated Invariant T (MAIT) cells secrete multiple cytokines after exposure to Salmonella enterica serovar Typhi (S. Typhi), the causative agent of typhoid fever in humans. However, whether cytokine secreting MAIT cells can enhance or attenuate the clinical severity of bacterial infections remain debatable. This study characterizes human MAIT cell functions in subjects participating in a wild-type S. Typhi human challenge model. Here, we found that MAIT cells exhibit distinct functional signatures associated with protection against typhoid fever. We also observed that the cytokine patterns of MAIT cell responses, rather than the average number of cytokines expressed, are more predictive of typhoid fever outcomes. These results might enable us to objectively, based on functional parameters, identify cytokine patterns that may serve as predictive biomarkers during natural infection and vaccination.
MeSH term(s)	Cytokines ; Humans ; Mucosal-Associated Invariant T Cells ; Salmonella typhi/physiology ; Typhoid Fever/microbiology ; Typhoid Fever/prevention & control ; Vaccination
Chemical Substances	Cytokines
Language	English
Publishing date	2022-06-20
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80094-6
ISSN	1090-2163 ; 0008-8749
ISSN (online)	1090-2163
ISSN	0008-8749
DOI	10.1016/j.cellimm.2022.104572
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