Salmonella Typhi Bactericidal Antibodies Reduce Disease Severity but Do Not Protect against Typhoid Fever in a Controlled Human Infection Model
Effective vaccines against Salmonella Typhi, a major cause of febrile illness in tropical regions, can have a significant effect as a disease control measure. Earlier work has shown that immunization with either of two Salmonella Typhi vaccines, licensed Ty21a or candidate M01ZH09, did not provide f...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01916/full |
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Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Helene B. Juel Helene B. Juel Helena B. Thomaides-Brears Thomas C. Darton Thomas C. Darton Claire Jones Elizabeth Jones Sonu Shrestha Rebecca Sie Andrew Eustace Ushma Galal Prathiba Kurupati Tan T. Van Nga T. V. Thieu Stephen Baker Stephen Baker Stephen Baker Christoph J. Blohmke Andrew J. Pollard |
| spellingShingle |
Helene B. Juel Helene B. Juel Helena B. Thomaides-Brears Thomas C. Darton Thomas C. Darton Claire Jones Elizabeth Jones Sonu Shrestha Rebecca Sie Andrew Eustace Ushma Galal Prathiba Kurupati Tan T. Van Nga T. V. Thieu Stephen Baker Stephen Baker Stephen Baker Christoph J. Blohmke Andrew J. Pollard Salmonella Typhi Bactericidal Antibodies Reduce Disease Severity but Do Not Protect against Typhoid Fever in a Controlled Human Infection Model Frontiers in Immunology typhoid infection bactericidal activity human challenge model Salmonella enterica Typhi immune responses |
| author_facet |
Helene B. Juel Helene B. Juel Helena B. Thomaides-Brears Thomas C. Darton Thomas C. Darton Claire Jones Elizabeth Jones Sonu Shrestha Rebecca Sie Andrew Eustace Ushma Galal Prathiba Kurupati Tan T. Van Nga T. V. Thieu Stephen Baker Stephen Baker Stephen Baker Christoph J. Blohmke Andrew J. Pollard |
| author_sort |
Helene B. Juel |
| title |
Salmonella Typhi Bactericidal Antibodies Reduce Disease Severity but Do Not Protect against Typhoid Fever in a Controlled Human Infection Model |
| title_short |
Salmonella Typhi Bactericidal Antibodies Reduce Disease Severity but Do Not Protect against Typhoid Fever in a Controlled Human Infection Model |
| title_full |
Salmonella Typhi Bactericidal Antibodies Reduce Disease Severity but Do Not Protect against Typhoid Fever in a Controlled Human Infection Model |
| title_fullStr |
Salmonella Typhi Bactericidal Antibodies Reduce Disease Severity but Do Not Protect against Typhoid Fever in a Controlled Human Infection Model |
| title_full_unstemmed |
Salmonella Typhi Bactericidal Antibodies Reduce Disease Severity but Do Not Protect against Typhoid Fever in a Controlled Human Infection Model |
| title_sort |
salmonella typhi bactericidal antibodies reduce disease severity but do not protect against typhoid fever in a controlled human infection model |
| publisher |
Frontiers Media S.A. |
| series |
Frontiers in Immunology |
| issn |
1664-3224 |
| publishDate |
2018-01-01 |
| description |
Effective vaccines against Salmonella Typhi, a major cause of febrile illness in tropical regions, can have a significant effect as a disease control measure. Earlier work has shown that immunization with either of two Salmonella Typhi vaccines, licensed Ty21a or candidate M01ZH09, did not provide full immunity in a controlled human infection model. Here, we describe the human humoral immune responses to these oral vaccines and their functional role in protection after challenge with S. Typhi. Serum, obtained from healthy volunteers before and after vaccination with Ty21a or M01ZH09 or placebo and before and after oral challenge with wild-type S. Typhi, was assessed for bactericidal activity. Single-dose vaccination with M01ZH09 induced an increase in serum bactericidal antibodies (p = 0.001) while three doses of Ty21a did not. No association between bactericidal activity and protection against typhoid after challenge was seen in either vaccine arm. Bactericidal activity after vaccination correlated significantly with delayed disease onset (p = 0.013), lower bacterial burden (p = 0.006), and decreased disease severity scores (p = 0.021). Depletion of antibodies directed against lipopolysaccharide significantly reduced bactericidal activity (p = 0.009). We conclude that antibodies induced after ingestion of oral live-attenuated typhoid vaccines or after challenge with wild-type S. Typhi exhibit bactericidal activity. This bactericidal activity is mediated by anti-O:LPS antibodies and significantly reduces clinical symptoms but does not provide sterile immunity. This directs future vaccine studies toward other antigens or mechanisms of protection against typhoid. |
| topic |
typhoid infection bactericidal activity human challenge model Salmonella enterica Typhi immune responses |
| url |
http://journal.frontiersin.org/article/10.3389/fimmu.2017.01916/full |
| work_keys_str_mv |
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| _version_ |
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| spelling |
doaj-ec4e2debbc1e481aba8e1564ed91b16c2020-11-24T23:05:03ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-01-01810.3389/fimmu.2017.01916302496Salmonella Typhi Bactericidal Antibodies Reduce Disease Severity but Do Not Protect against Typhoid Fever in a Controlled Human Infection ModelHelene B. Juel0Helene B. Juel1Helena B. Thomaides-Brears2Thomas C. Darton3Thomas C. Darton4Claire Jones5Elizabeth Jones6Sonu Shrestha7Rebecca Sie8Andrew Eustace9Ushma Galal10Prathiba Kurupati11Tan T. Van12Nga T. V. Thieu13Stephen Baker14Stephen Baker15Stephen Baker16Christoph J. Blohmke17Andrew J. Pollard18Oxford Vaccine Group, Department of Paediatrics, University of Oxford, The NIHR Oxford Biomedical Research Centre, Oxford, United KingdomStatens Serum Institut, Copenhagen, DenmarkOxford Vaccine Group, Department of Paediatrics, University of Oxford, The NIHR Oxford Biomedical Research Centre, Oxford, United KingdomOxford Vaccine Group, Department of Paediatrics, University of Oxford, The NIHR Oxford Biomedical Research Centre, Oxford, United KingdomDepartment of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United KingdomOxford Vaccine Group, Department of Paediatrics, University of Oxford, The NIHR Oxford Biomedical Research Centre, Oxford, United KingdomOxford Vaccine Group, Department of Paediatrics, University of Oxford, The NIHR Oxford Biomedical Research Centre, Oxford, United KingdomOxford Vaccine Group, Department of Paediatrics, University of Oxford, The NIHR Oxford Biomedical Research Centre, Oxford, United KingdomOxford Vaccine Group, Department of Paediatrics, University of Oxford, The NIHR Oxford Biomedical Research Centre, Oxford, United KingdomOxford Vaccine Group, Department of Paediatrics, University of Oxford, The NIHR Oxford Biomedical Research Centre, Oxford, United KingdomNuffield Department of Primary Care Health Sciences, Clinical Trials Unit, University of Oxford, Oxford, United KingdomWeatherall Institute of Molecular Medicine, University of Oxford, Oxford, United KingdomThe Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, VietnamThe Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, VietnamThe Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, VietnamCentre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United KingdomThe Department of Medicine, University of Cambridge, Cambridge, United KingdomOxford Vaccine Group, Department of Paediatrics, University of Oxford, The NIHR Oxford Biomedical Research Centre, Oxford, United KingdomOxford Vaccine Group, Department of Paediatrics, University of Oxford, The NIHR Oxford Biomedical Research Centre, Oxford, United KingdomEffective vaccines against Salmonella Typhi, a major cause of febrile illness in tropical regions, can have a significant effect as a disease control measure. Earlier work has shown that immunization with either of two Salmonella Typhi vaccines, licensed Ty21a or candidate M01ZH09, did not provide full immunity in a controlled human infection model. Here, we describe the human humoral immune responses to these oral vaccines and their functional role in protection after challenge with S. Typhi. Serum, obtained from healthy volunteers before and after vaccination with Ty21a or M01ZH09 or placebo and before and after oral challenge with wild-type S. Typhi, was assessed for bactericidal activity. Single-dose vaccination with M01ZH09 induced an increase in serum bactericidal antibodies (p = 0.001) while three doses of Ty21a did not. No association between bactericidal activity and protection against typhoid after challenge was seen in either vaccine arm. Bactericidal activity after vaccination correlated significantly with delayed disease onset (p = 0.013), lower bacterial burden (p = 0.006), and decreased disease severity scores (p = 0.021). Depletion of antibodies directed against lipopolysaccharide significantly reduced bactericidal activity (p = 0.009). We conclude that antibodies induced after ingestion of oral live-attenuated typhoid vaccines or after challenge with wild-type S. Typhi exhibit bactericidal activity. This bactericidal activity is mediated by anti-O:LPS antibodies and significantly reduces clinical symptoms but does not provide sterile immunity. This directs future vaccine studies toward other antigens or mechanisms of protection against typhoid.http://journal.frontiersin.org/article/10.3389/fimmu.2017.01916/fulltyphoid infectionbactericidal activityhuman challenge modelSalmonella enterica Typhiimmune responses |