Nontoxigenic Vibrio cholerae Challenge Strains for Evaluating Vaccine Efficacy and Inferring Mechanisms of Protection
ABSTRACT Human challenge studies are instrumental for testing cholera vaccines, but these studies use outdated strains and require inpatient facilities. Here, we created next-generation isogenic Ogawa and Inaba O1 V. cholerae challenge strains (ZChol strains) derived from a contemporary Zambian clin...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-04-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.00539-22 |
| _version_ | 1817991190931308544 |
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| author | Bolutife Fakoya Karthik Hullahalli Daniel H. F. Rubin Deborah R. Leitner Roma Chilengi David A. Sack Matthew K. Waldor |
| author_facet | Bolutife Fakoya Karthik Hullahalli Daniel H. F. Rubin Deborah R. Leitner Roma Chilengi David A. Sack Matthew K. Waldor |
| author_sort | Bolutife Fakoya |
| collection | DOAJ |
| description | ABSTRACT Human challenge studies are instrumental for testing cholera vaccines, but these studies use outdated strains and require inpatient facilities. Here, we created next-generation isogenic Ogawa and Inaba O1 V. cholerae challenge strains (ZChol strains) derived from a contemporary Zambian clinical isolate representative of current dominant pandemic V. cholerae. Since the primary mechanism of immune protection against cholera is thought to be antibody responses that limit V. cholerae colonization and not the diarrheagenic actions of cholera toxin, these strains were rendered nontoxigenic. In infant mice, the ZChol strains did not cause diarrhea and proved to accurately gauge reduction in intestinal colonization mediated by effective vaccination. ZChol strains were also valuable as targets for measuring vibriocidal antibody responses. Using barcoded ZChol strains, we discovered that vaccination and passive immunity in the infant mouse model tightens the infection bottleneck without restricting pathogen expansion during intestinal infection. Collectively, our findings suggest that ZChol strains have the potential to enhance the safety, relevance, and scope of future cholera vaccine challenge studies and be valuable reagents for studies of immunity to cholera. IMPORTANCE Human challenge studies are a valuable method for testing the efficacy of cholera vaccines. However, challenge studies cannot be performed in countries of cholera endemicity due to safety concerns; also, contemporary pandemic Vibrio cholerae strains are not used in current challenge studies. To facilitate cholera research, we derived nontoxigenic challenge strains of both V. cholerae serotypes from a 2016 clinical isolate from Zambia and demonstrated how they can be used to gauge cholera immunity accurately and safely. These strains were also genetically barcoded, adding the potential for analyses of V. cholerae population dynamics to challenge studies. Preclinical analyses presented here suggest that these strains have the potential to enhance the safety, relevance, and scope of future cholera vaccine challenge studies and be valuable reagents for studies of immunity to cholera. |
| first_indexed | 2024-04-14T01:09:58Z |
| format | Article |
| id | doaj.art-16de03fc57a943209fb73be604507da6 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-04-14T01:09:58Z |
| publishDate | 2022-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-16de03fc57a943209fb73be604507da62022-12-22T02:21:06ZengAmerican Society for MicrobiologymBio2150-75112022-04-0113210.1128/mbio.00539-22Nontoxigenic Vibrio cholerae Challenge Strains for Evaluating Vaccine Efficacy and Inferring Mechanisms of ProtectionBolutife Fakoya0Karthik Hullahalli1Daniel H. F. Rubin2Deborah R. Leitner3Roma Chilengi4David A. Sack5Matthew K. Waldor6Division of Infectious Diseases, Brigham & Women’s Hospital, Boston, Massachusetts, USADivision of Infectious Diseases, Brigham & Women’s Hospital, Boston, Massachusetts, USADivision of Infectious Diseases, Brigham & Women’s Hospital, Boston, Massachusetts, USADivision of Infectious Diseases, Brigham & Women’s Hospital, Boston, Massachusetts, USAEnteric Disease and Vaccine Research Unit, Centre for Infectious Disease Research in Zambia, Lusaka, ZambiaDepartment of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USADivision of Infectious Diseases, Brigham & Women’s Hospital, Boston, Massachusetts, USAABSTRACT Human challenge studies are instrumental for testing cholera vaccines, but these studies use outdated strains and require inpatient facilities. Here, we created next-generation isogenic Ogawa and Inaba O1 V. cholerae challenge strains (ZChol strains) derived from a contemporary Zambian clinical isolate representative of current dominant pandemic V. cholerae. Since the primary mechanism of immune protection against cholera is thought to be antibody responses that limit V. cholerae colonization and not the diarrheagenic actions of cholera toxin, these strains were rendered nontoxigenic. In infant mice, the ZChol strains did not cause diarrhea and proved to accurately gauge reduction in intestinal colonization mediated by effective vaccination. ZChol strains were also valuable as targets for measuring vibriocidal antibody responses. Using barcoded ZChol strains, we discovered that vaccination and passive immunity in the infant mouse model tightens the infection bottleneck without restricting pathogen expansion during intestinal infection. Collectively, our findings suggest that ZChol strains have the potential to enhance the safety, relevance, and scope of future cholera vaccine challenge studies and be valuable reagents for studies of immunity to cholera. IMPORTANCE Human challenge studies are a valuable method for testing the efficacy of cholera vaccines. However, challenge studies cannot be performed in countries of cholera endemicity due to safety concerns; also, contemporary pandemic Vibrio cholerae strains are not used in current challenge studies. To facilitate cholera research, we derived nontoxigenic challenge strains of both V. cholerae serotypes from a 2016 clinical isolate from Zambia and demonstrated how they can be used to gauge cholera immunity accurately and safely. These strains were also genetically barcoded, adding the potential for analyses of V. cholerae population dynamics to challenge studies. Preclinical analyses presented here suggest that these strains have the potential to enhance the safety, relevance, and scope of future cholera vaccine challenge studies and be valuable reagents for studies of immunity to cholera.https://journals.asm.org/doi/10.1128/mbio.00539-22cholerahuman challengevaccine testing |
| spellingShingle | Bolutife Fakoya Karthik Hullahalli Daniel H. F. Rubin Deborah R. Leitner Roma Chilengi David A. Sack Matthew K. Waldor Nontoxigenic Vibrio cholerae Challenge Strains for Evaluating Vaccine Efficacy and Inferring Mechanisms of Protection mBio cholera human challenge vaccine testing |
| title | Nontoxigenic Vibrio cholerae Challenge Strains for Evaluating Vaccine Efficacy and Inferring Mechanisms of Protection |
| title_full | Nontoxigenic Vibrio cholerae Challenge Strains for Evaluating Vaccine Efficacy and Inferring Mechanisms of Protection |
| title_fullStr | Nontoxigenic Vibrio cholerae Challenge Strains for Evaluating Vaccine Efficacy and Inferring Mechanisms of Protection |
| title_full_unstemmed | Nontoxigenic Vibrio cholerae Challenge Strains for Evaluating Vaccine Efficacy and Inferring Mechanisms of Protection |
| title_short | Nontoxigenic Vibrio cholerae Challenge Strains for Evaluating Vaccine Efficacy and Inferring Mechanisms of Protection |
| title_sort | nontoxigenic vibrio cholerae challenge strains for evaluating vaccine efficacy and inferring mechanisms of protection |
| topic | cholera human challenge vaccine testing |
| url | https://journals.asm.org/doi/10.1128/mbio.00539-22 |
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