Cholera is a severe dehydrating diarrheal disease caused by Vibrio cholerae, a Gram-negative rod that colonizes the small intestine and produces cholera toxin, whose actions largely account for the symptoms of cholera. Prevention of cholera through utilization of an effective vaccine could be of enormous benefit. However, the currently available vaccine, Shancol, a killed whole cell preparation, has several limitations including only modest efficacy, requirement for two doses, and a duration of activity that is likely less than that engendered by natural infection with wild type V. cholerae. Live-attenuated vaccines offer the possibility of overcoming these limitations, but the last live-attenuated vaccine for cholera that showed promise in human trials was created more than 25 years ago and is no longer being developed. In the interim, the V. cholerae strain causing cholera worldwide has evolved. A `variant' El Tor strain, the cause of the devastating and ongoing cholera outbreak in Haiti, is now the predominant cause of cholera globally. During the current grant period, we used the infant rabbit-based model of cholera we developed to create new approaches for deepening our understanding of V. cholerae-host interactions during infection and created a new live- attenuated vaccine, HaitiV, the first created in the variant El Tor V. cholerae background. Infant rabbits orogastrically infected with HaitiV are colonized, but do not develop diarrhea, due to the absence of cholera toxin and other diarrheagenic factors. Moreover, administration of HaitiV reduces subsequent intestinal colonization by and diarrhea associated with wild type V. cholerae even prior to the development of adaptive immunity. Killed HaitiV does not induce acute colonization resistance or protection from disease, suggesting that killed vaccines (e.g. Shancol) would likewise lack this benefit. Studies to address HaitiV immunogenicity are outside the scope of this proposal, but we anticipate, based on prior clinical studies of live vaccines, that HaitiV will induce long-term immunity to cholera after a single dose. Rapid HaitiV vaccination-induced colonization resistance also has great potential clinical impact and is amenable to study in infant rabbits.
In Aims 1 and 2 of this proposal, we will investigate how HaitiV antagonizes intestinal colonization by wild type V. cholerae.
In Aim 3, we will test whether we can augment HaitiV's capacity to prevent intestinal colonization and disease caused by wild type V. cholerae. Collectively, these experiments will broaden our understanding of the processes that govern V. cholerae intestinal colonization and colonization resistance. In addition, these studies will potentially yield a transformative, multifunctional agent that will be effective both as a traditional vaccine, inducing long term immunity, as well as for reactive vaccination for controlling the acute spread of epidemics even before stimulation of an adaptive, long-lived immune response.

Public Health Relevance

Cholera, a severe dehydrating diarrheal disease caused by Vibrio cholerae, remains a significant threat to public health worldwide. In this project, we will investigate how a new live-attenuated cholera vaccine we are developing can block intestinal colonization and disease caused by pathogenic V. cholerae prior to eliciting long-term adaptive immunity. Our studies will enhance the protective efficacy of this novel agent and provide greater understanding of bacterial processes contributing to and capable of countering V. cholerae pathogenicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI042347-23
Application #
9447769
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Hall, Robert H
Project Start
1998-01-01
Project End
2022-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
23
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Chao, Michael C; Abel, Sören; Davis, Brigid M et al. (2016) The design and analysis of transposon insertion sequencing experiments. Nat Rev Microbiol 14:119-28
Dörr, Tobias; Lam, Hubert; Alvarez, Laura et al. (2014) A novel peptidoglycan binding protein crucial for PBP1A-mediated cell wall biogenesis in Vibrio cholerae. PLoS Genet 10:e1004433
Lu, Xi; Skurnik, David; Pozzi, Clarissa et al. (2014) A Poly-N-acetylglucosamine-Shiga toxin broad-spectrum conjugate vaccine for Shiga toxin-producing Escherichia coli. MBio 5:e00974-14
Pacheco, Alline R; Curtis, Meredith M; Ritchie, Jennifer M et al. (2012) Fucose sensing regulates bacterial intestinal colonization. Nature 492:113-7
Chin, Chen-Shan; Sorenson, Jon; Harris, Jason B et al. (2011) The origin of the Haitian cholera outbreak strain. N Engl J Med 364:33-42
Waldor, Matthew K; Hotez, Peter J; Clemens, John D (2010) A national cholera vaccine stockpile--a new humanitarian and diplomatic resource. N Engl J Med 363:2279-82
Kimsey, Harvey H; Waldor, Matthew K (2009) Vibrio cholerae LexA coordinates CTX prophage gene expression. J Bacteriol 191:6788-95
Ritchie, Jennifer M; Waldor, Matthew K (2009) Vibrio cholerae interactions with the gastrointestinal tract: lessons from animal studies. Curr Top Microbiol Immunol 337:37-59
Shakhnovich, Elizabeth A; Davis, Brigid M; Waldor, Matthew K (2009) Hfq negatively regulates type III secretion in EHEC and several other pathogens. Mol Microbiol 74:347-63
Davis, Brigid M; Waldor, Matthew K (2009) High-throughput sequencing reveals suppressors of Vibrio cholerae rpoE mutations: one fewer porin is enough. Nucleic Acids Res 37:5757-67

Showing the most recent 10 out of 68 publications