Cholera remains an important cause of diarrheal illness, as evidenced by its recent emergence in post- earthquake Haiti. Scientific and policy leaders are increasingly calling for the use of preventive strategies such as vaccination for diarrheal diseases like cholera, but current cholera vaccines suffer from immunologic limitations. Most importantly, oral cholera vaccines elicit protection of short duration -- in contrast to naturl infection with V. cholerae, which induces long-lasting immunity. In the research proposed here, we seek to identify the earliest differences in the innate and B cell immune responses after natural infection versus cholera vaccination. We also aim to identify which of these early differences are most critical for the subsequent development of long term immunologic memory. Understanding these early differences may explain why only natural infection with V. cholerae gives rise to long term memory B cell responses which are important for protection against cholera. Because V. cholerae is a human-restricted pathogen, clinical studies are essential to address this question. We propose to draw upon existing collaborations between the Massachusetts General Hospital/Harvard Medical School (MGH/HMS), the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), the Emory Vaccine Center, and the Broad Institute of MIT/Harvard University to address this question in humans. Specifically, we will compare the activation of innate immune responses in mucosal tissue after cholera infection versus vaccination, and we will evaluate which of these differences correlate with long term memory B cell responses in cholera patients. We will also compare antibody secreting cell (ASC) responses in patients and vaccinees. Cloning of immunoglobulin genes and the production of these cloned antibodies from individual ASCs may improve our understanding of differences in the B cell responses between cholera patients and vaccine recipients, and the resulting antibodies may also provide tools with diagnostic and therapeutic potential. These studies will improve our understanding of the mechanisms through which innate immune responses at the mucosal surface foster long-lasting immunity and may point to novel strategies for improving upon current cholera vaccines.
Cholera is a severe diarrheal disease that is common in developing countries, and can cause massive epidemics. While infection leads to long lasting immunity, cholera vaccines more short term protection. Understanding how immune responses differ between the oral vaccine and natural infection will improve our ability to develop improved vaccines for cholera and other intestinal infections.
|Domman, Daryl; Chowdhury, Fahima; Khan, Ashraful I et al. (2018) Defining endemic cholera at three levels of spatiotemporal resolution within Bangladesh. Nat Genet 50:951-955|
|Haney, Douglas J; Lock, Michael D; Gurwith, Marc et al. (2018) Lipopolysaccharide-specific memory B cell responses to an attenuated live cholera vaccine are associated with protection against Vibrio cholerae infection. Vaccine 36:2768-2773|
|Bhuiyan, Taufiqur Rahman; Hoq, Mohammad Rubel; Nishat, Naoshin Sharmin et al. (2018) Assessing antigen specific HLA-DR+ antibody secreting cell (DR+ASC) responses in whole blood in enteric infections using an ELISPOT technique. Microbes Infect 20:122-129|
|Bourque, Daniel L; Bhuiyan, Taufiqur Rahman; Genereux, Diane P et al. (2018) Analysis of the Human Mucosal Response to Cholera Reveals Sustained Activation of Innate Immune Signaling Pathways. Infect Immun 86:|
|Levade, Inès; Terrat, Yves; Leducq, Jean-Baptiste et al. (2017) Vibrio cholerae genomic diversity within and between patients. Microb Genom 3:|
|Mayo-Smith, Leslie M; Simon, Jakub K; Chen, Wilbur H et al. (2017) The Live Attenuated Cholera Vaccine CVD 103-HgR Primes Responses to the Toxin-Coregulated Pilus Antigen TcpA in Subjects Challenged with Wild-Type Vibrio cholerae. Clin Vaccine Immunol 24:|
|Matias, Wilfredo R; Teng, Jessica E; Hilaire, Isabelle J et al. (2017) Household and Individual Risk Factors for Cholera among Cholera Vaccine Recipients in Rural Haiti. Am J Trop Med Hyg 97:436-442|
|Charles, Richelle C; Nakajima, Rie; Liang, Li et al. (2017) Plasma and Mucosal Immunoglobulin M, Immunoglobulin A, and Immunoglobulin G Responses to the Vibrio cholerae O1 Protein Immunome in Adults With Cholera in Bangladesh. J Infect Dis 216:125-134|
|Harris, Jason B (2016) Editorial Commentary: Resurrecting a Live Oral Cholera Vaccine. Clin Infect Dis 62:1336-7|
|Kauffman, Robert C; Bhuiyan, Taufiqur R; Nakajima, Rie et al. (2016) Single-Cell Analysis of the Plasmablast Response to Vibrio cholerae Demonstrates Expansion of Cross-Reactive Memory B Cells. MBio 7:|
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