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 natural 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.
|Uddin, Muhammad Ikhtear; Islam, Shahidul; Nishat, Naoshin S et al. (2016) Biomarkers of Environmental Enteropathy are Positively Associated with Immune Responses to an Oral Cholera Vaccine in Bangladeshi Children. PLoS Negl Trop Dis 10:e0005039|
|Harris, Jason B; LaRocque, Regina C (2016) Cholera and ABO Blood Group: Understanding an Ancient Association. Am J Trop Med Hyg 95:263-4|
|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:|
|Ivers, Louise C; Charles, Richelle C; Hilaire, Isabelle J et al. (2015) Immunogenicity of the Bivalent Oral Cholera Vaccine Shanchol in Haitian Adults With HIV Infection. J Infect Dis 212:779-83|
|Rychert, Jenna; Creely, David; Mayo-Smith, Leslie M et al. (2015) Evaluation of matrix-assisted laser desorption ionization-time of flight mass spectrometry for identification of Vibrio cholerae. J Clin Microbiol 53:329-31|
|David, Lawrence A; Weil, Ana; Ryan, Edward T et al. (2015) Gut microbial succession follows acute secretory diarrhea in humans. MBio 6:e00381-15|
|Bhuiyan, Taufiqur Rahman; Hoq, Mohammad Rubel; Nishat, Naoshin Sharmin et al. (2015) Enumeration of Gut-Homing Î²7-Positive, Pathogen-Specific Antibody-Secreting Cells in Whole Blood from Enterotoxigenic Escherichia coli- and Vibrio cholerae-Infected Patients, Determined Using an Enzyme-Linked Immunosorbent Spot Assay Technique. Clin Vaccine Immunol 23:27-36|
|Ellis, Crystal N; LaRocque, Regina C; Uddin, Taher et al. (2015) Comparative proteomic analysis reveals activation of mucosal innate immune signaling pathways during cholera. Infect Immun 83:1089-103|
|Leung, Daniel T; Bhuiyan, Taufiqur R; Nishat, Naoshin S et al. (2014) Circulating mucosal associated invariant T cells are activated in Vibrio cholerae O1 infection and associated with lipopolysaccharide antibody responses. PLoS Negl Trop Dis 8:e3076|
|Weil, Ana A; Begum, Yasmin; Chowdhury, Fahima et al. (2014) Bacterial shedding in household contacts of cholera patients in Dhaka, Bangladesh. Am J Trop Med Hyg 91:738-42|