Diarrheal disease is the second most common cause of death among children under five years of age globally, and infectious diarrhea is the second leading cause of global morbidity. Vibrio cholerae causes severe secretory diarrhea in humans, and is a prototypical mucosal infection that does not invade the intestinal epithelium;V. cholerae infection thus serves as an excellent model for the study of mucosal immunity and vaccination. Unfortunately, protective immunity following cholera is not currently understood, and available cholera vaccines either fail to produce full protective efficacy or induce less than optimal and relatively short-lived immune responses that fall to baseline within 6-36 months of vaccination. This is in comparison to natural infection with V. cholerae that induces protective immunity that lasts for 3-10 years. Serum vibriocidal and other serum antibody responses wane within 6-12 months of infection, suggesting that these current immunologic markers cannot be used as correlates of longer-term protective immunity. We have data to suggest that memory B cell responses to T-dependent protein antigens develop following V. cholerae infection and persist for at least one year, while memory B cell responses to a T-independent antigen, LPS, develop following cholera, but appear to wane by 9-12 months following infection. We have additional preliminary evidence of a CD4+ T helper cell response following V. cholerae infection, and we hypothesize that this response is necessary for the development and maintenance of B cell memory at the mucosal surface, that the T cell response may be qualitatively or quantitatively different between natural infection and cholera vaccination, and that these differences may explain the lessened efficacy of current vaccines for cholera and other mucosal infections. To address these questions, we propose five specific aims: (1) Characterize immune responses in blood following natural cholera, focusing on development and maintenance of memory B cell and T cell responses;(2) Evaluate mucosal innate and acquired immune responses following cholera using endoscopically obtained duodenal (EGD) samples, and correlate with responses seen in blood;(3) Assess innate and acquired immune responses early after exposure in household contacts to determine correlates of subsequent protective immunity to cholera;(4) Assess immune responses following cholera vaccination with the current killed oral rBS-WC cholera vaccine (synergizing with an on-going and separately funded cholera vaccine study), and compare responses to those following natural cholera;and (5) Evaluate host factors influencing susceptibility and immune responses to cholera. This proposal is built upon an on-going collaborative effort between researchers at the Massachusetts General Hospital-Harvard University and the ICDDR,B in Dhaka, Bangladesh.

Public Health Relevance

Cholera affects 5-7 million individuals each year, killing over 100,000, globally. Identification of protective immunity against cholera could not only directly affect cholera vaccination strategies, but could be applicable to the development of improved vaccines against other mucosal pathogens.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-GSM-M (J1))
Program Officer
Hall, Robert H
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
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
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
Levade, Inès; Terrat, Yves; Leducq, Jean-Baptiste et al. (2017) Vibrio cholerae genomic diversity within and between patients. Microb Genom 3:
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:
Bhuiyan, Taufiqur Rahman; Hoq, Mohammad Rubel; Nishat, Naoshin Sharmin et al. (2016) Enumeration of Gut-Homing ?7-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
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
Hatzios, Stavroula K; Abel, Sören; Martell, Julianne et al. (2016) Chemoproteomic profiling of host and pathogen enzymes active in cholera. Nat Chem Biol 12:268-274
Aktar, Amena; Rahman, M Arifur; Afrin, Sadia et al. (2016) O-Specific Polysaccharide-Specific Memory B Cell Responses in Young Children, Older Children, and Adults Infected with Vibrio cholerae O1 Ogawa in Bangladesh. Clin Vaccine Immunol 23:427-435
Sayeed, Md Abu; Bufano, Meagan Kelly; Xu, Peng et al. (2015) A Cholera Conjugate Vaccine Containing O-specific Polysaccharide (OSP) of V. cholerae O1 Inaba and Recombinant Fragment of Tetanus Toxin Heavy Chain (OSP:rTTHc) Induces Serum, Memory and Lamina Proprial Responses against OSP and Is Protective in Mice. PLoS Negl Trop Dis 9:e0003881
Chowdhury, Fahima; Kuchta, Alison; Khan, Ashraful Islam et al. (2015) The increased severity in patients presenting to hospital with diarrhea in Dhaka, Bangladesh since the emergence of the hybrid strain of Vibrio cholerae O1 is not unique to cholera patients. Int J Infect Dis 40:9-14

Showing the most recent 10 out of 109 publications