Physician Investigator (Cl) Infectious Disease, Mass General Research Institute

Professor of Medicine Harvard Medical School

Professor Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health

Director, Global Infectious Diseases Massachusetts General Hospital

Pediatrician Pediatrics-Pediatric Infectious Disease, Massachusetts General Hospital

Physician Infectious Disease, Massachusetts General Hospital

MD 1988

antibodies bacterial; antimicrobial resistance; bangladesh; cholera; cholera vaccines; diagnostics; enteric fever; global health; immunology; international travel; salmonella typhi; shigella; shigella vaccines; travel; typhoid fever; typhoid vaccines; vibrio cholerae; vibrio cholerae o1; zika

 

Our research focuses on host-bacterial pathogen interactions and immune responses, with a particular focus on enteric infections and the development of vaccines protective against enteric infections. Specific focus areas include Vibrio cholerae, the cause of cholera, and Salmonella enterica, the causes of typhoid and paratyphoid fever.
We work in collaborative efforts with researchers at the International Centre for Diarrhoeal Disease Research in Dhaka Bangladesh (ICDDR,B).

1. Immune responses during cholera

In a collaborative effort with researchers at the International Centre for Diarrhoeal Disease Research in Dhaka, Bangladesh (ICDDR,B), we are evaluating immune responses in humans infected with Vibrio cholerae, the cause of cholera.
V. cholerae is endemic in over 50 countries, infects approximately 3-5 million individuals globally, and results in the death of approximately 100,000 individuals each year. Individuals most affected by cholera are those most impoverished, especially those lacking safe water and sanitary facilities, as well as individuals displaced by war, famine, disasters, and conflict.
Cholera can be explosively epidemic, and the global burden of cholera may well increase with climate change, severe weather events, and increasing urbanization. V. cholerae is a human-restricted infection, and current cholera vaccines provide relatively short-term protection against disease.
The mediators of protective immunity against cholera are poorly understood. To address this, we are applying a number of high throughput and platform technologies to assess innate and adaptive immune responses in humans with cholera and their household contacts, stratifying responses in the latter by subsequent protection from disease, and comparing responses in the former to those that occur in recipients of current cholera vaccines.
The goal of these studies is to identify the mediators of protection against cholera, in order to advance improved prevention strategies, as well as to advance vaccine development and deployment.

2. Host-pathogen interactions during typhoid fever

In a collaborative effort with researchers at the International Centre for Diarrhoeal Disease Research in Dhaka, Bangladesh (ICDDR,B), we are evaluating host-pathogen interactions and immune responses in humans infected with Salmonella enterica serotype Typhi (the cause of typhoid fever) and S. Paratyphi (the cause of paratyphoid fever).
Together, S. Typhi and S. Paratyphi cause approximately 20 million cases of enteric fever world-wide, resulting in approximately 200,000 deaths each year. Most of these deaths occur in impoverished children and young adults.
Although usually caused by S. Typhi, one in four cases of enteric fever is caused by S. Paratyphi in many areas of the world. S. Typhi and S. Paratyphi are particularly common among urban residents in informal settlements and slums, although any individual lacking safe water and sanitary facilities is at risk of infection.
Vaccines against S. Typhi provide only 50-60% protection against disease for 2-5 years, and, at present, there is no commercially available vaccine against S. Paratyphi. There is also no good point-of-care test to diagnose individuals with enteric fever, and S. Typhi and S. Paratyphi are becoming increasingly resistant to antimicrobial agents.
To address this, we are evaluating host-pathogen interactions directly in humans infected with S. Typhi and S. Paratyphi. We are applying a number of technologies to evaluate innate and adaptive immune responses directly in humans infected with S. Typhi and S. Paratyphi in Bangladesh, and we are evaluating bacterial responses in humans during these human-restricted infections.
The goal of these studies is to develop improved diagnostic assays, antimicrobial agents, and preventative strategies against these infections.

3. Immunization approaches for enteric infection

A fundamental challenge facing many enteric and mucosal vaccines is their inability to induce long-term protective immunity. Many of these vaccines may not be prominent inducers of memory cells, which play critical roles in mediating long-term protection against disease.

Using our analysis of memory B and T cell induction during wild-type human enteric infection in Bangladesh, we are evaluating the ability of a number of vaccination approaches and strategies to induce long-term memory responses protective against mucosal and enteric infections, including oral-transcutaneous prime-boosting approaches.

4. Global TravEpiNet (GTEN)

To extend our analysis of infections associated with living in, traveling through, or immigrating from resource-limited areas, we also work with the U.S. Centers for Disease Control and Prevention through the GTEN (Global TravEpiNet; Global Travelers’ Epidemiology Network) Program. GTEN’s mission is to advance the health of American residents who travel internationally, as well as to lessen the likelihood of disease importation into home communities. GTEN-relate resources are available at Heading Home Healthy. Focus areas include vaccine preventable illnesses, and importation of highly drug resistant organisms.