Turning the Tide

April 16, 2010

In terms of killer diseases, HIV/AIDS, tuberculosis and malaria tend to share the media spotlight as the major public health threats in the world’s low-income countries. Philanthropists and aid agencies follow suit with concern and dollars. But diarrheal diseases like cholera and dysentery — mainly attributable to contaminated water and food — kill and incapacitate more people than any of those other diseases. In fact, diarrheal disease is the third-leading cause of death among adults in the developing world, and the second-leading cause of death among children under five years of age, according to the World Health Organization (WHO).

The problem, says Edward T. Ryan, MD, a member of the MGH Division of Infectious Diseases, is that “diarrheal diseases are hardly on the radar screen” of drug and vaccine developers. That’s because American pharmaceutical companies are, for the most part, focused on producing profit-generating drugs and vaccines for diseases that affect Western countries and  the cost of which insurance companies and individuals will bear. But with hundreds of millions of people contracting severe diarrheal diseases every year — and with more than 1.8 million deaths each year by WHO estimates —  a collaborative clinical research team co-led by Stephen B. Calderwood, MD, chief of the Division of Infectious Diseases, Dr. Ryan and Firdausi Qadri, PhD, at the International Centre for Diarrhoeal Disease Research in Bangladesh (ICDDR,B) has made finding a solution for cholera a top priority.

It’s an initiative that began 15 years ago,  when the Mass General group teamed up with Dr. Qadri, a fellow immunologist who was  working on cholera and a type of E. coli infection, and vaccines for them, with colleagues at the ICDDR,B, a nonprofit scientific institute that  also treats 120,000 patients a year, mostly with diarrheal disease.

Cholera is caused by strains of the bacterium Vibrio cholerae that are passed along in food  or water contaminated with human waste. Improved hygiene — water purification and chlorination, for example — in the countries where outbreaks commonly occur is one tactic to controlling  it, but with a third of the planet’s six billion people lacking adequate sanitation and housing facilities, according to the WHO, and urban populations growing fast, that approach  alone may not be practical and will likely need to be combined with an effective vaccine, says Dr. Calderwood.

“Cholera is a major issue for many resource-limited settings of the world and it is a disease in which vaccines can really make  a difference,” says Dr. Calderwood.

He’s not the only one saying so. The WHO is advocating for more widespread use of cholera vaccines, with the recognition that protecting hygiene in densely populated urban areas, particularly in crisis situations, is often insufficient. In a recent report (2006), the WHO pointed to successful mass cholera vaccination campaigns in countries including Mozambique, Sudan and Indonesia.

Less than a handful of cholera vaccines exist; they have been used mainly in parts of Africa, Southeast Asia and Latin America. Existing vaccines, however “may only offer protection for one to three years,” says Dr. Calderwood. “The search for a vaccine that could give longer-term protection would be useful since the need to revaccinate at a relatively frequent interval may not be as practical in the developing world.” Natural immunity, gained from contracting cholera, offers longer-term protection: about five to seven years. So the Mass General-ICDDR,B team is trying to understand the difference between natural immunity and vaccination, which, it hopes, will lead to a vaccine that will give longer-term protection.

In studies so far, the team has discovered that immunologic memory develops following cholera, and it is now studying how long this memory lasts and comparing development of memory after natural infection with what happens in the body after vaccination.

Today, about 50 scientists are working on the Mass General-ICDDR,B vaccine project, with most of the investigators at ICDDR,B. Members of the MGH team travel frequently to Dhaka, the Bangladeshi capital and the country’s largest city,  to work with Dr. Qadri and her team. They also conduct lab research here at Mass General. Various grants — including from the National Institutes of Health and the Harvard Initiative for Global Health — support both research and training, enabling MGH to send doctoral students and post-docs to Bangladesh and bringing Bangladeshi trainees for year-long training stints  at Mass General and Harvard University.

ICDDR,B is well-known for its development of oral rehydration solution, which is widely credited for saving millions of lives of people with severe diarrhea, and has played a critical role in the treatment of cholera. It is also known for its interest in development and testing of vaccines. Cholera is of real concern in Bangladesh, which has two peaks of the disease each year. In addition, the country often suffers from severe flooding which, combined with inadequate piping infrastructure, causes contamination to sources of drinking water, leading to more epidemics.

“The prevention of cholera could lead to a substantial decrease of severe dehydrating illness requiring hospitalization,” says Dr. Qadri, noting that about 30 percent of patients seeking care at the ICDDR,B diarrheal hospital come with severe cholera. In Dr. Qadri’s view, a multi-pronged approach to prevention of cholera is necessary, including widespread use of available vaccines while working to improve cholera vaccines and making them available to regions that need them the most.

In addition to Drs. Calderwood and Ryan, other members of the MGH team include infectious disease colleagues Jason B. Harris, MD, MPH, a pediatrician, and Regina C. LaRocque, MD, MPH, both of whom have spent extended time living in Bangladesh, and post-doctoral fellow Richelle Charles, MD. Currently, much of the work focuses on better understanding how the bacteria takes hold in the body, identifying proteins active in immune responses, characterizing the genetic factors that influence susceptibility to infection and determining how current vaccines can be made more effective.

Deployment of an effective cholera vaccine could provide a major health breakthrough for developing nations. It might preclude events like the 2008 and 2009 cholera outbreak in Zimbabwe, which claimed more than 4,000 lives. And during the war in Rwanda in 1994, 30,000 refugees living on a flood plain — 10 percent of the total that had fled there — died of cholera within three weeks of their arrival. In addition to improving approaches to cholera, the vaccine research could also play a role in improving vaccines for many other diarrheal diseases for which current vaccines do not exist or are ineffective, adds Dr. Calderwood.