When an outbreak of cholera unfolds, a vaccine that offers rapid protection could be the difference between life and death for tens of thousands of people. In a preclinical study, investigators at Brigham and Women's Hospital have designed an entirely new class of vaccine that can combat cholera by both training the immune system to detect and destroy the bacteria in the long term and protecting a host immediately from cholera's effects. Using mathematical modeling, the research team predicts that, if successful in humans, their highly innovative approach could change the trajectory of a cholera epidemic.
"Our work represents a whole new concept in vaccinology - this dual acting agent elicits a long-term immune response and also confers protection almost immediately," said corresponding author Matthew Waldor, MD, PhD, a principal investigator and physician in the Division of Infectious Diseases at BWH. "What we've done is something very different than what others have done before. We don't yet fully understand how, but in our preclinical model this novel therapeutic protects against cholera-like illness less than a day after it is administered."
Cholera, a rapidly fatal diarrheal disease with a long history of causing epidemics, remains a public health threat, with current outbreaks today in Yemen and Haiti. Traditional, oral cholera vaccines are made from strains that have been killed and take about 10 days to take effect. Waldor and colleagues have instead engineered a live vaccine based on the strain of cholera that, beginning in 2010, caused a large epidemic in Haiti. The research team engineered the strain by removing the genetic code that gives cholera its deadly abilities. Additionally, they encoded within it a CRISPR-Cas9 system that keeps out any toxin-producing genes, preventing the strain from ever regaining toxin production abilities. They also performed additional engineering to prevent other side effects, including mild diarrhea, and added in an antigen to elicit protection against enterotoxigenic Escherichia coli (ETEC, otherwise known as traveler's diarrhea, which is caused by a different bacterial species).
The team tested the vaccine in a small-animal model of cholera. Animals inoculated with the vaccine, known as HaitiV, did not exhibit cholera-like symptoms and had minimal or no fluid accumulation in the intestines after inoculation, even though the vaccine colonized the small intestine. When the team exposed vaccinated animals to cholera, 24 hours later, no animals exhibited signs of disease, but control animals had all succumbed to cholera at this point.
The team also performed mathematical modeling to predict the public health impact that the hypothetical vaccine might have compared to traditional vaccines. The researchers' simulations showed that in a population of 100,000 people, a fast-acting vaccine could avert 20,000 infections compared to vaccines that can take 10 days to confer immunity.
"The speed with which you respond to an outbreak significantly helps your ability to control that outbreak and prevent people from getting cholera," said lead author Troy Hubbard, PhD, a graduate student in the Waldor Laboratory. "We are very focused on feasibility - the idea of being able to come in with a single-dose intervention that works rapidly but confers immunity over a long period of time is our target for the best possible vaccine."
The team notes that evaluating the immune response that HaitiV elicits in human volunteer studies is a critical next step.
This work was supported by NIH R37-AI-042347 and Howard Hughes Medical Institute and F31 AI-120665. The authors have filed a provisional patent for HaitiV. They declare no competing interests.
Brigham and Women's Hospital (BWH) is a 793-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare. BWH has more than 4.2 million annual patient visits and nearly 46,000 inpatient stays, is the largest birthing center in Massachusetts and employs nearly 16,000 people. The Brigham's medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in patient care, quality improvement and patient safety initiatives, and its dedication to research, innovation, community engagement and educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Brigham Research Institute (BRI), BWH is an international leader in basic, clinical and translational research on human diseases, more than 3,000 researchers, including physician-investigators and renowned biomedical scientists and faculty supported by nearly $666 million in funding. For the last 25 years, BWH ranked second in research funding from the National Institutes of Health (NIH) among independent hospitals. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative as well as the TIMI Study Group, one of the premier cardiovascular clinical trials groups. For more information, resources and to follow us on social media, please visit BWH's online newsroom.