Enterics Research

Current Research

The Effects of Increased Inoculum on Oral Rotavirus Vaccine

Dr. Benjamin Lee HeadshotRotavirus vaccine has had less success preventing the diarrheal disease in developing countries than in wealthier nations. “There are a lot of proposed reasons why that occurs, but nobody knows for sure,” said Benjamin Lee, assistant professor of pediatrics at UVM Children’s Hospital and investigator in the UVM Vaccine Testing Center. Lee is studying whether a higher dose will help make the rotavirus vaccine more effective in developing countries, where the disease causes more than 200,000 children’s deaths each year due to related dehydration. Rotavirus, an enteric virus that infects the gastrointestinal system, and remains the most common cause of diarrheal disease in the developing world. In the U.S., babies aged two to six months have received the vaccine since 2006, greatly reducing infection rates.

Lee’s receipt of a Child Health Research Award from the Charles H. Hood Foundation is supporting a study in Bangladesh targeting 220 infants. Half of the participants will be randomly selected to receive the standard rotavirus vaccine dose used in the U.S., while the other half will receive a higher dose of the vaccine. The Vaccine Testing Center was part of an academic team, including the University of Virginia and the International Centre for Diarrhoeal Disease Research in Bangladesh, which previously studied the problems with rotavirus vaccines administered in low-income countries.

Dhaka baby receiving oral vaccine

Improving Rotavirus Vaccination: Refining Correlates of Protection and Evaluating Durability

Oral vaccines, which work exceptionally well to protect infants and children in the U.S., can fail to do so in developing countries. Case in point – the oral rotavirus vaccine has a strong track record in preventing the majority of cases of rotavirus-diarrhea hospitalizations and deaths in the U.S. In developing world settings, however, the vaccine has only worked half as well, leading to more than 450,000 children’s deaths annually due to rotavirus-related dehydration.

Understanding and remedying this paradox is the goal and challenge of a $2.2 million dollar 2.5-year research award from the Bill & Melinda Gates Foundation to University of Vermont Vaccine Testing Center (VTC) investigators. Led by Beth Kirkpatrick, M.D., Professor of Medicine and VTC Director, co-investigators on the grant include Sean Diehl, Ph.D., E. Ross Colgate, M.P.H., Dorothy Dickson, M.Sc., and Benjamin Lee, M.D., a pediatric infectious disease specialist who joined the VTC, UVM College of Medicine Department of Pediatrics, and The UVM Children’s Hospital in August 2015. The grant, titled “Improving Rotavirus Vaccination: Refining Correlates of Protection and Evaluating Durability,” builds on previous Gates Foundation-supported research performed by VTC team members between 2010 and 2014.

Cryptosporidium Infection Model

We have studied the role of host genetic susceptibility and HLA alleles to Cryptosporidium infection. This work was performed as part of a field trial cohort of children in Bangladesh, in collaboration with colleagues at the University of Virginia and the ICDDRB (Dhaka, Bangladesh,http://www.icddrb.org/). Current work is examining the role of mannose-binding lectin genotypes and susceptibility to Cryptosporidium, as well as E. histolytica infections. We are also interested in determining the contribution of the human intestine T-lymphocyte populations to intestinal inflammation, as well as age-dependent changes in the host immune response to intestinal protozoa.

Cryptosporidium is an intestinal protozoan infection which causes diarrhea, particularly in young children and immunocompromised individuals (such as persons with Acquired Immunodeficiency Syndrome, AIDS). In developing regions of the world, Cryptosporidium infection is associated with childhood malnutrition, including loss of linear growth/stunting of height. Our laboratory work has focused on how the immune response of young children to this enteric infection contributes to the vicious cycle of diarrhea, infectious diseases and malnutrition.

Past Research

Exploration of the Biologic Basis for Underperformance of Oral Polio and Rotavirus Vaccines in Bangladesh (Gates PROVIDE Study)

Oral polio and rotavirus vaccines are significantly less effective in children living in the developing world. Tropical enteropathy, which is associated with intestinal inflammation, decreased absorption and increased permeability, may contribute substantially to oral vaccine failure in developing country settings. Other possible causes of oral vaccine underperformance include malnutrition, interference with maternal or breast milk antibodies, changes in gut microbiota, and genetic susceptibility. The primary hypothesis of Exploration of the Biologic Basis for Underperformance of Oral Polio and Rotavirus Vaccines in Bangladesh clinical trial was that tropical enteropathy decreases the effectiveness of oral polio and rotavirus vaccines in infants by disrupting gut integrity. The study enrolled 700 healthy infants born in the urban slum of Mirpur, Dhaka, Bangladesh, as well as their mothers, and employ a prospective cohort, 2×2 factorial study design.

Cholera Vaccine Challenge Study

The University of Vermont Vaccine Testing Center (UVM VTC) conducted a clinical trial of a single-dose, oral vaccine against cholera. In 2017, the groundbreaking vaccine, named Vaxchora, was approved by the U.S. Food and Drug Administration for use in the U.S.

Cholera is an acute diarrheal illness whose symptoms include diarrhea, vomiting, and dehydration, caused by ingesting contaminated food and water. Annually, there are an estimated 100,000 deaths and 3-5 million cases worldwide, although most cases are asymptomatic or mild. Cholera is a disease of poverty, occurring most commonly in countries where access to proper water sanitation is limited. Cholera in the United States is rare, though travelers to endemic areas are at risk if they consume contaminated food or water. Often, cholera cases can be treated with oral rehydration, but more severe cases require intravenous fluid replacement and antibiotics, and untreated cholera can cause death. The approval of Vaxchora represent the first time that a vaccine has been for individuals from the United States traveling to areas where cholera is present.

Campylobacter jejuni Infection Model

Campylobacter jejuni, a Gram-negative bacteria, is a top cause of food-borne disease in the United States and a common cause of diarrhea in young children globally. It is uniquely associated with post-infectious sequelae, including reactive arthritis, irritable bowel syndrome and, via molecular-mimicry, ascending paralysis (the Guillain-Barré syndrome). Our lab is working to improve serodiagnostic tests for the detection of Campylobacter jejuni infections and to better understand the cellular immune responses to this infection.

Typhoid Fever Vaccine Study

Salmonella typhi is another gram-negative bacterium that causes a severe febrile illness and is spread through contaminated food and water. The infection spreads in the host via invasion of host macrophages, using a type-III secretion system (TTSS). Despite vaccines against typhoid fever having been used for more than 100 years, typhoid fever still infects 15-30 million persons annually, killing 600,000. While the clinical arm of the VTC has worked with biotech partners to develop new typhoid vaccines, the laboratory focused on understanding correlates of immune risk to S. typhi infection and evaluating the functional immunology of candidate vaccines.