UVM and icddr,b Work to Address Dengue Surge

UVM and icddr,b the first to study a promising dengue vaccine in dengue-endemic Bangladesh

Investigators from the International Centre for Research, Bangladesh (icddr,b) in Dhaka, Bangladesh, and the Larner College of Medicine at the University of Vermont (UVM), are the first to study a promising tetravalent dengue vaccine in dengue-endemic Bangladesh. Their work, evaluating the single-dose tetravalent dengue vaccine candidate TV005, demonstrated safety and immune responsiveness in children and adults. The accompanying study was recently published in the journal The Lancet Infectious Diseases.

Infection and illness from dengue, a mosquito-borne virus, is a growing risk throughout the world, especially in tropical regions. Mild cases of dengue cause fever and bone pain, and serious cases are associated with shock, bleeding, and sometimes death. Four distinct dengue viruses, or serotypes, can circulate alone or with other serotypes; all serotypes cause illness. The most severe manifestations of dengue are often associated with a second infection.

In Bangladesh, one of the world’s most densely populated (1119 persons/km²) countries—housing a total population of about 170 million people in an area the size of the U.S. state of Iowa—dengue outbreaks have occurred for over twenty years, but the outbreaks have grown exponentially in size and severity. The ongoing outbreak in 2023 represents the worst year on record, with dengue cases overwhelming the hospital system in the capital, Dhaka. During the course of the most recent ongoing outbreak, 190,758 hospitalizations and more than 920 deaths have been recorded until 25 September 2023 throughout the country. Other countries in South Asia are also experiencing a significant rise in dengue outbreaks. Currently, fluid management and symptom control are the only available treatments for dengue. Vaccine development against all four serotypes (a tetravalent vaccine) is a high global priority.

As the first research team studying dengue vaccines in Bangladesh, investigators at the icddr,b and UVM’s Vaccine Testing Center (VTC) began their “Dengue in Dhaka Initiative (DIDI)” in 2015. This collaborative effort aims to advance the development of dengue vaccines throughout Bangladesh. The clinical trials and laboratory assay infrastructure—as well as a preliminary dengue prevalence study—were established and performed at the icddr,b in 2015.

The study, published in The Lancet Infectious Diseases, was a subsequent phase II randomized and controlled clinical trial evaluating the safety, immunogenicity, and 3-year durability of the TV005 tetravalent live-attenuated dengue vaccine. Investigators followed almost 200 volunteers in four age cohorts (ages 1-49 years) who received the TV005 vaccine or placebo over the course of three years, beginning in 2016. TV005 was shown to be well-tolerated. Antibodies to all four dengue serotypes were found in most volunteers after vaccination; individuals who had been infected previously with dengue had higher antibody counts. Although the study was not designed to evaluate efficacy, no cases of dengue were detected in vaccinated volunteers. This data moves the TV005 dengue vaccine closer to widespread use in endemic populations while garnering support for ongoing large, phase III efficacy trials.

The UVM VTC has been evaluating dengue vaccines developed by the U.S. National Institutes of Health (NIH) since 2009. The UVM team is led by Beth Kirkpatrick, M.D. along with important contributions from Mary Claire Walsh, P.A., Kristen Pierce, M.D., Dorothy Dickson, M.S., Sean Diehl, Ph.D., and Marya Carmolli, B.S. Their dengue vaccine program is a longstanding collaboration between UVM VTC and Stephen Whitehead, Ph.D., senior investigator at the Laboratory of Viral Diseases at the U.S. National Institutes of Health (Whitehead is one of the virologists who designed the TV005 vaccine) and Anna Durbin M.D., of Johns Hopkins School Public Health. Prior to this collaborative work with the icddr,b work, the UVM VTC has participated in dozens of pivotal studies throughout the United States, focusing on monovalent and tetravalent formulations and evaluation through controlled human challenge models. Participating investigators at the icddr,b include lead investigator and senior scientist Rashidul Haque, M.B.B.S., Ph.D., and key contributors: Md. Shafiul Alam, Ph.D.; Sajia Afreen, M.B.B.S.; and Md. Masud Alam, M.B.B.S. A fully-trained clinical field site, led by Alam and Afreen, participated in the careful and ethical care of study volunteers.

“The development of an effective and tetravalent dengue vaccine is a very high priority for the large population of Bangladesh, which is now having increasingly severe dengue outbreaks,” stated Haque (icddr,b). “We are proud to participate in the evaluation of the TV005 vaccine in the Bangladeshi population and hope that our work will accelerate the development of dengue vaccines for our country.”

“The TV005 vaccine is the only single dose tetravalent dengue vaccine, which is an important feature of this vaccine,” added Kirkpatrick (UVM). It also appears to prompt immune responses to all four of the dengue serotypes, which is important for any tetravalent dengue vaccine.” Both investigators share the hope that the information is useful to Bangladesh and the large populations of South Asia. 

Kirkpatrick (L) alongside the members of the DIDI dengue vaccine team based at UVM’s Vaccine Testing Center.

All tetravalent dengue vaccines aspire to have a balanced immune response to all four serotypes. Pharmaceutical companies Sanofi and Takeda have had success with other tetravalent dengue vaccines; completing their own phase III trials. The 3-dose Sanofi vaccine is limited to children under nine years of age with known past exposure to dengue. The 2-dose Takeda vaccine has had the best response to dengue serotype 2.

Subsequent studies, including those by the DIDI team, of the efficacy, durability and immune responses of this tetravalent dengue vaccine are ongoing throughout the world. Read the full study here.