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Clinical Trial Advances Dengue Vaccine Candidate



17 March 2016. A small-scale clinical trial testing an experimental vaccine with people given live dengue viruses shows the vaccine is effective in preventing dengue infections. The team from Johns Hopkins University and University of Vermont published its findings in yesterday’s (16 March) issue of Science Translational Medicine; paid subscription required.

The vaccine, developed by researchers at National Institute of Allergy and Infectious Diseases that funded the trial and U.S. Food and Drug Administration, is designed to prevent all 4 types of dengue infections. Dengue is viral disease transmitted by infected mosquitoes (not person-to-person) that occurs most frequently in tropical urban regions of the world. World Health Organization estimates as many as 390 million infections occur each year, with half of the world’s population at risk. WHO says the disease is now endemic in more than 100 countries, especially in Asia, Africa, the Americas, eastern Mediterranean, and Pacific islands.

The disease is a collection of 4 major types, but all types can cause high fever, severe headache, muscle and bone pain, and bleeding. Dengue hemorrhagic fever is a severe form of the disease that can cause respiratory problems, severe bleeding, organ failure, and become fatal. There are no treatments for dengue other than caring for symptoms, but several vaccines are being tested in clinical trials.

One of the obstacles facing dengue vaccine developers is the need to cover all 4 types of the disease, since people infected with one type of dengue can face worse symptoms if subjected to another type. The vaccine tested in the clinical trial, code-named TV003, combines weakened viruses addressing each of the 4 types dengue viruses. Weakened viruses then stimulate an immune response, developing antibodies to fight dengue invaders, with at most mild symptoms.

The clinical trial, led by Anna Durbin at Johns Hopkins University’s school of public health in Baltimore and Beth Kirkpatrick at University of Vermont in Burlington, recruited 48 healthy individuals at their institutions to take part in what is called a human challenge study. Half of the participants were randomly assigned to receive TV003 inoculations while the remaining 24 individuals received placebo injections. Six months later, the 41 participants who remained in the study — 21 receiving the TV003 and 20 the placebo — were given a weakened form of dengue virus, resembling the type of the disease considered most difficult to prevent. Human challenge trials were used previously to test malaria vaccines, and are conducted under strict controls.

The results show participants receiving the placebo were found with virus in their blood. Most of the placebo recipients, 16 of 20, developed a mild rash, while 4 experienced low white blood cell counts, a condition known as neutropenia. In contrast, none of the 21 recipients of TV003 experienced any symptoms, nor were dengue viruses found in their blood.

Early reports of the findings in February provided enough evidence to authorities in Brazil to grant approval to a larger late-stage clinical trial of TV003. “Knowing what we know about this new vaccine, we are confident that it is going to work,” says Durbin in a university statement. “And we have to be confident: Dengue is unique and if you don’t do it right, you can do more harm than good.”

The challenge trial’s design, using a small sample of healthy volunteers to test a particular vaccine’s efficacy under controlled conditions, offers a tool to screen vaccine candidates in advance of large and expensive clinical trials. “What we’re trying to do is accelerate vaccine development,” adds Durbin, “weeding out poor candidates before testing them in large numbers of people in places where dengue is endemic.” She says this same method could be used to test vaccines for the Zika virus, also a mosquito-borne infection in the same family of viruses as dengue.

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