On March 16, 2016, the National Institutes of Health announced that an investigational dengue vaccine developed at the National Institute for Allergy and Infectious Disease (NIAID) has advanced into a phase 3 efficacy trial in Brazil. Lew Markoff, MD, and Barry Falgout, PhD, with the Laboratory of Vector-borne Virus Diseases in FDA’s Center for Biologics Evaluation and Research, made an early contribution to the development of this vaccine. The phase 3 trial is a direct result of success in a human challenge study where the vaccine protected healthy U.S volunteers from signs and symptoms of dengue. The study involved a total of 41 individuals, 21 of whom received the vaccine and 20 of whom received a placebo on the same day. After six months, all volunteers were infected with a strain of dengue virus chosen because it causes only mild manifestations of disease. All of the vaccine recipients were protected, while all 20 volunteers who received placebo experienced a rash and/or other mild manifestations of dengue fever, caused by the challenge dengue virus.
Dengue fever is a virus transmitted by the bite of infected Aedes aegypti mosquitoes. Symptoms include a high fever, headaches, joint and muscle pain, vomiting, and a rash. Occasionally, there is mild bleeding from the nose or gums or signs of bruising. Severe dengue may include much more severe bleeding from internal organs, failure of multiple internal organs such as the liver, even without bleeding, and shock, any of which may be life threatening. There are four different serotypes of dengue virus (DENV1-4), and because a primary infection with any one serotype can eventually lead to severe disease after infection with a second serotype, all vaccines under development aim to protect against all four serotypes simultaneously. For this reason, the study vaccine consists of a mixture of four dengue viruses, one for each serotype, and each virus has been attenuated (weakened). The intent of the vaccine is to cause an infection in the vaccinated person which results in protective immunity without causing signs of disease.
Although the investigational vaccine was developed primarily by scientists from NIAID, Drs. Markoff and Falgout uniquely had the expertise to assist scientists at NIAID in creating the DENV1 component of the vaccine, because they had already available a full-length DNA copy of the genome of a DENV1 strain that had been isolated in the Western Pacific islands, in 1974. They had demonstrated the ability to successfully introduce mutations into this genome, and they had already used it to produce a different DENV1 vaccine candidate. Drs. Markoff and Falgout introduced the deletion mutation that characterizes the investigational vaccine viruses into their DENV1 DNA and provided the mutated DNA to NIAID to produce the candidate vaccine. Dr. Markoff notes that, “a desire to make a difference drives our research and we are pleased that that we could contribute to this vaccine which is so far yielding encouraging results.”
The study results with this vaccine are encouraging for not only in the battle against dengue, but also for efforts to address other public health threats such as the Zika virus. The dengue virus is closely related to Zika virus and the same mosquitos transmit both viruses.