Dengue Vaccine 100% Effective in Human Challenge Study

Tara Haelle

March 17, 2016

The novel use of a human challenge model has shown that a live attenuated dengue virus vaccine not only induces antibodies to all four strains of dengue but also effectively prevented the most virulent strain's infection in 100% of vaccinated individuals, researchers report in an article published online March 16 in Science Translational Medicine.

"What we're trying to do is accelerate vaccine development, weeding out poor candidates before testing them in large numbers of people in places where dengue is endemic," senior author Anna P. Durbin, MD, from the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, said in a university news release.

The weeding out is necessary before testing in places where dengue circulates because prior infection with one serotype of dengue can make a subsequent infection with a different serotype more severe. This conundrum makes vaccine trials challenging because a vaccine could cause greater risk to recipients if it does not protect against all four serotypes.

In fact, children younger than 9 years who received the three-dose vaccine Dengvaxia (Sanofi Pasteur), licensed in Mexico, the Philippines, and Brazil in 2016, had a greater risk for hospitalization for dengue 2 virus (DENV-2) infection years later than children who had received the placebo. Vaccinated children aged 2 to 5 years were particularly vulnerable, with a risk for hospitalization more than seven times greater than that for those who received placebos, even though more than 95% of the vaccinated children showed evidence of seroconversion and successfully avoided infection in the first year after vaccination.

That Dengvaxia trial revealed how difficult it is to establish whether a vaccine can truly prevent infection independent from the antibody response. Other candidate vaccines have shown similar challenges or had low efficacy rates.

"For this reason, dengue vaccine manufacturers require strong evidence of potential success of a vaccine before initiating large clinical trials in dengue-endemic areas," the authors write. "Without a correlate of protection, identifying these candidates may be difficult." This new study's use of a human challenge model provides a possible solution to that problem.

"This model may serve as an early check for dengue vaccine candidates, limiting the risk of conducting large unsuccessful trials," Angela Colmone, PhD, senior editor at Science Translational Medicine, writes in an accompanying editor's summary.

Dr Durbin and colleagues recruited 48 healthy adult volunteers to test how effectively the tetravalent TV003 vaccine prevented infection against DENV-2. None of the volunteers had had a previous infection with a flavivirus, which dengue is.

"Because the DENV-2 component of TV003 induced the lowest frequency of seroconversion and the efficacy of CYD was lowest against DENV-2, the ability of the vaccine to protect against DENV-2 infection was of greatest interest," the authors explain. "The challenge model described here is similar to that of the controlled human challenge model for malaria in which infection, not disease, is the chosen endpoint."

The researchers randomly assigned 24 volunteers to receive the TV003 vaccine and 24 to receive the placebo. Race, sex, and mean age (29.4 and 30.8 years, respectively) were similar between the groups. The most common adverse event in vaccine recipients was a mild asymptomatic rash on the upper extremities and chest in 79.2% of volunteers that resolved in 5 to 10 days. All the vaccine recipients seroconverted to DENV-2, DENV-3, or DENV-4, and 91.7% seroconverted to DENV-1. Further, the researchers recovered the vaccine virus from 71% of the vaccinated individuals.

Six months later, 41 of the participants returned for the human challenge with DENV-2 derived from a genotype that caused mild disease and that was isolated during an outbreak in 1974 in the Kingdom of Tonga. Among the 21 volunteers who received the vaccine, none developed a rash, neutropenia, or thrombocytopenia, all of which are indications of infection, and the researchers did not recover the challenge virus from any of the vaccinated volunteers.

However, all 20 of the placebo recipients developed symptoms of a mild infection: 16 developed a maculopapular rash (six had moderate severity), four developed transient neutropenia (three graded moderate), and two developed thrombocytopenia. Further, the researchers recovered the challenge virus from all 20 participants.

The vaccine therefore showed 100% efficacy in the human challenge vaccine recipients against DENV-2.

The researchers have also done a challenge with a DENV-3 serotype and plan to conduct challenges with the other two serotypes, lead author Beth D. Kirkpatrick, MD, from the University of Vermont College of Medicine in Burlington, said in a press conference call.

"In the ideal world, we would do this with all of the serotypes," Dr Kirkpatrick said, "The most important thing, of course, is that before those challenges are begun, each of those strains has to be really fully vetted to make sure that safety is optimized when we use them."

The next step is to confirm the TV003 vaccine's efficacy in a phase 3 efficacy trial in dengue-endemic areas.

"This work is important for the rapidly changing landscape of dengue vaccine development," the authors write, noting how the previous trial's low efficacy against DENV-2 had complicated the clinical development of dengue vaccines. "The decision to embark on efficacy trials in endemic regions must be made with the knowledge that a poorly effective vaccine may, in the long run, pose a greater risk for developing severe dengue than no vaccine, possibly due to immune enhancement of disease."

The findings also suggest opportunities in the development of vaccines for other flaviviruses, including Zika, and for treatments for dengue infection, Dr Durbin said during a press conference call.

"What I'd really like to emphasize about this study is that we believe the dengue human challenge or human infection model is an extremely useful tool, not only for acceleration of vaccine development but also looking at therapeutics and moving therapeutics through clinical trials, and for really better understanding the virological and immune response to dengue viruses," Dr Durbin said during the call.

"We think this is a tool that can be extrapolated to other flaviviruses, and we hope to do this with Zika virus," Dr Durbin continued. "There's an urgent need for a Zika vaccine. We are looking at strategies to really accelerate that timeline, and we think a Zika human challenge model could be very useful in that endeavor."

The research was funded by the National Institutes of Allergy and Infectious Diseases Intramural Research Program. One coauthor is an inventor on three patents for an attenuated dengue virus, the tetravalent dengue vaccine, and dengue virus vaccine components. Dr Colmone has disclosed no relevant financial relationships.

Sci Transl Med. Published online March 16, 2016. Full text


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