Scientists have worked for nearly 80 years to produce a safe, effective vaccine for dengue, a flu-like illness that affects about 400 million people a year. The challenge is creating a vaccine that provides immunity against all four of the virus’s major strains to protect people from severe dengue.
Now there is a new, innovative approach to dengue vaccine development, according to a paper published August 20 in the Proceedings of the National Academy of Sciences. Researchers at the Fred Hutchinson Cancer Research Center and University of Washington School of Public Health led the study.
“In the past, vaccine development for dengue has focused on vaccines that represent all four different dengue serotypes inside the vaccine,” said senior author Dr. Peter Gilbert, director of biostatistics, bioinformatics and epidemiology at Fred Hutch’s Vaccine and Infectious Disease Division and research professor in the department of biostatistics at the School. “Our focus was on the amino acid sequences of dengue and our goal was to see if vaccine efficacy depended on these sequences.”
[Photo: Dr. Peter Gilbert]
Dengue is caused by four distinct serotypes of dengue virus, or variant types defined by whether antibodies can neutralize the virus in a lab experiment. The team focused on Dengvaxia (CYD-TDV), the first-ever dengue vaccine. Safety and efficacy trials of the vaccine, evaluated in children ages 2-14 years and 9-16 years, showed 56.5 percent and 60.8 percent success rates, respectively. Using trial data, researchers evaluated how vaccine efficacy varied based on characteristics of the amino acid sequence.
They first determined that vaccine efficacy was significantly greater against serotypes 3 and 4 than against serotypes 1 and 2. Further exploration revealed that the viral strain for serotype 2 included in the vaccine was not well matched to the serotype 2 viruses circulating and infecting humans in the efficacy trials; serotype 3 and 4 vaccine strains were better matched to the real-life circulating viruses.
“It’s the first time that anyone has proved that you better take protein sequences seriously, not just the serotypes,” Dr. Gilbert said. “We’re breaking the mold by saying it’s not that simple. You can’t just get these discrete serological types. You have to deal with the dimensionality of the protein sequences.”
The international study also sheds light on issues that must be considered when developing vaccines for children. The team discovered that in older children (9-16 years), who had been exposed to dengue and were more likely to possess antibodies against many strains of dengue, the protein sequence did not matter. However, in vulnerable younger children (2-8 years), who face serious morbidity and mortality caused by dengue, the vaccine failed in a protein-sequence-dependent manner against serotype 4.
Lead author Dr. Michal Juraska and senior author Dr. Paul Edlefsen are both staff scientists at Fred Hutch’s Vaccine and Infectious Disease Division; Dr. Edlefsen is also an affiliate associate professor of biostatistics at the UW School of Public Health. Collaborating institutions were Emory University, the Oxford University Clinical Trial Unit in Vietnam, the World Mosquito Program at Monash University and Sanofi Pasteur, developers of Dengvaxia.