Shots protect against three virus subtypes, but not fourth
The first large-scale test of a vaccine against dengue fever has failed to consistently prevent the viral disease in children, researchers report online September 11 in the Lancet. The mixed results have left scientists wondering how one form of the virus dodged what looked like a potent immunization regimen.
The shaky showing in Thai children won’t send scientists back to the drawing board, since the vaccine is already being tested extensively elsewhere. Officials at vaccine maker Sanofi Pasteur even point out that the vaccine engendered respectable defense, protecting against three of the four viral subtypes of dengue in 61 to 90 percent of vaccinated children.
But the vaccine failed to fend off one subtype of dengue, called dengue serotype 2. That subtype is common in the region of Thailand where the trial was conducted. What’s more, the specific version of the dengue subtype 2 in that area turned out to be particularly aggressive, says study coauthor Nadia Tornieporth, a physician and head of global clinical research at Sanofi Pasteur U.S. headquarters in Swiftwater, Pa.
“This trial is a cautionary tale for investigators designing future dengue vaccine trials,” says Scott Halstead, a physician at the International Vaccine Institute in Seoul, Korea, writing in the same issue of Lancet. Most of the children in the study had previous exposure to a dengue subtype or a related virus, a situation that makes it difficult to establish the effectiveness of the new vaccine, he says.
According to the World Health Organization, dengue affects 50 million to 100 million people globally each year, with 500,000 needing hospitalization.
To elicit an immune reaction, the vaccine uses a yellow fever vaccine as a platform for ferrying viral proteins from the four dengue subtypes. The vaccine had previously generated ample neutralizing antibodies in people, Halstead says. The version of dengue serotype 2 virus circulating in Thailand might have evaded these antibodies, he suggests, or the vaccine might have failed to generate balanced immune responses to all four subtypes of dengue.
The researchers enrolled 4,002 children ages 4 to 11 in the study. The kids were randomly assigned to get three shots spaced over one year — either three doses of the dengue vaccine or placebo shots. In all, 2,452 children got three shots and full follow-up tests, while 1,221 got the control shots.
The researchers diagnosed 134 dengue infections in all children in the study over two years. Dengue serotype 2 caused three-fifths of the infections. “We were surprised when we saw there was no protection against this particular dengue serotype,” Tornieporth says.
Overall, 2.8 percent of the vaccinated children and 4.4 percent of the controls came down with dengue fever, a difference too small to establish a benefit. Five children contracted severe dengue — three who got the vaccine and two controls — but all recovered fully.
Questions arising from these mixed results will probably be answered in 2014 when Sanofi Pasteur releases findings from an ongoing trial of the same vaccine in more than 30,000 children and teenagers in 10 countries, Tornieporth says.
A. Sabchareon et al. Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: A randomised, controlled phase 2b trial. Lancet. doi.org/10.1016/ S0140-6736(12)61428-7
S. Halstead. Dengue vaccine development: A 75% solution? Lancet. doi.org/10.1016/ S0140-6736(12)61510-4
J.L. Poo et al. Live-attenuated tetravalent dengue vaccine in dengue-naïve children, adolescents and adults in Mexico City: Randomized controlled phase 1 trial of safety and immunogenicity. Pediatric Infectious Diseases, Vol. 30, January 2011, p. e9. doi: 10.1097/INF.0b013e3181fe05af