FROM SCIENCE

Pediatric patients with previous natural exposure to dengue virus benefit from the dengue virus vaccine, while vaccination of seronegative patients leads to an increased risk for hospitalization because of dengue, according to the results of a mathematical model simulation.

Because of the first approved dengue vaccine’s highly variable efficacy rates among pediatric patients, the vaccine should only be used in moderate to high transmission settings, the investigators who designed the model concluded in a paper published in Science.

Dengvaxia, developed by Sanofi-Pasteur , is a recombinant chimeric live attenuated dengue virus vaccine based on a yellow fever vaccine backbone. The vaccine’s development was “considerably more challenging than for other Flavivirus infections because of the immunological interactions between the four dengue virus serotypes and the risk of immune-mediated enhancement of disease” which causes secondary infections to lead to more severe disease, Neil Ferguson, PhD , of the Imperial College of London and his associates wrote (Science. 2016 Sep 2;353:1033-6. doi: 10.1126/science.aaf9590 ).

Despite the complexity of the virus and vaccine, Dengvaxia was recently approved for use in six countries, and two large multicenter phase III clinical trials recently concluded. Investigators for the trials, which involved over 30,000 children in Southeast Asia and Latin America , reported an overall vaccine efficacy of about 60% in cases of symptomatic dengue disease. However, the vaccine’s efficacy varied by severity of dengue infection and by age and serotype of the patient at time of vaccination. Investigators for both trials reported higher efficacy in patients with severe infection and in patients who were seropositive for dengue virus (indicating previous exposure to the virus) at the time of vaccination. In addition, investigators for both trials reported lower vaccine efficacies in younger patients, a pattern “consistent with reduced efficacy in individuals who have not lived long enough to experience a natural infection,” the authors noted.

In an effort to provide guidance for future clinical trials and to predict the impact of wide-scale use of Dengvaxia, investigators developed a mathematical model of dengue transmission based on data from the two trials.

In the model, the effect of vaccination was “comparable to a silent natural infection,” the investigators explained. “We deliberately examined ages below the 9-year minimum age approved by regulators to give greater insight into the interaction between age, transmission intensity, seroprevalence, and the impact of vaccination on dengue disease,” Dr. Ferguson and his associates wrote.

The model confirmed that secondary infections were nearly twice as likely to cause symptomatic infection, compared with primary and postsecondary infections.

In a highly important result, the model simulation showed that seropositive recipients always gained a substantial benefit – more than a 90% reduction in the risk of hospitalization because of dengue – from vaccination. However, among seronegative recipients, the vaccine initially induced near-perfect protection, but this protection rapidly decayed (mean duration, 7 months). Moreover, the model showed that seronegative recipients who received the vaccine were at an increased risk for hospitalization with dengue.

“This is true both in the short term and in the long term and raises fundamental issues about individual versus population benefits of vaccination,” investigators wrote. “Individual serological testing, if feasible, might radically improve the benefit-risk trade-off.”

The model also demonstrated that the optimal age for vaccination depends on the transmission intensity rate in a region where a child lives. In high-transmission settings, the optimal age to target for vaccination can be 9 years or younger, and as intensity of transmission decreases, optimal age of vaccination should increase, according to investigators.

The study was funded by the UK Medical Research Council, the UK National Institute of Health Research, the National Institutes of Health, and the Bill and Melinda Gates Foundation. Authors did not report any relevant disclosures.

jcraig@frontlinemedcom.com

On Twitter @jessnicolecraig

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