Dengue Vaccine Candidate Shows Uneven Efficacy

Jennifer Garcia

July 29, 2015

A tetravalent dengue vaccine candidate (CYD-TDV) may decrease the risk for infection among children aged 2 to 16 years, according to results of an interim analysis of three pediatric clinical trials. A higher incidence of hospitalization for dengue among children younger than 9 years underscores the need for further review, however. These results were published online July 27 in the New England Journal of Medicine.

The researchers report on results from a long-term interim analysis of safety and efficacy data from three clinical trials (two phase 3 trials and one phase 2b trial) evaluating the effects of the CYD-TVD vaccine in endemic Asian-Pacific and Latin American regions. The vaccine was administered at baseline, 6 months, and 12 months, for a total of three doses for each patient. The researchers reviewed data from more than 35,000 children aged 2 to 16 years in the 3 to 6 years after the initial vaccine series. They compared the results with those of age- and sex-matched control participants.

The "[p]ooled relative risks of hospitalization for dengue were 0.84 (95% confidence interval [CI], 0.56 to 1.24) among all participants, 1.58 (95% CI, 0.83 to 3.02) among those under the age of 9 years, and 0.50 (95% CI, 0.29 to 0.86) among those 9 years of age or older," Sri Rezeki Hadinegoro, MD, PhD, from the Cipto Mangunkusumo Hospital, University of Indonesia, Jakarta, and the other members of the CYD-TDV Dengue Vaccine Working Group report.

The frequency of signs and symptoms, as well as levels of viremia, were similar between the vaccine and control groups during the efficacy and long-term follow-up phase in all three studies, the researchers note. There were limited data, however, regarding markers of dengue severity.

When evaluated according to age group, one trial demonstrated "a clear trend toward a higher relative risk for hospitalization for virologically confirmed dengue among younger children," citing a relative risk of 7.45 among children 2 to 5 years of age compared with 0.63 among those aged 6 to 11 years and 0.25 among those aged 12 to 14 years. In addition, the researchers noted that approximately 80% of participants aged 9 years or older in two of the three trials were seropositive for dengue at baseline.

The authors acknowledge the limitations of hospital-based surveillance for gauging the incidence of symptomatic infections and note that ongoing follow-up in these trials has been amended to allow evaluation of data from both hospitalized and nonhospitalized participants.

They theorize that a lower-quality immune response may have played a role in waning immunity among the younger participants, particularly those who were seronegative at baseline. They also posit that age alone may have played a role in this imbalance, given the immature immune response noted in young patients.

In an accompanying editorial, Cameron P. Simmons, PhD, from the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Australia, discusses the elevated risk for hospitalization among vaccinated children younger than 9 years and notes that it might be a chance finding. If not, however, one possible explanation is "that CYD-TDV immunization of some young children elicits only transient antibody-mediated full or partial immunity." He also notes that "antibody-dependent enhancement of challenge virus infection, particularly by non-neutralizing vaccine-elicited antibodies, could explain this increased epidemiologic risk."

Dr Simmons acknowledges that although these studies have been greatly informative, the benefits of the CYD-TDV vaccine in children younger than 9 years are still unclear and highlight the need for greater research into a "vaccine-based solution for dengue."

Funding for this study was provided by Sanofi Pasteur. Various authors report personal fees or other support from Sanofi Pasteur outside the submitted work. Dr Simmons has received grants from Sanofi Pasteur and is a collaborating scientist with the Eliminate Dengue Program, which aims to use Wolbachia-infected mosquitoes to control dengue virus transmission.

N Engl J Med. Published online July 27, 2015. Article full text, Editorial full text

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