Dengue virus, a mosquito-borne pathogen that can cause severe and fatal flu-like and hemorrhagic disease, threatens almost four billion people globally with cases increasing in recent years. As there are currently no effective antiviral treatments for dengue, prevention measures are limited to mosquito vector control and do not fully halt transmission. Therefore, a vaccine is of high priority with several candidates currently in development. One of these vaccines is the recombinant live attenuated tetravalent vaccine (CYD-TDV), developed by Sanofi Pasteur, which has been shown to provide significant vaccine efficacy (VE) against dengue infection. However, a question remains whether periods of high dengue transmission intensity, or increased infection incidence, affect the efficacy of CYD-TDV, as has been observed in vaccine trials for other infectious diseases. Dengue virus transmission varies in response to season and precipitation, with more infections occurring during the rainy seasons and during high temperatures. To determine if CTD-TDV efficacy wanes during increased dengue transmission intensity, graduate student Chloé Pasin (Université de Bordeaux) and Dr. Zoe Moodie (Vaccine and Infectious Disease Division) headed a recent study published in Plos One that used existing data from past CYD-TDV phase III clinical trials to evaluate vaccine efficacy during the rainy season, as a proxy for increased dengue incidence.
CYD-TDV has been previously tested in two phase III clinical trials: a placebo-controlled trial in 2 to 14-year-olds in South East Asia between 2011 and 2013 (CYD14), and a second in 9 to 16-year-olds during 2011 to 2014 in Latin America (CYD15). Both trials displayed increased vaccine-mediated protection from overall infection and severe dengue disease, prompting the licensing of CYD-TDV for use in dengue-endemic countries. The children (CYD14: 10,275 participants; CYD15: 20,869 participants) received three injections of either CYD-TDV or placebo at six month intervals and were actively followed for symptomatic virologically-confirmed dengue infection for 25 months post-initial immunization. Using site-level climatological data from the geographical regions of the trials, the authors of the current study assigned a binary “rainy season” or “other” status to each month during which data collection occurred in the original trials. Next, the authors used the data generated in the clinical trial to calculate dengue infection incidence by month. When observing the placebo groups, the authors found that dengue attack rates were statistically increased during rainy season months, confirming the validity of rainy season as a proxy for increased dengue risk. However, when comparing the risk of dengue in CYD14 and CYD15-vaccinated and placebo participants over time, VE was not decreased in rainy months, as had been the case in candidate vaccines for other infectious pathogens. Additionally, their statistical analyses found in both trials that younger children are at higher risk of symptomatic, virally-confirmed dengue disease, confirming a result that had been previously observed.
Figure from publication.
This study not only demonstrated that periods of increased rainfall, as defined by the authors, are an accurate proxy of dengue incidence, but also that “vaccine efficacy of CYD-TDV, the first licensed dengue vaccine, remains high during periods of higher dengue incidence,” explains senior author Zoe Moodie. However, these results raise questions regarding other factors that affect VE, such as age and previous dengue exposure. Previous evidence has suggested that those with prior dengue exposure are afforded better protection from dengue by CYD-TDV than those who are naïve to the virus prior to vaccination. Potentially in line with these findings, this study found that after vaccination, younger children were less protected from dengue than were older children, suggesting that younger children may have had less time to be exposed to dengue and therefore were more likely to be seronegative prior to receiving the vaccine. However, the relationships between age, serostatus, and VE are unclear and warrant further exploration. Moodie says they are “interested in assessing whether these results also hold for vaccine efficacy among baseline dengue-naïve and baseline dengue-exposed groups."
Pasin C, Halloran ME, Gilbert PB, Langevin E, Ochiai RL, Pitisuttithum P, Capeding MR, Carrasquilla G, Frago C, Cortés M, Chambonneau L, Moodie Z. 2018. Periods of high dengue transmission defined by rainfall do not impact efficacy of dengue vaccine in regions of endemic disease. PLOS One. 13(12):e0207878.
This work was funded by the Ecole Normale Supérieur de Cachan (Vaccine Research Institute), the National Institute of Allergy and Infectious Diseases, and Sanofi-Pasteur.
Cancer Consortium members Betz Halloran (UW/FH) and Peter B. Gilbert (UW/FH) contributed to this work.