Dengue virus is the causative pathogen of dengue hemorrhagic fever and is endemic in many parts of the tropics and subtropics. The virus is carried by mosquitoes and can infect people multiple times in their lifetime, ranging in severity from a mild, sub-clinical infection to full-blown hemorrhagic fever. In the case of dengue, secondary infections are often more severe than primary infections; this effect is thought to be caused by antibody-dependent enhancement, which is when non-neutralizing antibodies lead to increased viral infectivity of cells. Enhancement is a concern when it comes to vaccine development and deployment, because it is believed that antibodies developed after vaccination could cause enhancement. There have been three clinical trials of a recombinant, live-attenuated, tetravalent dengue vaccine (CYD-TDV) that led to licensing of the vaccine. However, after licensing, there were increased reports of hospitalizations in vaccinated children (ages 2-5 years), leading to reconsideration of the requirements for age and baseline serostatus. Unfortunately, at the time of the trials, only 7.5-20% of baseline serostatus was known, which is not high enough to extrapolate the effects of this factor on immunogenicity. In a study recently published in The New England Journal of Medicine, researchers from Fred Hutch and their colleagues used a new assay and blood samples taken at month 13 (after the third vaccination) to determine serostatus post-hoc.
Figure provided by Dr. Gilbert.
The researchers developed a new enzyme-linked immunosorbent assay (ELISA) that detects dengue anti-nonstructural protein 1 (NS1) in order to identify the difference between dengue infection and vaccination. This is possible because the vaccine has a yellow fever NS1 in place of dengue NS1. Samples were either considered seropositive or seronegative by viral plaque reduction test (done at baseline) or by NS1 ELISA (done at month 13) . Efficacy was followed for 25 months and safety for up to 6 years. Risk was associated with serostatus and age and is shown in figure 1. Generally, risk increased with vaccination in the seronegative group and increased in controls (non-vaccinated patients) in the seropositive group. Over time, the cumulative risk in seropositive people increased in the control group compared to vaccinated seropositive group. This effect was reversed in the seronegative group. In severe cases of dengue, the duration of fever, symptoms, and hospitalization did not change based on serostatus or vaccination. Vaccine efficacy differed between seronegative and positive participants, with 39% and 76%, respectively not becoming sick (ages 9-16).
In conclusion, vaccination of seropositive patients protects against further disease and decreased risk of severe disease. Among seronegative patients, vaccination increases risk of severe dengue symptoms and hospitalization. This suggests serostatus as a major factor in vaccine performance. These results also support the hypothesis that vaccination in previously uninfected patients may mimic primary infection and lead to antibody-induced immunogenicity after future infections (which is similar to what is seen with natural secondary infections). This suggests that serostatus should be assessed before vaccine is administered in the future. The World Health Organization changed its recommendation to state that the vaccine should only be given to those who are believed to have been infected in the past.
Sridhar S, Luedtke A, Langevin E, Zhu M, Bonaparte M, Machabert T, Savarino S, Zambrano B, Moureau A, Khromava A, Moodie Z, Westling T,Mascarenas C, Frago C, Cortes M, Chansinghakul D, Noriega F, Bouckenooghe A, Chen J, Ng S-P, Gilbert PB, Gurunathan S, DiazGranados CA. 2018. Effect of Dengue Serostatus on Dengue Vaccine Safety and Efficacy. N Engl J Med.
Funding was provided by Sanofi Pastier.
Fred Hutch/UW Cancer Consortium faculty members Drs. Peter Gilbert and Alex Luedtke contributed to this research.