In a new study reported in PLoS Medicine, researchers used mathematical modeling to generate predictions about the long-term safety and public health impact of Dengvaxia, Sanofi Pasteur’s dengue vaccine that has recently been approved for use in 11 countries.1
The mosquito-borne virus affects up to 400 million people annually and is a top cause of mortality in tropical and subtropical regions. While cases are rare in the US, approximately 40% of the global population lives in at-risk areas such as those where the disease is endemic–including roughly 100 countries in Asia, Africa, the Pacific, the Caribbean, and the Americas.2
The phase 3 trials of Dengvaxia showed an average efficacy of 60.3% (95% confidence interval [CI], 55.7%-64.5%) in children aged 2-16 years, and it was doubly effective in children who had been previously infected with any of the 4 dengue serotypes that cause the disease.3,4 However, there are concerns that vaccination could actually increase the risk of hospitalization with subsequent infections, especially among dengue-naïve children. Though an initial infection with dengue virus often results in only minimal symptoms, a secondary infection significantly increases the risk of severe disease, which is believed to be due to antibody-dependent enhancement (ADE).
During the first year of follow-up after the active phase of those trials, all age groups showed continued protection from the vaccine except for children who were 2-5 years old. This group had a greater incidence of hospitalization with dengue compared to unvaccinated control subjects, and additional evidence suggests diminished effectiveness of the vaccine in all age groups following the active phase.5
Eight modeling groups from US and international universities responded to a call from the World Health Organization (WHO) to develop long-term, model-based predictions about the vaccine, which the WHO incorporated into recommendations about its appropriate use. The models generally adopted a mode of action that “assumed that vaccination, similarly to natural infection, induces transient, heterologous protection and, further, establishes a long-lasting immunogenic memory, which determines disease severity of subsequent infections,” explained the authors.
All models resulted in the following predictions:
- In settings with moderate-to-high dengue endemicity, as defined by seroprevalence levels among 9-year-old children (SP9) ≥ 50%, the default policy of routine vaccination of 9-year-olds at 80% coverage would reduce symptomatic and hospitalized dengue incidence by 6%-25% over 30 years
- In high-transmission settings (SP9 ≥ 70%), vaccination would reduce symptomatic and hospitalized dengue incidence by 13%-25%
- In low-transmission settings (SP9 ≤ 30%), vaccination could lead to a significant increase in hospitalization with dengue
- In moderate-transmission settings (SP9 = 50%), targeting older children may increase the net benefit of vaccination
- Vaccination was most cost-effective in settings where SP9 = 70%
In high-transmission settings, most people in the target age range have been infected with dengue before, and the vaccine may act like a silent second infection in such individuals. “This means that they never have their actual second, dangerous infection,” explained study co-author Mark Jit, BSc, PhD, MPH, a professor in vaccine epidemiology at the London School of Hygiene and Tropical Medicine.
“But in settings with little dengue transmission, most people have never had dengue before, so the vaccine acts like a silent first infection, and when vaccinees actually get dengue, they have a second infection which is more likely to lead to hospitalization,” he told Infectious Disease Advisor.
These findings underscore the need to accurately identify areas in which the vaccine can be of most benefit–meaning those with the highest rates of dengue transmission and where most people who are at least 9 years old have had the virus previously. “This kind of information is vital now that countries are making decisions about whether or not to introduce dengue vaccination into their populations,” noted Dr Jit.
- Flasche S, Jit M, Rodríguez-Barraquer I, et al. The long-term safety, public health impact, and cost-effectiveness of routine vaccination with a recombinant, live-attenuated dengue vaccine (Dengvaxia): a model comparison study. PLoS Med. 2016; 13: e1002181. doi: 10.1371/journal.pmed.1002181
- Dengue. Centers for Disease Control and Prevention. https://www.cdc.gov/dengue/. Updated January 19, 2016. Accessed December 18, 2016.
- Capeding MR, Tran NH, Hadinegoro SR, et al. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: A phase 3, randomised, observer-masked, placebo-controlled trial. Lancet. 2014; 384:1358-1365. doi: 10.1016/S0140-6736(14)61060-6
- Villar L, Dayan GH, Arredondo-García JL, et al. Efficacy of a tetravalent dengue vaccine in children in Latin America. N Engl J Med. 2015; 372:113-123. doi: 10.1056/NEJMoa1411037
- Hadinegoro SR, Arredondo-García JL, Capeding MR, et al. Efficacy and long-term safety of a dengue vaccine in regions of endemic disease. N Engl J Med. 2015; 373:1195-1206. doi: 10.1056/NEJMoa1506223