Ana is a 9-year-old girl who lives in Brazil with her 7-year-old brother José and her mother Maria. Three months ago, Ana had an episode of dengue hemorrhagic fever. Today, she visits the clinic with her mother to receive the first dengue vaccine dose. Maria asks the pediatrician if José, who has never had dengue, could also receive the vaccine.
The first dengue vaccine licensed for use in some countries is CYD-TDV (Dengvaxia® Sanofi Pasteur), a recombinant, live, attenuated, tetravalent vaccine. CYD-TDV is administered as a three-dose series given 6 months apart. The World Health Organization currently recommends the CYD-TDV vaccine only in children who are dengue-seropositive because of its association with a higher risk of severe dengue and hospitalization in dengue-seronegative children. New dengue vaccines are in development, including TAK-003 (Takeda), a tetravalent vaccine based on a live attenuated DENV-2 virus.
NEJM recently published the primary efficacy results of a phase 3 randomized clinical trial of TAK-003 in healthy children and adolescents aged 4 to 16 years. After 12 months of follow-up, overall vaccine efficacy of two doses of TAK-003 given 3 months apart was 80%. Analysis of a secondary end point in dengue-seronegative children showed vaccine efficacy of 75%.
For children like José who are dengue-seronegative, no licensed dengue vaccines are currently available. TAK-003 has potential for use in both seronegative and seropositive children, although its long-term efficacy and safety will still need to be assessed.
The following NEJM Journal Watch summary explains the study and results in more detail.
Tetravalent Dengue Vaccine Efficacious in Endemic Regions
Mary E. Wilson, MD reviewing Biswal S et al. N Engl J Med 2019 Nov 21
TAK-003, a tetravalent dengue vaccine candidate, was protective against virologically confirmed infection in children in endemic areas for 12 months after vaccination.
Dengue infection incidence continues to increase; nearly half the world's population lives in dengue-endemic areas. TAK-003 is a tetravalent vaccine candidate based on a live-attenuated dengue serotype-2 virus (DENV-2) which provides the genetic backbone for all four dengue serotypes. Investigators report results from a manufacturer-supported, double-blind, placebo-controlled phase 3 trial of TAK-003 in healthy children (4−16 years) at 26 dengue-endemic sites in the Americas and Asia. Participants (>20,000) were randomly assigned (2:1 ratio) to receive two doses of vaccine (0, 3 months) or saline placebo administered subcutaneously. Results are reported for 12 months after vaccination completion.
Efficacy against virologically confirmed dengue (any serotype) was about 80% and was 95.4% against dengue requiring hospitalization. Among participants seronegative at baseline (27.7%), vaccine efficacy was 74.9%. Efficacy after the first dose was 81%, but numbers were small. Efficacy varied by dengue serotype, was highest against DENV-2 (97.7%), and ranged from 62.6% to 73.7% against other serotypes. Adverse events were similar with vaccine and placebo.
Comment: The world needs a dengue vaccine that can be administered without serologic prescreening. Use of the currently licensed dengue vaccine (Dengvaxia; NEJM JW Infect Dis Jul 2019) is limited to individuals with a previous dengue infection. The TAK-003 vaccine results, though preliminary, are welcome, suggesting that TAK-003 can be used in dengue-naive individuals. The apparent protection after a first dose suggests that the vaccine might be useful in an outbreak. Unsurprisingly, efficacy was highest against DENV-2, which provides the genetic backbone for the vaccine. Follow-up studies will be needed to assess longer-term efficacy and safety, and the durability of protection against other serotypes beyond 12 months.
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Ken is a 2019-2020 NEJM Editorial Fellow and a paediatrician working in the National Health Service of the United Kingdom. He graduated from Imperial College School of Medicine and is training in general paediatrics in London.