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Indian Pediatr 2015;52: 237-240

Tetravalent Dengue Vaccine for Children

Source Citation: Villar L, Dayan GH, Arredondo-García J, Rivera DM, Cunha R, Deseda C, et al. Efficacy of a tetravalent dengue vaccine in children in Latin America. N Engl J Med. 2015;372:113-23.

Section Editor: Abhijeet Saha


In this phase-3 efficacy trial of a tetravalent dengue vaccine in five Latin American countries, 20,869 healthy children between the ages of 9 and 16 years were randomly assigned in a 2:1 ratio to receive three injections of recombinant, live attenuated, tetravalent dengue vaccine (CYD-TDV) or placebo at months 0, 6, and 12 under blinded conditions, and followed for 25 months. The primary outcome was vaccine efficacy against symptomatic, virologically-confirmed dengue occurring more than 28 days after the third injection. At baseline, 79.4% of an immunogenicity subgroup of 1944 children had seropositive status for one or more dengue serotypes. In the per-protocol population, there were 176 dengue cases (with 11,793 person-years at risk) in the vaccine group and 221 dengue cases (with 5,809 person-years at risk) in the control group, for a vaccine efficacy of 60.8% (95% CI 52.0%, 68.0%). Serotype-specific vaccine efficacy was 50.3% for serotype 1, 42.3% for serotype 2, 74.0% for serotype 3 and 77.7% for serotype 4. Among the severe confirmed dengue cases, 1 of 12 was in the vaccine group, for an intention-to-treat vaccine efficacy of 95.5%. Vaccine efficacy against hospitalization for dengue was 80.3%. The authors concluded that CYD-TDV dengue vaccine was efficacious against virologically-confirmed dengue infection, including severe disease.


Evidence-based Medicine Viewpoint

Relevance: Dengue is a common and serious infection in many parts of the world, including India [1]. An effective vaccine against dengue is eagerly awaited. This randomized controlled trial (RCT) of a tetravalent dengue vaccine, conducted in five South American countries [2], suggests progress towards a safe and effective vaccine. It also provides an excellent opportunity to learn about well-conducted RCTs, and vaccine trials in particular.

Critical appraisal: A detailed critical appraisal is presented in Table I. Most of the criteria for a trial with low risk of bias are fulfilled.

Extendibility: The data in this RCT can be extrapolated to similar epidemiologic settings in terms of disease endemicity, burden of infection, and affected population group. Prior to initiating a similar trial in India (which is highly likely given the trends of new vaccine trials in recent years), an estimation of burden of disease, age-specific infection rate, hospitalization rate, mortality rate, and complication rate of dengue should be calculated (at least in the areas believed to have significant burden). The lack of efficacy among sero-negative individuals and slightly higher local adverse reactions also advocate in favour of further evaluation of efficacy and safety.

This trial has shown efficacy of the vaccine against dengue serotype 2, unlike the previous trial of the same vaccine in Asian countries [3]. This could have implications for India as serotype 2 predominated in the major outbreak of 1998. However, the 2003 outbreak was mainly with serotype 3 [4], whereas a study from Uttar Pradesh noted serotype 2 to be predominant during 2009 to 2012 [5]. In contrast, molecular analysis suggests that serotype 3 is also prevalent [6]. Currently, it is believed that all four serotypes are circulating, suggesting the need for pan-serotype efficacy [4,7].

Conclusions: Although there are some concerns regarding safety and efficacy, this well-designed RCT raises hope that a safe and efficacious dengue vaccine can be available in the near future.


1. Shepard DS, Halasa YA, Tyagi BK, Adhish SV, Nandan D, Karthiga KS, et al. Economic and disease burden of dengue illness in India. Am J Trop Med Hyg. 2014; 91:1235-42.

2. Villar L, Dayan GH, Arredondo-García JL, Rivera DM, Cunha R, Deseda C, et al. Efficacy of a tetravalent dengue vaccine in children in Latin America. N Engl J Med. 2015;372:113-23.

3. Capeding MR, Tran NH, Hadinegoro SR, Ismail HI, Chotpitayasunondh T, Chua MN, 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;384:1358-65.

4. Gupta E, Ballani N. Current perspectives on the spread of dengue in India. Infect Drug Resist. 2014;7:337-42.

5. Mishra G, Jain A, Prakash O, Prakash S, Kumar R, Garg RK, et al. Molecular characterization of dengue viruses circulating during 2009-2012 in Uttar Pradesh, India. J Med Virol. 2015;87:68-75.

6. Bedi SK, Prasad A, Mathur K, Bhatnagar S. Positive selection and evolution of dengue type-3 virus in the Indian subcontinent. J Vector Borne Dis. 2013;50:188-96.

7. Vinodkumar CS, Kalapannavar NK, Basavarajappa KG, Sanjay D, Gowli C, Nadig NG, et al. Episode of coexisting infections with multiple dengue virus serotypes in central Karnataka, India. J Infect Public Health. 2013;6:302-6.

Joseph L Mathew
Department of Pediatrics,
PGIMER, Chandigarh, India.
Email: dr.joseph.l.mathew@gmail.com

Vaccinologist’s Viewpoint

Dengue is global public health problem with about 2.5 billion (40% 0f world population) at risk. In addition to vector control measures, an effective and safe vaccine is required for reducing mortality and morbidity due to the disease. In this trial conducted in South America, recombinant live attenuated tetravalent dengue vaccine (CYD-TVD) has been studied in a large population with adequate follow up for clinical disease in an endemic area. Population studied were 9-16 years with 80% already seropositive. Since the disease occurs in all age groups, even children less than 9 years or earliest possible age when the vaccine is to be given should have been studied. No definite immunological correlate of the vaccine is known and hence the strength of the study is a 25 month follow up for clinical disease to demonstrate efficacy of the vaccine. If the genotype included in the vaccine is similar to the circulating genotype, the efficacy of the vaccine can be considered as good; hence the need to know the circulating genotypes in the area before introduction of the vaccine [1]. Dengue infection has a wide range of clinical manifestations and severity. Heterotypic immunity is protective for some time but later leads to increases in severity of disease – a paradoxical challenge of the immunopathogenesis of dengue [2,3]. Hence, there is a need to include all circulating genotypes in the vaccine.


1. Usme-Ciro JA, Méndez JA, Laiton KD, Páez A. The relevance of dengue virus genotypes surveillance at country level before vaccine approval. Hum Vaccine Immunother. 2014;10:2674-8.

2. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, et al. The global distribution and burden of dengue. Nature. 2013;496:504-7.

3. Smith AW, Macary P. Dengue: Challenges for policy makers and vaccine developers. Curr Infect Dis Rep. 2014;16:404.

Anju Aggarwal
Department of Pediatrics,
UCMS & GTB Hospital,
Delhi, India.
Email: aanju67@gmail.com

Pediatrician’s Viewpoint

Antibody-dependent enhancement and its role in severe dengue supports the necessity for tetravalent dengue vaccines that stimulate balanced immune responses to the four serotypes. Only one Chimeric Tetravalent vaccine has undergone Phase III trials so far with promising efficacy.

The authors in this article have used a recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV) and reported an efficacy of 60.8% against symptomatic virologically-confirmed dengue, after a three-dose vaccination schedule among children between the ages of 9 and 16 years; an efficacy of 80.3% against hospitalization for dengue, and 95.5% against severe dengue were observed over the 25-month period. No safety concerns or evidence of more severe disease in breakthrough cases in the vaccine group over the 25-month surveillance period were observed by the authors. It is not known whether this favourable safety profile will be sustained through periods of waning immunity and successive dengue exposures remote from vaccination in endemic areas.

The efficacy results reported here are consistent with those of the similarly designed Asian trial [1]. The observation of vaccine efficacy against hospitalization for dengue of 80.3% is encouraging from the public health point of view, particularly in the Indian context. Excellent safety and reactogenicity profiles in this study are reassuring. Vaccine immunogenicity was consistent as in the earlier Thailand study. This study and the Asian study provide a consistent picture of the efficacy and safety of this dengue vaccine after 25 months of active surveillance in 10 countries among different populations.

There is an urgent need for large, multicenter phase 3 trials to test investigational dengue vaccines in heterogeneous epidemiologic settings, and to obtain confirmatory data for serotype-specific efficacy.


1. Capeding MR, Tran NH, Hadinegoro SR, Ismail HI, Chotpitayasunondh T, Chua MN, 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: 1358-65.

S Balasubramanian
Department of Pediatrics,
Child Trust Hospital, Chennai, India.
Email: sbsped@gmail.com


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