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Indian Pediatr 2015;52: 237-240 |
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Tetravalent Dengue Vaccine for Children
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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
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Summary
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.
Commentaries
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.
References
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:
[email protected]
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.
References
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: [email protected]
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.
References
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: [email protected]
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