Efficacy of Tetravalent
Dengue Vaccine –
Meta-analysis of Randomized
A G N I B HO M O N DA L 1, BI SHA L G UPTA2A N D R AMA PR O SA D G O SWA MI1
1. D E PA R T M EN T O F T R O P I C A L M ED I C I N E
2. D E PA R T M EN T O F M I C R O B I OL O G Y
SCH O OL OF T RO P ICA L M E DI C I NE , KO LK ATA
Presented at the Annual Conference of API WB Chapter on October 18, 2019
Dengue, the mosquito borne viral illness, is a serious health issue worldwide and
can sometimes be life threatening as well.
Around 390 million people worldwide gets infected by dengue every year,
among which 96 million people have clinical dengue (2013)
Around 3.9 billion people across 128 countries are at risk of dengue infections
The tetravalent dengue vaccine CYD-TDV has been licensed in 2015
This vaccine has been shown to be well-tolerated and immunogenic
CYD-TDV is currently approved in 20 countries
About the vaccine
CYD-TDV is a recombinant, live, attenuated, tetravalent
Chimeric vaccine with yellow fever and dengue antigen
Each dose contains 0.5 ml of reconstituted vaccine
Total 3 doses
◦At 0, 6 and 12 months
Can CYD-TDV actually prevent dengue?
◦In this meta-analysis we tried to analyze the efficacy data from
multiple studies to answer the question.
We searched the PubMed and Cochrane database for published papers on
Keyword: “dengue AND vaccine AND randomized controlled trial [pt]”
PubMed and Cochrane database search yielded 74 and 80 results respectively
The authors independently filtered the search results
◦First by title, then by abstract and lastly by full text
◦Duplicate results were removed
Finally 7 studies were included
◦Comparing CYD-TDV with placebo for efficacy
1. Virologically confirmed dengue
2. Hospitalization due to dengue
Risk of Bias was analyzed by RoB Tool version 2
created by Cochrane Collaboration
Analysis was carried out using RevMan 5.3 software
created by Cochrane Collaboration
A random effects model was used for analysis
Data for all age groups were combined together for
the purpose of analysis
Risk of Bias
Outcome analysis: Confirmed dengue
Total number of patients = 90120
◦Total dengue among vaccine recipients = 807 / 60178
◦Total dengue among placebo recipients = 983 / 29942
Risk ratio = 0.48
◦Confidence interval = 0.37-0.61
◦I2 = 83%
◦Z = 5.79 (P<0.00001)
Hospitalization due to dengue
Total number of patients = 104447
◦Total dengue among vaccine recipients = 198 / 69384
◦Total dengue among placebo recipients = 249 / 35063
Risk ratio = 0.56
◦Confidence interval = 0.34-0.94
◦I2 = 84%
◦Z = 2.18 (P=0.03)
CONFIRMED DENGUE HOSPITALIZATION
CYD-TDV vaccine is efficacious in preventing dengue
◦Risk ratio 0.48 (0.37-0.61) in favor of vaccine
◦Calculated vaccine efficacy is 52% (39%-63%)
It is also efficacious in preventing hospitalizations due to dengue
◦Risk ratio 0.56 (0.34-0.94) in favor of vaccine
Both results were statistically significant (P<0.05)
High heterogeneity among the studies may be due to
◦Different follow-up periods among studies
The funnel plots had some asymmetry
◦There may be some publication bias
CYD-TDV vaccine is efficacious in preventing both dengue
and hospitalizations related to dengue
CYD-TDV vaccine may be considered to reduce the burden
of dengue in India
References to included studies
Arredondo-García JL, Hadinegoro SR, Reynales H, Chua MN, Rivera Medina DM, Chotpitayasunondh T, Tran NH, Deseda CC, Wirawan DN, Cortés Supelano
M, Frago C, Langevin E, Coronel D, Laot T, Perroud AP, Sanchez L, Bonaparte M, Limkittikul K, Chansinghakul D, Gailhardou S, Noriega F, Wartel TA,
Bouckenooghe A, Zambrano B; CYD-TDV Dengue Vaccine Study Group.. Four-year safety follow-up of the tetravalent dengue vaccine efficacy randomized
controlled trials in Asia and Latin America.. Clin Microbiol Infect. 2018 Jul;24(7):755-763.
Maria Rosario Capeding, Ngoc Huu Tran, Sri Rezeki S Hadinegoro, Hussain Imam HJ Muhammad Ismail, Tawee Chotpitayasunondh,Mary Noreen Chua,
Chan Quang Luong, Kusnandi Rusmil, Dewa Nyoman Wirawan, Revathy Nallusamy, Punnee Pitisuttithum, Usa Thisyakorn,In-Kyu Yoon, Diane van der Vliet,
Edith Langevin, Thelma Laot, Yanee Hutagalung, Carina Frago, Mark Boaz, T Anh Wartel, Nadia G Tornieporth,Melanie Saville, Alain Bouckenooghe, and the
CYD14 Study Group. Clinical efficacy and safety of a novel tetravalent denguevaccine in healthy children in Asia: a phase 3, randomised,observer-masked,
placebo-controlled trial. Lancet July 11, 2014;384:1358-65.
Hanna El Fezzazi, Marie Branchu, Gabriel Carrasquilla, Punnee Pitisuttithum, Ana Paula Perroud, Carina Frago and Laurent Coudeville. Resource Use and
Costs of Dengue: Analysis of Data from Phase III EfficacyStudies of a Tetravalent Dengue Vaccine. Am. J. Trop. Med. Hyg. 2017;97(6):1898-1903.
Sophia Gailhardou, Anna Skipetrova, Gustavo H. Dayan, John Jezorwski, Melanie Saville, Diane Van der Vliet, T. Anh Wartel. Safety Overview of a
Recombinant Live-Attenuated Tetravalent Dengue Vaccine:Pooled Analysis of Data from 18 ClinicalTrials. PLOS Neglected Tropical Diseases July 14,
S.R. Hadinegoro, J.L. Arredondo‐García, M.R. Capeding, C. Deseda,T. Chotpitayasunondh, R. Dietze, H.I. Hj Muhammad Ismail, H. Reynales,K. Limkittikul,
D.M. Rivera‐Medina, H.N. Tran, A. Bouckenooghe,D. Chansinghakul, M. Cortés, K. Fanouillere, R. Forrat, C. Frago, S. Gailhardou,N. Jackson, F. Noriega, E.
Plennevaux, T.A. Wartel, B. Zambrano, and M. Saville,for the CYD-TDV Dengue Vaccine Working Group. Efficacy and Long-Term Safety of a DengueVaccine in
Regions of Endemic Disease. The New England Journal of Medicine July 17, 2015.
Arunee Sabchareon, Derek Wallace, Chukiat Sirivichayakul, Kriengsak Limkittikul, Pornthep Chanthavanich, Saravudh Suvannadabba,Vithaya Jiwariyavej,
Wut Dulyachai, Krisana Pengsaa, T Anh Wartel, Annick Moureau, Melanie Saville, Alain Bouckenooghe, Simonetta Viviani,Nadia G Tornieporth, Jean Lang.
Protective efficacy of the recombinant, live-attenuated,CYD tetravalent dengue vaccine in Thai schoolchildren:a randomised, controlled phase 2b trial.
Lancet September 11, 2012;380:1559-67.
Luis Villar, M.D., Gustavo Horacio Dayan, M.D., José Luis Arredondo-García, M.D.,Doris Maribel Rivera, M.D., Rivaldo Cunha, M.D., Carmen Deseda,
M.D.,Humberto Reynales, M.D., Maria Selma Costa, M.D.,Javier Osvaldo Morales-Ramírez, M.D., Gabriel Carrasquilla, M.D.,Luis Carlos Rey, M.D., Reynaldo
Dietze, M.D., Kleber Luz, M.D., Enrique Rivas, M.D.,Maria Consuelo Miranda Montoya, M.D., Margarita Cortés Supelano, M.D.,Betzana Zambrano, M.D.,
Edith Langevin, M.Sc., Mark Boaz, Ph.D.,Nadia Tornieporth, M.D., Melanie Saville, M.B., B.S.,and Fernando Noriega, M.D., for the CYD15 Study Group.
Efficacy of a Tetravalent Dengue Vaccinein Children in Latin America. The New England Journal of Medicine November 3, 2014.