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Efficacy of Tetravalent Dengue Vaccine - Meta-analysis of Randomized Controlled Trials

Authors:

Abstract

Objective: A tetravalent dengue vaccine (CYD-TDV) has been licensed in 2015 and is currently approved in 20 countries. We did a meta-analysis to determine whether CYD-TDV is effective in preventing dengue. Methods: We did a pubmed search to find published papers on dengue vaccine (keyword: dengue AND vaccine AND randomized controlled trial [pt]) and found 74 results. We filtered those papers first by titles, then abstracts and lastly by full text and included 6 studies which compared CYD-TDV with placebo. We used virologically confirmed dengue as our primary endpoint. We combined data for all age groups together. We used RevMan software for statistical analysis. Results: We included 6 studies which had 122,660 participants in total, 82165 in vaccine group and 40495 in control group. Virologically confirmed dengue occurrence was 865 in vaccine group and 1087 in control group. Fixed effect model was used and the heterogeneity was I2 =81%. Confidence interval was chosen as 95%. Overall effect was Z=20.69 (P<0.000001). The meta-analysis showed a risk ratio of 0.39 in favor of the tetravalent dengue vaccine. Conclusion: The meta-analysis showed a lower incidence of virologically confirmed dengue in the vaccine group which indicates that CYD-TDV vaccine is efficacious in preventing dengue. However, our study did not look into different age-groups separately. Not all studies looked into the severity of dengue in vaccine group. Most studies were in dengue endemic regions. A single large study in 2017 dominated the meta-analysis. Based on the current meta-analysis it can be said that tetravalent dengue vaccine is effective in preventing dengue and should be considered for implementation in endemic regions. Further meta-analysis may be warranted to look into dengue vaccine efficacy in specific age groups.
Efficacy of Tetravalent
Dengue Vaccine
Meta-analysis of Randomized
Controlled Trials
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
Background
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
(2012)
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
dengue vaccine
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
Subcutaneous route
The Question
Can CYD-TDV actually prevent dengue?
In this meta-analysis we tried to analyze the efficacy data from
multiple studies to answer the question.
Literature search
We searched the PubMed and Cochrane database for published papers on
dengue vaccine
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
Outcome
1. Virologically confirmed dengue
2. Hospitalization due to dengue
Analysis
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
Studies
Randomization
Process
Deviation from
intended
intervention
Missing
outcome data
Measurement
of Outcome
Selection of
reported result
Overall risk
Arredondo-
Garcia 2018
Low risk
Some concerns
Low risk
Low risk
Some
concerns
Some
concerns
Capeding
2014
Low risk
Low risk
Low risk
Some concerns
Low risk
Some
concerns
Fezzazi
2017
Some concerns
High risk
Low risk
High risk
Some
concerns
High risk
Gailhardou 2015
Some concerns
High risk
High risk
High risk
Some
concerns
High risk
Hadinegoro
2015
Low risk
Low risk
Low risk
Low risk
Some
concerns
Some
concerns
Sabchareon
2012
Low risk
High risk
Low risk
Low risk
Some
concerns
High risk
Villar
2015
Low risk
Low risk
Low risk
Low risk
Some
concerns
Some
concerns
Outcome analysis:
Confirmed dengue
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
Heterogeneity
I2 = 83%
Overall effect
Z = 5.79 (P<0.00001)
Outcome analysis:
Hospitalization
Outcome analysis:
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
Heterogeneity
I2 = 84%
Overall effect
Z = 2.18 (P=0.03)
Funnel plots
CONFIRMED DENGUE HOSPITALIZATION
Summary
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)
Limitations
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
Conclusion
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,
2016;10(7).
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.
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