Efficacy profile of the CYD-TDV dengue vaccine revealed by Bayesian survival analysis of individual-level phase III data
Daniel J Laydon, Ilaria Dorigatti, Wes R Hinsley, Gemma Nedjati-Gilani, Laurent Coudeville, Neil M Ferguson, Daniel J Laydon, Ilaria Dorigatti, Wes R Hinsley, Gemma Nedjati-Gilani, Laurent Coudeville, Neil M Ferguson
Abstract
Background: Sanofi-Pasteur's CYD-TDV is the only licensed dengue vaccine. Two phase three trials showed higher efficacy in seropositive than seronegative recipients. Hospital follow-up revealed increased hospitalisation in 2-5- year-old vaccinees, where serostatus and age effects were unresolved.
Methods: We fit a survival model to individual-level data from both trials, including year 1 of hospital follow-up. We determine efficacy by age, serostatus, serotype and severity, and examine efficacy duration and vaccine action mechanism.
Results: Our modelling indicates that vaccine-induced immunity is long-lived in seropositive recipients, and therefore that vaccinating seropositives gives higher protection than two natural infections. Long-term increased hospitalisation risk outweighs short-lived immunity in seronegatives. Independently of serostatus, transient immunity increases with age, and is highest against serotype 4. Benefit is higher in seropositives, and risk enhancement is greater in seronegatives, against hospitalised disease than against febrile disease.
Conclusions: Our results support vaccinating seropositives only. Rapid diagnostic tests would enable viable 'screen-then-vaccinate' programs. Since CYD-TDV acts as a silent infection, long-term safety of other vaccine candidates must be closely monitored.
Funding: Bill & Melinda Gates Foundation, National Institute for Health Research, UK Medical Research Council, Wellcome Trust, Royal Society.
Clinical trial number: NCT01373281 and NCT01374516.
Keywords: bayesian statistics; dengue; epidemiology; global health; human; mathematical modelling; survival analysis; vaccine; virus.
Conflict of interest statement
DL, ID, WH, GN, NF No competing interests declared, LC Laurent Coudeville is employed by Sanofi-Pasteur
© 2021, Laydon et al.
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References
- Aguas R, Dorigatti I, Coudeville L, Luxemburger C, Ferguson NM. Cross-serotype interactions and disease outcome prediction of dengue infections in Vietnam. Scientific Reports. 2019;9:9395. doi: 10.1038/s41598-019-45816-6.
- Aguiar M, Stollenwerk N. Dengvaxia: age as surrogate for serostatus. The Lancet Infectious Diseases. 2018;18:245. doi: 10.1016/S1473-3099(17)30752-1.
- Bhat HS, Kumar N. On the Derivation of the Bayesian Information Criterion School of Natural Sciences. University of California; 2010.
- Capeding MR, Tran NH, Hadinegoro SRS, Ismail H, Chotpitayasunondh T, Chua MN, Luong CQ, Rusmil K, Wirawan DN, Nallusamy R, Pitisuttithum P, Thisyakorn U, Yoon I-K, van der Vliet D, Langevin E, Laot T, Hutagalung Y, Frago C, Boaz M, Wartel TA, Tornieporth NG, Saville M, Bouckenooghe A. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in asia: a phase 3, randomised, observer-masked, placebo-controlled trial. The Lancet. 2014;384:1358–1365. doi: 10.1016/S0140-6736(14)61060-6.
- Cattarino L, Rodriguez-Barraquer I, Imai N, Cummings DAT, Ferguson NM. Mapping global variation in dengue transmission intensity. Science Translational Medicine. 2020;12:eaax4144. doi: 10.1126/scitranslmed.aax4144.
- Clapham HE, Quyen TH, Kien DT, Dorigatti I, Simmons CP, Ferguson NM. Modelling virus and antibody dynamics during dengue virus infection suggests a role for antibody in virus clearance. PLOS Computational Biology. 2016;12:e1004951. doi: 10.1371/journal.pcbi.1004951.
- Dagum L, Menon R. OpenMP: an industry standard API for shared-memory programming. IEEE Computational Science and Engineering. 1998;5:46–55. doi: 10.1109/99.660313.
- Dengue vaccine Dengue vaccine: who position paper, September 2018 – Recommendations. Vaccine. 2019;37:4848–4849. doi: 10.1016/j.vaccine.2018.09.063.
- Dorigatti I, Donnelly CA, Laydon DJ, Small R, Jackson N, Coudeville L, Ferguson NM. Refined efficacy estimates of the Sanofi Pasteur dengue vaccine CYD-TDV using machine learning. Nature Communications. 2018;9:1–9. doi: 10.1038/s41467-018-06006-6.
- Ferguson NM, Rodríguez-Barraquer I, Dorigatti I, Mier-y-Teran-Romero L, Laydon DJ, Cummings DAT. Benefits and risks of the Sanofi-Pasteur dengue vaccine: Modeling optimal deployment. Science. 2016;353:1033–1036. doi: 10.1126/science.aaf9590.
- Flasche S, Jit M, Rodríguez-Barraquer I, Coudeville L, Recker M, Koelle K, Milne G, Hladish TJ, Perkins TA, Cummings DA, Dorigatti I, Laydon DJ, España G, Kelso J, Longini I, Lourenco J, Pearson CA, Reiner RC, Mier-Y-Terán-Romero L, Vannice K, Ferguson N. The Long-Term safety, public health impact, and Cost-Effectiveness of routine vaccination with a recombinant, Live-Attenuated dengue vaccine (Dengvaxia): A model comparison study. PLOS Medicine. 2016;13:e1002181. doi: 10.1371/journal.pmed.1002181.
- Flasche S, Smith PG. Sensitivity and negative predictive value for a rapid dengue test. The Lancet Infectious Diseases. 2019;19:465–466. doi: 10.1016/S1473-3099(19)30167-7.
- Guzman MG, Halstead SB, Artsob H, Buchy P, Farrar J, Gubler DJ, Hunsperger E, Kroeger A, Margolis HS, Martínez E, Nathan MB, Pelegrino JL, Simmons C, Yoksan S, Peeling RW. Dengue: a continuing global threat. Nature Reviews Microbiology. 2010;8:S7–S16. doi: 10.1038/nrmicro2460.
- Hadinegoro SR, Arredondo-García JL, Capeding MR, Deseda C, Chotpitayasunondh T, Dietze R, Hj Muhammad Ismail HI, Reynales H, Limkittikul K, Rivera-Medina DM, Tran HN, Bouckenooghe A, Chansinghakul D, Cortés M, Fanouillere K, Forrat R, Frago C, Gailhardou S, Jackson N, Noriega F, Plennevaux E, Wartel TA, Zambrano B, Saville M. Efficacy and Long-Term safety of a dengue vaccine in regions of endemic disease. New England Journal of Medicine. 2015;373:1195–1206. doi: 10.1056/NEJMoa1506223.
- Katzelnick LC, Gresh L, Halloran ME, Mercado JC, Kuan G, Gordon A, Balmaseda A, Harris E. Antibody-dependent enhancement of severe dengue disease in humans. Science. 2017;358:929–932. doi: 10.1126/science.aan6836.
- Laydon DJ. Dengue vaccine trial survival model. swh:1:rev:d4964b7240312a371b2767533099643c59025dbfSoftware Heritage. 2021
- Nascimento EJM, George JK, Velasco M, Bonaparte MI, Zheng L, DiazGranados CA, Marques ETA, Huleatt JW. Development of an anti-dengue NS1 IgG ELISA to evaluate exposure to dengue virus. Journal of Virological Methods. 2018;257:48–57. doi: 10.1016/j.jviromet.2018.03.007.
- Olivera-Botello G, Coudeville L, Fanouillere K, Guy B, Chambonneau L, Noriega F, Jackson N. Tetravalent dengue vaccine reduces symptomatic and asymptomatic dengue virus infections in healthy children and adolescents aged 2–16 Years in Asia and Latin America. Journal of Infectious Diseases. 2016;214:994–1000. doi: 10.1093/infdis/jiw297.
- R Development Core Team . Vienna, Austria: R Foundation for Statistical Computing; 2019.
- Sabchareon A, Wallace D, Sirivichayakul C, Limkittikul K, Chanthavanich P, Suvannadabba S, Jiwariyavej V, Dulyachai W, Pengsaa K, Wartel TA, Moureau A, Saville M, Bouckenooghe A, Viviani S, Tornieporth NG, Lang J. Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial. The Lancet. 2012;380:1559–1567. doi: 10.1016/S0140-6736(12)61428-7.
- Salje H, Cummings DAT, Rodriguez-Barraquer I, Katzelnick LC, Lessler J, Klungthong C, Thaisomboonsuk B, Nisalak A, Weg A, Ellison D, Macareo L, Yoon I-K, Jarman R, Thomas S, Rothman AL, Endy T, Cauchemez S. Reconstruction of antibody dynamics and infection histories to evaluate dengue risk. Nature. 2018;557:719–723. doi: 10.1038/s41586-018-0157-4.
- Sridhar S, Luedtke A, Langevin E, Zhu M, Bonaparte M, Machabert T, Savarino S, Zambrano B, Moureau A, Khromava A, Moodie Z, Westling T, Mascareñas C, Frago C, Cortés M, Chansinghakul D, Noriega F, Bouckenooghe A, Chen J, Ng S-P, Gilbert PB, Gurunathan S, DiazGranados CA. Effect of dengue serostatus on dengue vaccine safety and efficacy. New England Journal of Medicine. 2018;379:327–340. doi: 10.1056/NEJMoa1800820.
- St John AL, Rathore APS. Adaptive immune responses to primary and secondary dengue virus infections. Nature Reviews Immunology. 2019;19:218–230. doi: 10.1038/s41577-019-0123-x.
- Stanaway JD, Shepard DS, Undurraga EA, Halasa YA, Coffeng LE, Brady OJ, Hay SI, Bedi N, Bensenor IM, Castañeda-Orjuela CA, Chuang TW, Gibney KB, Memish ZA, Rafay A, Ukwaja KN, Yonemoto N, Murray CJL. The global burden of dengue: an analysis from the global burden of disease study 2013. The Lancet Infectious Diseases. 2016;16:712–723. doi: 10.1016/S1473-3099(16)00026-8.
- Villar L, Dayan GH, Arredondo-García JL, Rivera DM, Cunha R, Deseda C, Reynales H, Costa MS, Morales-Ramírez JO, Carrasquilla G, Rey LC, Dietze R, Luz K, Rivas E, Miranda Montoya MC, Cortés Supelano M, Zambrano B, Langevin E, Boaz M, Tornieporth N, Saville M, Noriega F. Efficacy of a Tetravalent Dengue Vaccine in Children in Latin America. New England Journal of Medicine. 2015;372:113–123. doi: 10.1056/NEJMoa1411037.
- Watanabe S. A widely applicable bayesian information criterion. Journal of Machine Learning Research. 2013;14:867–897.
- WHO Global advisory committee on vaccine safety, 6–7 December 2017–Comité consultatif mondial pour la sécurité des vaccins, 6-7 décembre 2017. Weekly Epidemiological Record= Relevé Épidémiologique Hebdomadaire. 2018;93:17–30.
Source: PubMed