Shibadas Biswal1, Charissa Borja-Tabora2, Luis Martinez Vargas3, Hector Velásquez4, Maria Theresa Alera5, Victor Sierra6, Edith Johana Rodriguez-Arenales7, Delia Yu8, V Pujitha Wickramasinghe9, Edson Duarte Moreira10, Asvini D Fernando11, Dulanie Gunasekera12, Pope Kosalaraksa13, Felix Espinoza14, Eduardo López-Medina15, Lulu Bravo16, Suely Tuboi17, Yanee Hutagalung18, Pedro Garbes19, Ian Escudero18, Martina Rauscher20, Svetlana Bizjajeva20, Inge LeFevre20, Astrid Borkowski20, Xavier Saez-Llorens21, Derek Wallace19. 1. Takeda Vaccines, Boston, MA, USA. Electronic address: shibadas.biswal@takeda.com. 2. Research Institute For Tropical Medicine, Muntinlupa, Philippines. 3. Centro de Atención e Investigación Médica, Dominicana, Santo Domingo, Dominican Republic. 4. Centro de Atención e Investigación Médica, Acacias, Colombia. 5. Philippines-Armed Forces Research Institute of Medical Sciences Virology Research Unit, Cebu City, Philippines. 6. Centro de Atención e Investigación Médica, Yopal, Colombia. 7. Centro de Atención e Investigación Médica, Aguazul, Colombia. 8. De La Salle Medical and Health Sciences Institute, Dasmariñas, Philippines. 9. University of Colombo, Colombo, Sri Lanka. 10. Associação Obras Sociais Irmã Dulce Hospital Santo Antônio and Oswaldo Cruz Foundation, Bahia, Brazil. 11. Faculty of Medicine, University of Kelaniya, Kelaniya, Sri Lanka. 12. Faculty of Medical Sciences, University of Sri Jayawardenenpura, Gangodawila, Sri Lanka. 13. Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. 14. National Autonomous University of Nicaragua, León, Nicaragua. 15. Centro de Estudios en Infectología Pediátrica, Universidad del Valle and Centro Médico Imbanaco, Cali, Colombia. 16. University of the Philippines Manila, Ermita, Philippines. 17. Takeda Pharmaceuticals, São Paulo, Brazil. 18. Takeda Vaccines, Singapore. 19. Takeda Vaccines, Boston, MA, USA. 20. Takeda Pharmaceuticals International, Zurich, Switzerland. 21. Hospital del Niño Dr José Renán Esquivel, Sistema Nacional de Investigación at Secretaría Nacional de Ciencia y Tecnología, Centro de Vacunación Internacional (Cevaxin), Panama City, Panama.
Abstract
BACKGROUND: A substantial unmet need remains for safe and effective vaccines against dengue virus disease, particularly for individuals who are dengue-naive and those younger than 9 years. We aimed to assess the efficacy, safety, and immunogenicity of a live attenuated tetravalent dengue vaccine (TAK-003) in healthy children aged 4-16 years. METHODS: We present data up to 18 months post-vaccination from an ongoing phase 3, randomised, double-blind trial of TAK-003in endemic regions of Asia and Latin America (26 medical and research centres across Brazil, Colombia, Dominican Republic, Nicaragua, Panama, Philippines, Sri Lanka, and Thailand). Healthy children aged 4-16 years were randomly assigned 2:1 (stratified by age and region) to receive two doses of TAK-003 or two doses of placebo, 3 months apart. Investigators, participants and their parents or guardians, and sponsor representatives advising on trial conduct were masked to trial group assignments. Participants presenting with febrile illness were tested for virologically confirmed dengue (VCD) by serotype-specific RT-PCR. In timeframes beginning 30 days post-second dose, the primary endpoint (overall vaccine efficacy) was assessed in the first 11 months, and the secondary endpoints (efficacy by baseline serostatus, serotype, hospitalised dengue, and severe dengue) in the first 17 months. This study is registered with ClinicalTrials.gov, NCT02747927. FINDINGS:20 099 participants were randomly assigned and vaccinated between Sept 7, 2016, and Aug 18, 2017; 19 021 (94·6%) were included in the per protocol analysis, and 20 071 (99·9%) in the safety set. The primary endpoint was achieved with an overall vaccine efficacy of 80·2% (95% CI 73·3 to 85·3; 61 cases of VCD in the TAK-003 group vs 149 cases of VCD in the placebo group). In the secondary endpoint assessment timeframe, an overall vaccine efficacy of 73·3% (95% CI 66·5 to 78·8) was observed. Analysis of secondary endpoints showed efficacies of 76·1% (95% CI 68·5 to 81·9) in individuals who were seropositive at baseline, 66·2% (49·1 to 77·5) in individuals who were seronegative at baseline, 90·4% (82·6 to 94·7) against hospitalised dengue, and 85·9% (31·9 to 97·1) against dengue haemorrhagic fever. Efficacy varied by individual serotypes (DENV 1, 69·8% [95% CI 54·8 to 79·9]; DENV 2, 95·1% [89·9 to 97·6]; DENV 3, 48·9% [27·2 to 64·1]; DENV 4, 51·0% [-69·4 to 85·8]). Cumulative rates of serious adverse events were similar in TAK-003 (4·0%) and placebo (4·8%) recipients, and were consistent with expected medical disorders in the study population. Infection was the most frequent reason leading to serious adverse events. 20 participants (<0·1% of the safety set) were withdrawn from the trial due to 21 adverse events by the end of part two; 14 of these participants received TAK-003 and six received placebo. INTERPRETATION:TAK-003 was well tolerated and efficacious against symptomatic dengue in children regardless of serostatus before immunisation. Vaccine efficacy varied by serotype, warranting continued follow-up to assess longer-term vaccine performance. FUNDING: Takeda Vaccines.
RCT Entities:
BACKGROUND: A substantial unmet need remains for safe and effective vaccines against dengue virus disease, particularly for individuals who are dengue-naive and those younger than 9 years. We aimed to assess the efficacy, safety, and immunogenicity of a live attenuated tetravalent dengue vaccine (TAK-003) in healthy children aged 4-16 years. METHODS: We present data up to 18 months post-vaccination from an ongoing phase 3, randomised, double-blind trial of TAK-003 in endemic regions of Asia and Latin America (26 medical and research centres across Brazil, Colombia, Dominican Republic, Nicaragua, Panama, Philippines, Sri Lanka, and Thailand). Healthy children aged 4-16 years were randomly assigned 2:1 (stratified by age and region) to receive two doses of TAK-003 or two doses of placebo, 3 months apart. Investigators, participants and their parents or guardians, and sponsor representatives advising on trial conduct were masked to trial group assignments. Participants presenting with febrile illness were tested for virologically confirmed dengue (VCD) by serotype-specific RT-PCR. In timeframes beginning 30 days post-second dose, the primary endpoint (overall vaccine efficacy) was assessed in the first 11 months, and the secondary endpoints (efficacy by baseline serostatus, serotype, hospitalised dengue, and severe dengue) in the first 17 months. This study is registered with ClinicalTrials.gov, NCT02747927. FINDINGS: 20 099 participants were randomly assigned and vaccinated between Sept 7, 2016, and Aug 18, 2017; 19 021 (94·6%) were included in the per protocol analysis, and 20 071 (99·9%) in the safety set. The primary endpoint was achieved with an overall vaccine efficacy of 80·2% (95% CI 73·3 to 85·3; 61 cases of VCD in the TAK-003 group vs 149 cases of VCD in the placebo group). In the secondary endpoint assessment timeframe, an overall vaccine efficacy of 73·3% (95% CI 66·5 to 78·8) was observed. Analysis of secondary endpoints showed efficacies of 76·1% (95% CI 68·5 to 81·9) in individuals who were seropositive at baseline, 66·2% (49·1 to 77·5) in individuals who were seronegative at baseline, 90·4% (82·6 to 94·7) against hospitalised dengue, and 85·9% (31·9 to 97·1) against dengue haemorrhagic fever. Efficacy varied by individual serotypes (DENV 1, 69·8% [95% CI 54·8 to 79·9]; DENV 2, 95·1% [89·9 to 97·6]; DENV 3, 48·9% [27·2 to 64·1]; DENV 4, 51·0% [-69·4 to 85·8]). Cumulative rates of serious adverse events were similar in TAK-003 (4·0%) and placebo (4·8%) recipients, and were consistent with expected medical disorders in the study population. Infection was the most frequent reason leading to serious adverse events. 20 participants (<0·1% of the safety set) were withdrawn from the trial due to 21 adverse events by the end of part two; 14 of these participants received TAK-003 and six received placebo. INTERPRETATION:TAK-003 was well tolerated and efficacious against symptomatic dengue in children regardless of serostatus before immunisation. Vaccine efficacy varied by serotype, warranting continued follow-up to assess longer-term vaccine performance. FUNDING: Takeda Vaccines.
Authors: Robert K M Choy; A Louis Bourgeois; Christian F Ockenhouse; Richard I Walker; Rebecca L Sheets; Jorge Flores Journal: Clin Microbiol Rev Date: 2022-07-06 Impact factor: 50.129
Authors: Laura J White; Ellen F Young; Mark J Stoops; Sandra R Henein; Elizabeth C Adams; Ralph S Baric; Aravinda M de Silva Journal: PLoS Negl Trop Dis Date: 2021-03-12
Authors: Jaime A Cardona-Ospina; Kovy Arteaga-Livias; Wilmer E Villamil-Gómez; Carlos E Pérez-Díaz; D Katterine Bonilla-Aldana; Álvaro Mondragon-Cardona; Marco Solarte-Portilla; Ernesto Martinez; Jose Millan-Oñate; Eduardo López-Medina; Pio López; Juan-Carlos Navarro; Luis Perez-Garcia; Euler Mogollon-Rodriguez; Alfonso J Rodríguez-Morales; Alberto Paniz-Mondolfi Journal: J Med Virol Date: 2020-07-11 Impact factor: 20.693