Desenvolvimento de uma vacina tetravalente contra dengue

Abstract

Este artículo es una revisión sobre el desarrollo de una vacuna candidata tetravalente contra el dengue (VTD) compuesta por 4 cepas recombinantes vivas atenuadas de virus de dengue. Cada cepa expresa los genes de la premembrana (prM) y del cierre de uno de los cuatro serotipos del virus del dengue y tiene por base la cepa de la vacuna de la fiebre amarilla 17D (YF 17D). Los estudios preclínicos demostraron que las cepas de la VTD son estables genética y fenotípicamente, no hepatotrópicas, menos neurovirulentas que la cepa YF 17D y no infectan a mosquitos por la vía oral. La VTD induce estímulo controlada de las células dendríticas humanas y respuestas inmunes significativas. Estudios de Fase I se realizaron en los Estados Unidos, México y Filipinas. La seropositividad luego de tres dosis de la VTD para los cuatro virus del dengue en personas naive a flavivirus fue de 100% en los adultos norteamericanos y de 88 a 100% en niños mexicanos. En los filipinos con inmunidad previa a flavivirus, se observaron mayores tasas de seroconversión. Más de 6 mil personas con edades entre 2 y 45 años ya han recibido al menos una dosis de la VTD en los estudios de Fase I y II. Todos los resultados disponibles confirman la inmunogenicidad favorable y la seguridad de la VTD a corto plazo. En octubre de 2010, se inició el programa de desarrollo final de la vacuna (Fase III), que deberá incluir a miles de personas residentes en países endémicos, incluyendo a Brasil, en donde la enfermedad está considerada como uno de los más grandes desafíos en salud pública.

The Sanofi Pasteur tetravalent dengue vaccine candidate is composed of 4 recombinant live attenuated vaccines based on a yellow fever vaccine 17D (YFV 17D) backbone, each expressing the prM and envelope genes of one of the four dengue virus serotypes. Pre-clinical studies have demonstrated that the TV dengue vaccine is genetically and phenotypically stable, non-hepatotropic, less neurovirulent than YFV 17D and does not infect mosquitoes by the oral route. In vitro and in vivo preclinical studies also showed that the TV dengue vaccine induced controlled stimulation in human dendritic cells, and significant immune responses in monkeys. TV dengue vaccine reactogenicity, viraemia induction and antibody responses were investigated in three Phase I trials in the USA, the Philippines and Mexico, in a two or three-dose regimen over a 12 month period. Results showed that the majority of adverse events were mild to moderate and transient in nature. Viraemia was transient and low, and was not increased after initial dengue TV administration, even in the case of incomplete responses. Seropositivity [ ³ 10 in a PRNT 50 assay] was 100% for all four serotypes in flavivirus-naive adults injected with 3 doses of TV dengue vaccine in the USA. Similarly, seropositivity was 88–100% following three administrations in flavivirus-naive Mexican children aged 2–5 years. Furthermore, the proportion of seropositive subjects increased with each dengue TV injection in the Philippines where baseline flavivirus immunity was high. Responses were also monitored at the cellular level in humans, and their level and nature were in good agreement with the observed safety and the immunogenicity of the vaccine. Finally, the challenges inherent to the development of such TV dengue vaccines will also be discussed in the last part of this review. In conclusion, preclinical and clinical results support the favorable immunogenicity and short-term safety of the dengue TV vaccine. The final stage of development of the VTD (Phase III) started in October 2010 and will comprise thousands of individuals living in endemic countries, such as Brazil, where dengue is considered one of the biggest challenges in public health.