WHO's efforts for the development of a dengue vaccine.
AbstractBackground: Dengue fever and dengue haemorrhagic fever (DF/DHF) are caused by dengue (DENV)viruses. There are four antigenically related, but distinct, DENV serotypes (DENV-1 through DENV-4).Humans are the amplifying vertebrate hosts and Aedes mosquitoes are the primary mosquito vectors aswell as the reservoir of infection.DENV infections cause a spectrum of diseases, ranging from asymptomatic infections to infections complicated by haemorrhage, shock and death. Infection with DENV of one serotype results in apparentlife-long monotypic immunity against that serotype but not against any other serotype. Thus, separateinfections with all four DENV serotypes are theoretically possible in a single host. It should be noted thatin Thailand, all the four DENV serotypes co-circulate, thereby resulting in multiple exposures and thepotential for re-infection with different serotypes.Initial vaccine development: In 1980, Mahidol University committed to develop a live-attenuatedtetravalent DENV vaccine. The DENV vaccine development project was supported by a grant from the WHO Regional Office for South-East Asia (ICP RPD 002/DHF). DENV-1 and -2 obtained from DHFpatients and DENV-4 obtained from a DF patient were serially passaged in primary dog kidney (PDK)cells certified to be free from human and canine infectious agents. DENV-3 obtained from DHF patientswas first passaged in primary green monkey kidney (PGMK) cells and then in certified Fetal Rhesus Lung(FRhL) cells. The degree of attenuation was empirically based on certain biological markers.Bulk seed productions were eventually prepared in pilot production facilities at Mahidol University’sCentre for Vaccine Development at the Institute of Molecular Biosciences. They were subjected togeneral safety tests and monkey neurovirulence tests in accordance with the US FDA requirements.These pre-clinical tested candidate DENV viruses were approved for proceeding to the clinical evaluationphase by a WHO-appointed Scientific Steering Committee and by the Ethical Review Committee of the Thai Ministry of Public Health.The monovalent live-attenuated viruses – DENV-1 PDK-13, DENV-2 PDK-53, DENV-3 PGMK-30/FRhL-3 and DENV-4 PDK-48 – were first tested in flavivirus non-immune adult subjects, followed by bivalent,trivalent and tetravalent vaccine clinical trials. All vaccine recipients developed either a mild or noadverse reaction to the vaccine. The immunogenicity data were discussed. Due to viral interference of each DENV components in the combinations, 12 DENV formulations wereevaluated for confirmation of safety and immunoginecity profiles in 155 Thai children aged 3–15years. Preliminary data were analysed and processed for further development.Collaboration with Sanofi Pasteur: In order to make productive use of this research, Mahidol Universityentered into a collaborative licensing agreement in DENV vaccine production in 1993 with France-based Sanofi Pasteur, the vaccine division of Sanofi-Aventis Group and the largest company in theworld devoted entirely to human vaccines. DENV vaccine based on this approach was prepared forproduction on an industrial scale in France using specific-pathogen-free (SPF) dog colony and FRhLcells. The vaccine was presented in a lyophilized (freeze-dried) form and reconstituted with water forinjection in order to deliver a 0.5 ml specified dose. Multiple dose presentations were planned for atarget population of children and adults living in or travelling to DENV-endemic areas.The current strategy of creating tetravalent DENV vaccine formulations can lead to an unbalancedimmune response. This is attributed to viral interference that apparently comes into play when threemonovalent vaccine viruses DENV-1, DENV-2 and DENV-4 are mixed with DENV-3 to create a tetravalentformulation.More research is needed on a priority basis to work out the viral interference factor in order to make theproduction of a tetravalent vaccine out of our attenuated DENV-3 candidate vaccine strain a success.
Yoksan, Sutee. (2008). WHO's efforts for the development of a dengue vaccine.. WHO Regional Office for South-East Asia.. http://www.who.int/iris/handle/10665/170463