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Vaccine Research

There is no vaccine to protect against dengue. Although progress is underway, developing a vaccine against the disease is challenging. With four different serotypes of the dengue virus that can cause the disease, the vaccine must immunize against all four types to be effective. Vaccination against only one serotype could possible lead to severe DHS when infected with another serotype due to Antibody-Dependent Enhancement. There is still limited knowledge of how the disease typically behaves and how the virus interacts with the immune system. Another difficulty is that there is no reliable animal model for DHF and thus also not a suitable animal model to test immune responses to potential vaccines. In addition, progress in vaccine development is slow mainly because dengue viruses grow poorly in cell culture (see also Clinical Trials).

As there is no cross-protection between the four dengue serotypes, and because of the possibility of immune enhancement by monotypic antibody leading to DHF with subsequent natural infections, the control of dengue will be possible only after an efficient tetravalent vaccine has been developed. This means a vaccine that protects against all four dengue serotypes. The most favored strategy is to develop a live vaccine. Attenuation was obtained by repeated passage of wild-type strains of dengue viruses in cell culture. The difficulty in this approach has been to find the correct balance between insufficient attenuation and over-attenuation of the candidate vaccine strains, as criteria of virus attenuation in vitro, such as small plaque phenotype and temperature-sensitive growth, do not appear to be predictive of attenuation in vivo. In addition, whereas monovalent attenuated vaccine lots showed good immunogenicity, their combination into a tetravalent vaccine initially generated disappointing immunogenicity results, due to a phenomenon of interference between strains.

Video 1: Scientists Seek Better Treatment for Dengue Fever
Video 2: Vaccine for Dengue Fever Near

Other approaches for vaccine development include inactivated and subunit vaccines, DNA vaccines and recombinant vaccinia virus (MVA) vectors. Most advanced are efforts to develop a subunit, tetravalent vaccine using a mixture of the E protein from the four dengue serotypes and the nonstructural NS1 protein of DV-2 as immunogens in a proprietary adjuvant. Live attenuated vaccine candidates are the furthest along in development. See also dengue vaccine research website of the WHO.

CYD-TDV is a live attenuated tetravalent chimeric vaccine made using recombinant DNA technology by replacing the PrM (pre-membrane) and E (envelope) structural genes of the yellow fever attenuated 17D strain vaccine with those from each of the four dengue serotypes. Ongoing phase III trials in Latin America and Asia involve over 31,000 children between the ages of 2 and 14 years. In the first reports from the trials, vaccine efficacy was 56.5% in the Asian study and 64.7% in the Latin American study in patients who received at least one injection of the vaccine. Efficacy varied by serotype. In both trials vaccine reduced by about 80% the number of severe dengue cases. An analysis of both the Latin American and Asian studies at the 3rd year of follow-up showed that the efficacy of the vaccine was 65.6% in preventing hospitalization in children older than 9 years of age, but considerably greater (81.9%) for children who were seropositive (indicating previous dengue infection) at baseline. The vaccination series consists of three injections at 0, 6 and 12 months. The vaccine was approved in Mexico, Philippines, and Brazil in December 2015, expected to be the first among the 20 countries in the coming weeks. Tradenamed Dengvaxia, it is approved for use for those aged nine and older and can prevent all four serotypes.

DEN-Vax is a recombinant chimeric vaccine with DENV1, DENV3, and DENV4 components on a dengue virus type 2 (DENV2) backbone developed at Mahidol University in Bangkok. Phase I and II trials are ongoing in the United States, Colombia, Puerto Rico, Singapore and Thailand.

TetraVax-DV is a tetravalent admixture of monovalent vaccines that were tested separately for safety and immunogenicity. The vaccine passed phase I trials and is being tested in phase II studies in Thailand and Brazil.

TDEN PIV is inactivated tetravalent vaccine undergoing phase I trials as part of a collaboration between GSK and the Walter Reed Army Institute of Research. A synergistic formulation with another live attenuated candidate vaccine (prime-boost strategy) is also being evaluated in a phase II study. In prime-boosting, one type of vaccine is followed by a boost with another type in an attempt to improve immunogenicity.