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Vaccine Research

A vaccine for dengue fever has been approved and is commercially available in a number of countries. The World Health Organization recommends that countries should consider vaccination with the dengue vaccine Denvaxia (CYD-TDV) only if the risk of severe dengue in seronegative individuals can be minimized either through pre-vaccination screening or recent documentation of high seroprevalence rates in the area (at least 80% by age 9 years). In 2017 the manufacturer recommended that the vaccine only be used in people who have previously had a dengue infection, as outcomes may be worsened in those who have not been previously infected.

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

The development of vaccine for dengue fever began as early as 1929, but has been hindered first by incomplete knowledge of the disease pathogenesis, and later by the need to simultaneously create a stable immunity against all four dengue serotypes. Several vaccine candidates are in development including live attenuated, inactivated, DNA and subunit vaccines. Live attenuated vaccine candidates are the furthest along in development. In 2016 a partially effective vaccine for dengue fever (Dengvaxia) became commercially available in 11 countries: Mexico, the Philippines, Indonesia, Brazil, El Salvador, Costa Rica, Paraguay, Guatemala, Peru, Thailand, and Singapore. WHO updated its recommendations regarding the use of Dengvaxia in September 2018 based on the evidence that seronegative vaccine recipients have an excess risk of severe dengue compared to unvaccinated seronegative individuals. It is not clear why the vaccinated sereonegative population have more serious adverse outcomes.

See also dengue vaccine research website of the WHO.

CYD-TDV (Dengvaxia)
CYD-TDV, sold under the brand name Dengvaxia and made by Sanofi Pasteur, 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 the four dengue serotypes. In 2017 the manufacturer recommended that the vaccine only be used in people who have previously had a dengue infection as otherwise there was evidence it may worsen subsequent infections. The initial protocol did not require baseline blood samples prior to vaccination in order to establish an understanding of increased risk of severe dengue in participants who had not been previously exposed. In November 2017 Sanofi acknowledged that some participants were put at risk of severe dengue if they had no prior exposure to the infection; subsequently the Philippines government suspended the mass immunization program with the backing of the WHO which began a review of the safety data.
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, and in El Salvador, Costa Rica, Paraguay, Guatemala, Peru, Indonesia, Thailand and Singapore in 2016. Tradenamed Dengvaxia, it is approved for use for those aged nine and older and can prevent all four serotypes

DENVax or TAK-003 is a recombinant chimeric vaccine with DENV1, DENV3, and DENV4 components on a dengue virus type 2 (DENV2) backbone originally developed at Mahidol University in Bangkok and now funded by Inviragen (DENVax) and Takeda (TAK-003). Phase I and II trials are ongoing in the United States, Colombia, Puerto Rico, Singapore and Thailand. Based on the latest 18-month data published in the journal Lancet Infectious Diseases, indicated that TAK-003 produced sustained antibody responses against all four virus strains, regardless of previous dengue exposure and dosing schedule

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.