User:Rotcaeroib/Dengue

The development of a 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. As of 2019, there is only one clinically available vaccine to prevent dengue fever in humans, CYT-TDV, brand name Dengvaxia. The value of this vaccine is limited by the fact that it may worsen outcomes in those who have not previously been infected. Several other vaccine candidates are in development including live attenuated, inactivated, DNA and subunit vaccines. Live attenuated vaccine candidates are the furthest along in development.

CYD-TDV
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. Evidence indicates that CYT-TDV is partially effective in preventing infection, but may lead to a higher risk of severe disease in those who have not been previously infected and then do go on to contract the disease.

Dengvaxia became commercially available in 2016 in 11 countries: Mexico, the Philippines, Indonesia, Brazil, El Salvador, Costa Rica, Paraguay, Guatemala, Peru, Thailand, and Singapore. In Indonesia it costs about US$207 for the recommended three doses.

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. This led to the 2017–18 Philippine dengue vaccination controversy where more than 733,000 children and more than 50,000 adult volunteers were vaccinated regardless of serostatus.

The World Health Organization recommends that countries should consider vaccination with the dengue vaccine 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).

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. A plausible hypothesis is the phenomenon of antibody-dependent enhancement.

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
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
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. In Brazil, the studies are being done in collaboration with the Instituto Butantan.

TDENV PIV
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.

V180
Merck is studying recombinant subunit vaccines expressed in Drosophila cells. Studies are in phase I stage as of 2015.

DNA vaccines
The Naval Medical Research Center attempted to develop a monovalent DNA plasmid vaccine, but early results showed it to be only moderately immunogenic.

Manufacturer in India and Vietnam
Panacea Biotec and Biological E. Limited have vaccine candidates in the earliest stages of development. A company in Vietnam (VABIOTECH) is conducting safety tests and developing a clinical trial plan. All three companies are involved in studies of a TetraVax-DV vaccine in conjunction with the National Institutes of Health.

Philippines controversy
The 2017 dengue vaccine controversy in the Philippines involved a vaccination program run by the Philippines Department of Health. It vaccinated schoolchildren with Sanofi Pasteur's CYD-TDV (Dengvaxia) dengue vaccine. Some of the children who received the vaccine had never been infected by the dengue virus before. The program was stopped when Sanofi Pasteur advised the government that the vaccine could put previously uninfected people at a somewhat higher risk of a severe case of dengue fever. A political controversy erupted over whether the program was run with sufficient care and who should be held responsible for the alleged harm to the vaccinated children.