Dengue vaccine

In December 2018, Dengvaxia was approved in the European Union.[6]

In May 2019, Dengvaxia was approved in the United States as the first vaccine approved for the prevention of dengue disease caused by all dengue virus serotypes (1, 2, 3 and 4) in people ages nine through 16 who have laboratory-confirmed previous dengue infection and who live in endemic areas.[14][5] Dengue is endemic in the US territories of American Samoa, Guam, Puerto Rico, and the US Virgin Islands.[14]

The safety and effectiveness of the vaccine was determined in three randomized, placebo-controlled studies involving approximately 35,000 individuals in dengue-endemic areas, including Puerto Rico, Latin America and the Asia Pacific region.[14] The vaccine was determined to be approximately 76 percent effective in preventing symptomatic, laboratory-confirmed dengue disease in individuals 9 through 16 years of age who previously had laboratory-confirmed dengue disease.[14]

In March 2021, the European Medicines Agency the filing package for TAK-003 (Qdenga) intended for markets outside of the EU.[13]

In August 2022, the Indonesian FDA approved Qdenga for use in individuals six years to 45 years of age and become the first authority in the world to approve Qdenga.[15][16] Qdenga was approved in the European Union in December 2022.[7]

CYD-TDV, sold under the brand name Dengvaxia and made by Sanofi Pasteur, is a live attenuated tetravalent vaccine that is administered as three separate injections, with the initial dose followed by two additional shots given six and twelve months later.[14] The US Food and Drug Administration (FDA) granted the application for Dengvaxia priority review designation and a tropical disease priority review voucher.[14] The approval of Dengvaxia was granted to Sanofi Pasteur.[14]

The vaccine has been approved in 19 countries and the European Union,[14] but it is not approved in the US for use in individuals not previously infected by any dengue virus serotype or for whom this information is unknown.[14][5]

Dengvaxia is a 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.[17][18] Evidence indicates that CYD-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. It is not clear why the vaccinated seronegative population have more serious adverse outcomes. A plausible hypothesis is the phenomenon of antibody-dependent enhancement (ADE).[19] American virologist Scott Halstead was one of the first researchers to identify the ADE phenomenon.[20] Dr. Halstead and his colleague Dr. Phillip Russell proposed that the vaccine only be used after antibody testing, to check for prior dengue exposure and avoid vaccination of sero-negative individuals.[21]

Common side effects include headache, pain at the site of injection, and general muscle pains.[8] Severe side effects may include anaphylaxis.[8] Use is not recommended in people with poor immune function.[8] Safety of use during pregnancy is unclear.[8] Dengvaxia is a weakened but live vaccine and works by triggering an immune response against four types of dengue virus.[14][8]

Dengvaxia became commercially available in 2016 in 11 countries: Mexico, the Philippines, Indonesia, Brazil, El Salvador, Costa Rica, Paraguay, Guatemala, Peru, Thailand, and Singapore.[22][23][24] In 2019 it was approved for medical use in the United States.[14][25] It is on the World Health Organization's List of Essential Medicines.[26][27] In Indonesia it costs about US$207 for the recommended three doses as of 2016.[24]

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.[28] This led to a controversy in the Philippines where more than 733,000 children and more than 50,000 adult volunteers were vaccinated regardless of serostatus.[12]

The World Health Organization (WHO) 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 nine years).[10]

The WHO updated its recommendations regarding the use of Dengvaxia in 2018, based on long-term safety data stratified by serostatus on 29 November 2017. Seronegative vaccine recipients have an excess risk of severe dengue compared to unvaccinated seronegative individuals. For every 13 hospitalizations prevented in seropositive vaccinees, there would be 1 excess hospitalization in seronegative vaccinees per 1,000 vaccinees. WHO recommends serological testing for past dengue infection [29]

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.[28] 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 Philippine government suspended the mass immunization program with the backing of the WHO which began a review of the safety data.[30]

Phase III trials in Latin America and Asia involved over 31,000 children between the ages of two 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.[31][32] Efficacy varied by serotype. In both trials vaccine reduced by about 80% the number of severe dengue cases.[33] 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 nine years of age, but considerably greater (81.9%) for children who were seropositive (indicating previous dengue infection) at baseline.[34] The vaccination series consists of three injections at 0, 6 and 12 months.[18] The vaccine was approved in Mexico, the Philippines, and Brazil in December 2015, and in El Salvador, Costa Rica, Paraguay, Guatemala, Peru, Indonesia, Thailand, and Singapore in 2016.[22] Under the brand name Dengvaxia, it is approved for use for those aged nine years of age and older and can prevent all four serotypes.[35]

TAK-003 or DENVax, sold under the brand name Qdenga and made by Takeda,[15] is a recombinant chimeric attenuated 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 (TAK-003).[36][37] Phase I and II trials were conducted in the United States, Colombia, Puerto Rico, Singapore and Thailand.[37] Based on the 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.[38]

Data from the phase III trial, which began in September 2016, show that TAK-003 was efficacious against symptomatic dengue.[39] TAK-003 appears to not lack efficacy in seronegative people or potentially cause them harm, unlike CYD-TDV. The data appear to show only moderate efficacy in other dengue serotypes than DENV2.[40]

Qdenga received approval for use in the European Union in 2022 for people aged 4 and above,[41][42][43] and is also approved in the United Kingdom, Brazil, Argentina, Indonesia, and Thailand. Takeda voluntarily withdrew their application for the vaccination's approval in the United States in July 2023 after the FDA sought further data from the firm, which the company stated could not be addressed during the current review cycle.[43][44]

• "Dengue Vaccine Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC). December 2021.
• Dengue Vaccines at the U.S. National Library of Medicine Medical Subject Headings (MeSH)