By the Dengue Vaccine Initiative

Dengue, also known as breakbone fever, is a painful and sometimes fatal viral disease transmitted by the Aedes aegypti mosquito. Dengue fever typically impacts urban environments in tropical and subtropical regions. There is no specific medication or cure available for dengue. Without proper treatment of symptoms, fatality rates of the severe forms, such as hemorrhagic fever, can exceed 20 percent.

Dengue prevention efforts to date have focused on vector control, through insecticide spraying and emptying containers of standing water. Vaccine development for dengue is particularly challenging because dengue fever is caused by one of four related, but distinct, virus serotypes (DENV 1-4). While recovery from infection by one virus provides lifelong immunity against that virus, it provides only partial and transient immunity against the other three. For vaccine development, this means that an effective vaccine against dengue needs to be tetravalent, providing protection against all four dengue viruses. In recent years, the race to develop a safe and effective vaccine against dengue has accelerated dramatically.

In 2015, Sanofi Pasteur’s Dengvaxia® became the first dengue vaccine to be licensed for use in a country, gaining marketing authorization in four dengue-endemic countries so far. Mexico, the Philippines and Brazil approved the vaccine in December, followed by El Salvador in February. Following registration, ministries of health will still face crucial decisions about whether or how to introduce the vaccine into national immunization programs. These decisions will likely vary according to each country’s specific demographic characteristics, dengue epidemiology and public health system capacity.

The national regulatory agencies in each country approved the vaccine for use specifically in people age 9-45, living in dengue-endemic areas. A recent study demonstrated that in children and adolescents aged nine years and above, Dengvaxia reduced dengue cases overall by approximately 65 percent; dengue cases requiring hospitalization by 81 percent; and severe dengue cases by 93 percent during a 25-month period after the first of three doses administered over the course of a year. The vaccine’s efficacy was most apparent in individuals with evidence of prior dengue virus exposure.

In children less than nine years old and in those with no evidence of prior dengue, the vaccine’s efficacy was substantially lower. There was also an increased risk of cases requiring hospitalization during the third year after vaccine initiation in children under nine. This is an important observation, considering dengue is a leading cause of hospitalization of children in endemic countries.

The extent of Dengvaxia's impact will vary depending on several factors including background, predominant serotype(s) and level of pre-existing dengue exposure in the population. It will be important to continue to explore several unknowns surrounding vaccine use to understand Dengvaxia’s ultimate impact. Some of these questions include: long-term safety effects in vaccine recipients of any age with no evidence of prior dengue exposure, duration of protection, price and impact on overall dengue virus transmission, given that the youngest and oldest age groups will not be vaccinated.

As countries assess whether to introduce this vaccine into their immunization programs, they must also consider the vaccine candidates under evaluation in clinical trials. One candidate in advanced stages of development is TV003. Currently in Phase III trials, TV003 is in development by the U.S. National Institutes of Health (NIH) and Butantan Institute. In a Phase II challenge trial in adults in Brazil, 41 participants received the vaccine or a placebo, then were infected six months later with a mild form of dengue virus. The vaccinated subjects showed no symptoms or signs of the virus in their blood. "The bottom line is that the vaccine appears to be 100 percent efficacious," Beth Kirkpatrick, a professor of medicine at the University of Vermont, told the Washington Post. Kirkpatrick called the results, "very straightforward and quite conclusive." In addition, this small-scale challenge trial model could set an important precedent for dengue vaccine development, enabling researchers to quickly test a vaccine’s efficacy in humans without mounting an expensive, large-scale, multi-year trial.

View our quick guide to the vaccine candidates below and read on to learn more about each candidate:

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REGISTRATION PHASE:

Sanofi Pasteur’s Dengvaxia® (aka CYD-TDV), is a tetravalent live recombinant vaccine, using a yellow fever virus backbone carrying the premembrane and envelope protein genes from the each of the four dengue serotypes. Dengvaxia is administered subcutaneously in a three-dose regimen over a 12-month period.

Dengvaxia is currently licensed in four countries. Vaccine licensure was based on safety and efficacy results from two Phase III trials in Asia and Latin America published in 2014. The Phase III trial in Asia enrolled 2-14 year olds from Indonesia, Malaysia, the Philippines, Thailand and Vietnam; the trial in Latin America enrolled 9-16 years olds from Brazil, Colombia, Honduras, Mexico and Puerto Rico. Follow up of the trial subjects is expected to continue for up to six years after the first dose.

PHASE III:

NIH and Butantan Institute are developing a tetravalent live recombinant vaccine, TV003, comprised of full-length DENV-1, DENV-3, DENV-4 and a chimeric DENV-2 component. In a Phase II trial in 41 adults in Brazil, dengue-naïve and primed subjects received the vaccine (21 subjects) or a placebo (20 subjects), then were infected six months later with a mild form of dengue virus. The vaccine protected against infection in all participants who received the vaccine. In contrast, all participants who received the placebo were infected with dengue. In December 2015, Brazil’s national regulatory authority, ANVISA, approved a Phase III trial of TV003. This trial will enroll 16,944 subjects aged 2-59 years old. The vaccine will be administered as a single subcutaneous dose with the primary efficacy outcome being virologically-confirmed dengue cases from 28 days to 52 weeks after injection.

A separate Phase II age de-escalation trial of TV003 and TV005 is being conducted in 294 subjects in Thailand. TV003 and TV005 are similar formulations of the vaccine except that TV005 contains a higher quantity of DENV-2 than TV003. TV005 as a single dose regimen has been age de-escalated to subjects in the 1-4 year age group.

The NIH dengue virus strains have also been licensed by the NIH to several other vaccine manufacturers, including VaBiotech (Vietnam), Panacea (India), Serum Institute of India (India), and Merck.

PHASE II:

Takeda is developing a tetravalent live recombinant vaccine, TDV, using an attenuated DENV–2 backbone with the premembrane and envelope protein genes of DENV-1, DENV-3 and DENV-4. TDV has been administered in Phase II trials in adults in the United States using various vaccine formulations, and in children aged 2-17 years old in Colombia, Dominican Republic, Panama, the Philippines and Thailand using different dosing regimens. The vaccine is also currently undergoing a Phase II trial in Singapore testing two potencies of the DENV-2 component. Plans for a Phase III trial are underway.

PHASE I:

GlaxoSmithKline, Fiocruz and Walter Reed are collaborating to develop a tetravalent purified inactivated whole virus vaccine. Two similar candidates are being evaluated. TDENV-PIV, developed by Walter Reed, has undergone Phase I trials; while DPIV, developed by GlaxoSmithKline (GSK), is currently in preclinical studies. The candidates are administered in two doses, four weeks apart, with different adjuvants under evaluation to include GSK’s proprietary adjuvants AS01 and AS03. Phase I trials of TDENV-PIV have been conducted in dengue-naïve and dengue-primed subjects. Separately, Walter Reed is conducting a Phase I trial involving a heterologous prime-boost strategy using TDENV-PIV and TDENV-LAV. The latter is a live classically attenuated vaccine serially passaged through primary dog kidney cells, which had previously been in development by Walter Reed and GSK. The purpose of this heterologous prime-boost study is mainly to assess immunological response rather than as a separate development effort.

Merck & Co. is developing a tetravalent subunit protein vaccine, V180, using recombinant envelope protein expressed in an insect cell system. The vaccine is being tested in a three-dose schedule of intramuscular injections given one month apart. The candidate has been evaluated in a Phase I dose-ranging trial using CSL’s proprietary adjuvant Iscomatrix®. In addition, Merck has recently obtained a license for the live recombinant vaccine, TV005, from the NIH (referenced above).

Naval Medical Research Center is developing a tetravalent plasmid DNA vaccine, TVDV, administered in three doses via the intramuscular route over a three-month period. TVDV has been evaluated in a Phase I dose-ranging trial in combination with Vical’s proprietary adjuvant Vaxfectin®.