FDA Approvals for Dengvaxia Appear Too Narrow and Inconsistent with WHO Guidelines-Medium Article

Dengvaxia is a vaccine created by Sanofi against the dengue virus, which causes dengue fever. It was approved by the FDA in May for use in the U.S. for individuals who have both laboratory confirmed prior Dengue infection and live in an area where Dengue is endemic. The vaccine is not approved, however, for individuals who have evidence of prior dengue infection and plan to travel to areas where dengue is endemic or live in regions of the continental U.S. where dengue outbreaks have been previously observed. The reason Dengvaxia is not approved for these individuals is unclear, and will be discussed further later.

Dengvaxia is a live attenuated tetravalent vaccine containing all 4 strains of Dengue. It is made by replacing certain genes in the yellow fever attenuated vaccines with proteins from the 4 serotypes of dengue. Dengvaxia became available in 2016 for use in 11 countries, but soon after in 2017, it was discovered that individuals who had not been previously infected with dengue but had received the vaccine were susceptible to increased disease if infected with dengue. This is thought to be due to a phenomenon called antibody dependent enhancement (ADE). 

ADE (in dengue specifically) occurs when an individual is infected with one strain of dengue virus and develops neutralizing antibodies that create lifelong immunity against that strain. However, if that individual is to become reinfected with a different strain of dengue, the antibodies against the original strain react with the new strain, but do not neutralize them. Instead, they can bind to antibodies without being neutralized, and the antibodies are eventually endocytosed by dendritic cells with the virus still bound. This allows the virus access to the inside of these dendritic cells, giving the virus the ability to replicate almost undetected. This then results in very high viral load in the blood (viremia), which can lead to increased severity of disease when compared with the first infection. Oftentimes, the first infection leads to more minor infections, such as dengue fever, whereas reinfection with a different strain more often leads to dengue shock syndrome or dengue hemorrhagic fever. 

A similar process is thought to occur when an individual is vaccinated with dengvaxia. A plausible mechanism may be that, while the vaccine contains components of all four serotypes, the antibody response induced may be weak. Since antibodies should be made against all four strains, while some antibodies from one strain would likely be able to neutralize the virus, non-neutralizing antibodies from the other 3 would likely make it easier for the virus to potentially enter dendritic cells and replicate. Studies have found that individuals who are seronegative have an increased chance of hospitalization and complications, but it is not known if the mechanism suggested above is correct.

In individuals who have previously been infected with one strain of dengue, the vaccine is also more effective. The vaccine is estimated to be 78% effective against dengue virus in individuals who have previously been infected with dengue, versus 38% in those who have not. This has led the World Health Organization (WHO) to recommend that individuals who are interested in getting dengvaxia be screened, and that only dengue seropositive individuals be vaccinated. 

As discussed earlier, the U.S. has taken a similar, but slightly different approach. In addition to the requirement that individuals have proof of previous dengue infection, the only people that are approved to get the vaccine are those that live in areas where dengue is endemic, such as Puerto Rico, the US Virgin Islands, and American Samoa. The U.S. does not allow individuals who do not live in endemic areas, even if seropositive, to get dengvaxia. The reasoning listed for this is that “the safety and effectiveness of DENGVAXIA have not been established in individuals living in dengue non-endemic areas who travel to dengue endemic areas.” This line of reasoning seems odd, as this sounds like they are suggesting that a study needs to be done to evaluate the safety and efficacy of Dengvaxia specifically in people who are seropositive, live in non-endemic areas, and travel to endemic areas. Nothing WHO, or any other sources that I have seen, mentions why there would be any decrease in efficacy or safety just because the individual lives in a non-endemic area and then travels to an endemic area as long as they are also seropositive. 

The Dengvaxia vaccine has shown relatively good efficacy in seropositive populations, so I believe that the U.S. should not restrict the vaccine to individuals in endemic areas only. I believe people who are seropositive and plan to go to an area where dengue is endemic, or even those who want to be vaccinated for increased safety in case an outbreak occurs in the U.S., as has happened in Florida, Texas, and Hawaii, should be allowed to be vaccinated. There does not seem to be any reason to restrict these populations, as there is no evidence of decreased efficacy or safety.

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Jacob Thoenen

Sources:

Questions and Answers on Dengue Vaccines-WHO

Summary Basis for Regulatory Action of Dengvaxia-FDA

Dengue Vaccine-CDC

Dengue in the US States and Territories

The Complexity of Antibody-Dependent Enhancement of Dengue Virus Infection