Dengue fever: etiology, pathogenesis, and vaccine development
OA Version
Citation
Abstract
Dengue fever is the most prevalent mosquito-borne human disease where half of the global population is at risk. Dengue virus is a flavivirus, but unlike other flaviviruses such as yellow fever, developing a vaccine against dengue has been a difficult decades-long challenge. This is partially because there are four serotypes of the dengue virus, DENV-1, DENV-2, DENV-3, and DENV-4 so the vaccines would have to confer protection against all four serotypes. Basically, four different vaccines are made and then the ratio of each is adjusted to elicit a balanced immune response against all four serotypes. Another unique challenge to dengue vaccine development is a phenomenon known as antibody-dependent enhancement or ADE. This occurs when an individual’s secondary DENV infection is a different serotype than the primary DENV infection because the immune system will attempt to neutralize the secondary DENV using the antibodies from the primary DENV which are specific to that serotype. As a result, the primary DENV antibodies are unable to neutralize the new DENV serotype and help it infect more immune cells because they were recruited to the infection site to neutralize the virus.
Currently, only one dengue vaccine has been approved for use called Dengvaxia®. It uses the successful yellow fever virus vaccine as the backbone and replaced the premembrane and envelope protein genes with the respective DENV ones for each serotype. Then they were combined to form a tetravalent vaccine against all four serotypes. Dengvaxia® was only approved to be used by dengue-primed individuals over the age of nine because the vaccine effectively served as the primary infection for dengue-naïve individuals. As a result, if these individuals were infected with a different serotype of DENV, which is highly likely in dengue-endemic countries, they experienced ADE. The increased viral load is associated with more severe forms of dengue known as dengue hemorrhagic fever or dengue shock syndrome. Since it is difficult to know for sure if you have been infected with DENV before due to lack of resources or insensitive serological tests, this vaccine cannot be used by a majority if the individuals that are at risk of developing dengue.
Therefore, there is a dire need for a vaccine that can prevent dengue fever across various age groups and regardless of dengue immunity status. One of the vaccines that is currently undergoing clinical trials is the TAK-003 vaccine, which is the most promising vaccine because it contains the NS1 protein, a nonstructural dengue protein, that was not present Dengvaxia®. A study has shown that NS1 is responsible for causing the potentially lethal plasma leakage that is seen in DHF and especially in DSS. Additionally, NS1 does not induce ADE; therefore, it is safe for dengue-naïve individuals especially children who are at high risk of developing ADE with a secondary infection. The current clinical trials on TAK-003 have shown that it is safe for adults and children as young as two years old. Therefore, of all the dengue vaccines are that currently undergoing clinical trials, TAK-003 shows the most promise as a universal dengue vaccine.