Recent trends seen in the clinical trials of the dengue vaccine

Mar 29,2017

Among vector-borne diseases, dengue is one of the most common and a rising medical concern on account of rapid globalisation. Approximately half of the world’s population resides in countries where the virus is endemic, and nearly 100 million people suffer from dengue annually. The bulk of infections are seen in tropical and sub-tropical countries and nearly 500,000 cases morph into serious forms of the disease such as dengue shock syndrome or dengue haemorrhagic fever. The global epicentre of dengue is India with a third of the recorded cases. For a potentially fatal and infectious disease not having any form of treatment or preventive measures in place, the public importance of a preventive vaccine for dengue becomes immediately apparent.

Dengue fever is caused by four different dengue viruses namely DENV-1, DENV-2, DENV-3, and DENV-4 that belong to the genus Flavivirus in the family Flaviviridae. The four strains of dengue viruses are cross-reactive and the major virus transmission vectors are the Aedes albopictus and Aedes aegypti mosquito. A patient afflicted with dengue suffers from a high fever, joint and muscle pain, and headaches from which there is a strong chance of full recovery. Dengue haemorrhagic fever, on the other hand, leads to haemorrhagic manifestation and plasma leakage that can even cause shock. Currently, managing a dengue virus infection uses control measures that target environmental management, source reduction and prophylactic measures.

Vaccines are one of the most important medical inventions of the 20th century and also one of the cheapest public health initiatives. A number of dengue vaccines are being developed such as live chimeric virus vaccines, live attenuated virus vaccines, live recombinant, inactivated virus vaccines, subunit and DNA vaccines. Efforts to create a strong dengue vaccine began in earnest as early as 1929 by utlising infected human plasma when treated with an ox virus grown inside a mosquito and then inactivated with the help of formalin. The pioneer attempt by live-attenuated DENV-1 and DENV-2 viruses that is mouse-passaged to achieve immunisation was conducted in Mahidol University. In 2004, Sanofi Pasteur attempted to create a live-attenuated virus dengue vaccine by using a primary dog kidney cell passage. GlaxoSmithKline Biologicals used primary dog kidney cell passage to reduce vaccine virus strain candidates. By targeting mutagenesis, the US NIH attempted to reduce DENV strains; the strains created then functioned as chimeric backbones.

Live attenuated virus vaccines comprise weakened viruses that cause adaptive immune responses to either structural or non-structural protein. A highly desirable, effective and safe dengue vaccine would be tetravalent as immunisation to only one strain of dengue virus could pose a potential risk of later infection to greater disease severity from a different strain of dengue virus. Live chimeric virus vaccines in which particular proteins from one virus are replaced with those from another virus, is the most advanced product. In the case of the dengue vaccine, a chimeric viruses is created by exchanging prM/E genes of every dengue virus strain for homologous genes of the yellow fever virus strain 17D. The vaccine trial for a chimeric dengue vaccine has been conducted in India. There are two main benefits of inactivated virus vaccines over live virus vaccines; the probability of returning to virulence is slim and it induces a balanced immune response. Recent genetic engineering technological advancements have emulated dengue vaccine research with subunit vaccines and live recombinant DNA. The main challenge in developing the dengue vaccine is that the four serotypes of dengue are in global circulation, so any vaccine should be tetravalent. A neutralising titer to all four virus strains must be achieved, whatever the preceding immune status of the individual who is vaccinated may be.

The global trouble of dengue is quite significant and vaccination would provide immense value while becoming the foremost tool to prevent and control the spread of dengue. There is an urgent need to increase efforts towards dengue vaccine research keeping in mind the urgency of the situation.

      

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