Vol. 23, Issue 1: Fall 2015

Dengue Vaccine Research Reaches New Heights

Ahaana Singh

Even before modern medicine, the prevalence of mosquito-borne illnesses has been rampant. Today, 128 countries worldwide are at risk of suffering from one of the most rapidly growing mosquito-related viruses. Causing severe joint pain, nausea, high fevers, and countless other symptoms, this virus infects approximately 390 million people every year according to the World Health Organization’s (WHO) studies. The number of cases is not only locally increasing with the spread of the disease to new areas, but there are also explosive outbreaks occurring worldwide. In 2013, the Americas alone reported 2.35 million cases, and 37,687 of those cases were severe.

Up until now, no treatments have been discovered for this growing epidemic; however, the combined efforts of a variety of research institutes have resulted in the development of six possible vaccine candidates to tackle the Dengue Fever. Of the six vaccine candidates in clinical trials, one has made it to the most advanced clinical development stage.

While it was initially concentrated in tropical areas, the Dengue Fever is now spreading far beyond its tropical origins. The virus is closely related to the viruses that cause West Nile and Yellow Fever. Typically, cases within the US have been attributed to international travel and contraction of the virus from more, but recent developments show that there is an increased risk along the Texas-Mexico border, as well as in Florida. The Aedes mosquito, found on every continent today, is the transmitter of the four-strain virus, posing risk to anyone exposed to it.

“[Dengue] is an increasing public health issue because the spread of mosquito vectors,” says Dr. Robert Beatty, a lecturer of immunology at the University of California, Berkeley, whose research focuses on developmental recombinant proteins for dengue vaccines. “Urbanization is also a huge factor--this is urban disease as opposed to rural disease."

Typical symptoms of Dengue mirror those of the flu--sudden high fever, severe headaches, fatigue, nausea, vomiting, and skin rashes. Although most cases are fairly mild and can be taken care of over the typical ten-day symptomatic period, there are still many cases that have become significantly more severe and sometimes fatal. Extreme cases result in the development of hemorrhagic fever, damage to lymph and blood, enlargement of the liver, and circulatory system failure. In some cases these symptoms may progress to what is known as dengue shock syndrome (DSS)--causing abdominal pain, hemorrhage, and circulatory collapse. It also may lead to the dengue hemorrhagic fever (DHF), which begins abruptly with high continuous fever and headache in addition to respiratory and intestinal symptoms such as a sore throat, cough, nausea, vomiting, and severe abdominal pain.

These unsettling symptoms paired with the increased spread of the virus has lead to a major push for Dengue prevention and treatment worldwide. However, the development of the live recombinant tetravalent vaccine--a four-strain vaccination that targets all four of the Dengue viruses--has progressed without the benefit of a full understanding of the pathogenesis of dengue. Triggering an immune response to each of the four Dengue viruses is predicted to minimize the overall risk of disease enhancement. At the same time, it must be kept in mind that antibody-dependent enhancement of the virus may still occur with the antibodies that are meant to counter the virus. Accordingly, a vaccine must attack the virus but not remain in the patient’s immune system for too long. Several other concerns exist regarding live attenuated virus vaccines, such as the tetravalent strain undergoing testing; these include cell-culture-derived adventitious agents, community spread of the vaccine virus by resident vector mosquitoes, vaccine virus causing disease in the nervous system, and the effects of vaccine administration to immunocompromised hosts. These, however, are very unlikely although theoretically possible and must be accounted for.

“It’s hard to gauge effectiveness [of potential vaccines] because people can get repeatedly infected with dengue,” according to Beatty, “Looking at complete prevention and looking at reduced disease, reduced disease is a more important focus.”

The first major efforts to create a vaccine have been unsuccessful for several different reasons, including problems of unbalanced immune responses and inconsistent reactions to the vaccine. The US National Institutes of Health, however, has introduced new Dengue vaccine research with direct mutation-altering technology. The National Institutes of Health has licensed the resulting vaccine candidates to several institutions for further testing.

Of the several vaccines--including a chimeric virus, inactivated virus, subunit vaccines, DNA vaccines, and vectored vaccines--the tetravalent chimeric dengue virus vaccine has progressed to phase III testing. The Center for Disease Control and Prevention (CDC) created the vaccine by inserting DENV-1, -3 and -4 prM and E genes into cDNA derived from the attenuated DEN-2 component that was developed in the Sanofi Pasteur live attenuated dengue virus vaccine at the Mahidol University in Bangkok, Thailand. The chimeric tetravalent vaccine candidate was then formulated and licensed to Inviragen, Inc. and Takeda, respectively, and has undergone clinical testing with those pharmaceutical companies. After additional testing and manipulation, the candidate vaccine has now progressed to efficacy studies--required to prove efficacy against dengue in the field and to build a robust safety database, according to research conducted by Wallace, D.

The live chimeric dengue vaccines, when inoculated into dengue-immune children or adults, have not resulted in enhanced disease caused by vaccine virus, which suggests that the live virus in the vaccine is controlled and unlikely to cause vector transmission of the dengue virus. Numerous dengue vaccine developers have also performed risk assessments to gauge this. According to Sardelis et al, “The results of published studies indicate a very low likelihood that a vaccine could transmit vaccine-derived dengue viruses to a mosquito.” Still, however, studies must continue in order to observe the interference that may be caused by the mixture of four dengue viruses in a single strain vaccine.

Despite the advances in research and development, Professor Beatty still has concerns about the ultimate utilization of the vaccine, “How do you decide whether or not it’s worth public health dollars? If you can commit big nations to buy it then public health money will provide for other [needy] nations.” If this is not a focus during development, vaccine production is essentially useless because it will not reach the countless nations that need it. Currently, a licensed dengue vaccine is not available but the studies conducted and that continue to progress, are providing increased knowledge of the dengue virus and vaccine development. Although only one vaccine has progressed to phase III testing, several other possible candidates are undergoing preclinical and clinical trials and appear to be promising. “It’s going be very difficult to settle on one vaccine that is going to be very successful,” says Professor Beatty, “There’s a lot of challenges to deciding on one [of the several] vaccines to work.” Continued research, however, along with economic pushes and technological advancements, shows promise of a dengue vaccine reaching the markets shortly.

With each academic, technological, and economical investment contributed towards this growing Dengue vaccine research, there are hopes of eliminating one of the largest, growing mosquito-transmitted viruses in the world.

About the Author

Ahaana Singh is a freshman at Cal from Boston. She is an intended Public Health major following the pre-med track. She is very passionate about Global Health and Health Policy. One day she hopes to be a pediatric oncologist but also dabble in health-policy work and Doctors without Borders.