Dengue, a mosquito-borne disease, is gradually becoming a global health crisis due to the absence of specific therapeutics and a registered vaccine. Over 90 million cases of dengue are reported worldwide annually, of which 34% hail from India alone. Tropical climatic conditions along with unplanned urbanization and poor sanitation have accelerated this situation in recent years. Now, a new study from Navin Khanna’s laboratory at the International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, illustrates the development of an inexpensive vaccine effective against all known strains of the Dengue virus. 

The symptoms of Dengue, which range from mild fever, rash or headache to fatal hemorrhagic fever, are the outcome of infection by four closely related Dengue virus strains (E1, E2, E3 and E4), which differ in their envelope protein content. Unfortunately, due to close similarity between different envelope proteins, the body generates cross-reactive antibodies upon infection by any one of the strains. These antibodies are ineffective in neutralising the current infection and can lead to dengue hemorrhagic fever. Further, subsequent attacks by different Dengue strains can trigger ​“false memory” in the immune system leading it to produce dysfunctional antibodies which worsen the situation, at times leading to fatal outcomes. 

Therefore, in case of Dengue virus infection, vaccinations against any one of the viral serotypes are not only ineffective but dangerous, as the immune system of vaccinated individuals might start generating self-destructive antibodies upon subsequent infection, which is commonly known as ​“dengue shock syndrome”. 

To address this problem, Khanna’s team decided to generate a tetravalent vaccine capable of mounting an immune response against all four Dengue virus serotypes. According to Khanna, the challenge was to formulate a ​“ONE-shot” vaccine instead of multiple vaccines in a cost-effective manner. The researchers chose viral envelope proteins, which are critical for the survival of the virus in the host, as vaccine targets. 

The specificity and efficiency of a vaccine depend on the careful selection, assembly and manufacturing of the non-infectious virus-like particles, which closely resemble the target virus and trigger the host immune response to prepare antibodies against the virus for a future attack. Khanna’s group assembled four different envelope proteins belonging to different Dengue virus strains in a single virus-like particle, eliminating the infectious viral parts capable of causing or aggravating the disease. This sophisticated bioengineering gave rise to the tetravalent vaccine, following which yeast (Pichia pastoris) cells were used as tiny factories for propagation and assembly of the virus-like particles. 

The researchers tested the efficacy of this tetravalent vaccine in two mouse models – mice with normal immune systems, and severely immunocompromised mice. The immune response elicited by the new tetravalent vaccine reduced viral titer in mice infected by the Dengue virus. In addition, the new vaccine did not induce production of cross-reactive antibodies in the severely immunocompromised mice, thereby preventing dengue shock syndrome. Guruprasad R Medigeshi, Associate Professor, Translational Health Science and Technology Institute (THSTI), Faridabad, who was not associated with this study, suggested that if new strains of Dengue arise in future, this vaccine could still be effective because of the intelligent selection of the target regions of the virus. 

Sankar Bhattacharya, Research Scientist, TSHTI, who was also not associated with the study, said, ​“I think the tetravalent vaccine is definitely a big step forward in the fight against Dengue using prophylactic methods. We have to wait for human volunteer studies to see how the vaccine fares in generating immunity against Dengue virus in humans.”

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