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A New Strategy for Developing Dengue Vaccines

Despite the global public health threat of dengue, it is notoriously difficult to develop an effective vaccine. Researchers from the SMART programme in Singapore may have found a new approach for dengue vaccine development through sequential immunisation.

Dengue fever has been a longstanding challenge in the Asia Pacific region and globally, particularly as climate conditions worldwide become increasingly unpredictable, with higher temperatures and humidity levels, which contribute to more favourable breeding conditions for dengue vectors. Several countries in the Asia Pacific, including Thailand, Bangladesh, and the Philippines, are especially affected by seasonal outbreaks of dengue fever, partly due to increasing populations and warmer climates.

Dengue is a mosquito-borne viral infection transmitted by female mosquitoes, particularly of the species Aedes aegypti and Aedes albopictus. The dengue virus has four known serotypes, DENV1-4.

Individuals who are infected by one DENV serotype and recover are believed to have been conferred lifelong immunity against dengue caused by that particular serotype. Unfortunately, this does not mean that they are immune against dengue altogether, as these individuals can still be infected by the remaining three serotypes.

Such instances, known as secondary infections, can even be more dangerous as they increase one’s risk of developing severe dengue, which can cause serious complications, including severe bleeding, organ impairment, and plasma leakage, thereby increasing the risk of death.

Possible secondary infection due to the existence of various DENV serotypes poses a major challenge to researchers involved in vaccine development. It is traditionally thought that an effective vaccine would need to target all four DENV serotypes to equal extents, otherwise an infection by a serotype that a patient does not have immunity to would be akin to a secondary infection and could result in severe dengue.

Currently, the only commercially available dengue vaccine is CYD-TDV, also known as Dengvaxia®, which is a tetravalent vaccine that introduces antigens of all four dengue DENV serotypes in order to stimulate immune responses and therefore confer immunity against all four dengue serotypes. Even then, use of the vaccine remains controversial as it increases the risk of severe dengue in individuals without prior dengue infection. Therefore, vaccination is recommended only to people who have been infected by dengue in the past. Furthermore, CYD-TDV does not confer full immunity against DENV1 and DENV2.

A team of researchers from the Singapore-MIT Alliance for Research and Technology (SMART) may have found a way to overcome these limitations. SMART was established by the Massachusetts Institute of Technology (MIT) in partnership with the National Research Foundation of Singapore (NRF) and is MIT’s research enterprise in Singapore.

The team involved in this study are from SMART’s Infectious Diseases (ID) and Antimicrobial Resistance (AMR) Interdisciplinary Research Groups (IRGs), and their findings were published this year in NPJ Vaccines. In proof-of-concept studies using mice, the researchers were able to induce a strong and broad immunity to dengue.

In their study, the investigators compared the effectiveness of tetravalent immunisation, such as that employed by CYD-TDV, with their novel method of sequential immunisation. In the case of sequential immunisation, mice were immunised on four separate occasions, with each dose corresponding to a particular DENV serotype.

The researchers found that the mice that had undergone sequential immunisation displayed significantly higher levels of dengue virus-specific T cell responses than in mice that had gone through tetravalent immunisation. Promisingly, they also found that sequential immunisation induced higher production levels of neutralising antibodies against all four DENV serotypes.

These results not only suggest that sequential immunisation could be a more effective vaccine against all four DENV serotypes but could also help us understand the complexities of the dengue virus, such as questions regarding cross-protection against other serotypes following a primary dengue infection.

According to Professor Ooi Eng Eong, SMART AMR Principal Investigator and senior author of this study, the findings of this study “will pave the way for a safe and effective use of the vaccine and to combat the virus.”

Given the potential for these results to be revolutionary in the development of dengue vaccines, the team hopes to work towards testing sequential immunisation in humans. [APBN]