Decoding dengue: India’s first prospective DNA vaccine against disease is promising; but challenges lie ahead

Developing an effective vaccine against dengue is tricky because it is caused by four closely related viruses called serotypes; an ideal vaccine must target all four

By Rohini Krishnamurthy
Published: Wednesday 01 March 2023

Illustration: Yogendra Anand

Illustration: Yogendra Anand / CSE

In a significant development in DNA vaccination research, India’s first and only DNA vaccine candidate for dengue has shown promising results. In preliminary trials on mice, the candidate generated a robust immune response and improved survival rates after exposure to the disease.

The DNA vaccine candidate has been in development since 2019 by scientists from the National Centre for Biological Sciences (NCBS), Bengaluru, in collaboration with nine institutions in India, Africa and the US. The team at NCBS is led by Sudhir Krishna, a professor specialising in biochemistry.

While his laboratory primarily works on human cervical cancer research, the team became interested in dengue vaccination in 2011 after collaborating with St John’s Medical College, Bengaluru, to sequence samples collected from dengue patients.

“We need a dengue vaccine because it is a major public health burden in India,” says Arun Sankaradoss, research lead of the dengue vaccine programme at NCBS. In 2021, India reported 110,473 dengue cases, ranking fourth among the worst-affected nations.

The team chose DNA technology since it is considered stable, cost-effective and safer than whole-virus vaccines. “Traditional vaccines essentially contain the whole virus. But we speculate some regions in the virus could be responsible for adverse effects,” says Swetha Raghavan, a postdoctoral researcher at NCBS.

A DNA platform, she explains, allows researchers to pick certain regions that can provoke an effective response and eliminate those likely to cause harm. Further, this vaccine can be modified to target other viruses.

The world’s first DNA vaccine—ZyCoV-D, developed by Ahemdabad-based pharmaceutical firm Zydus Cadila—was approved in 2021 for emergency use against COVID-19. Globally, DNA vaccines are being developed for diseases like tuberculosis and chikungunya. Some 19 DNA dengue vaccines are being evaluated, but yet to reach final clinical trials, says a 2021 paper published in Frontiers.

Krishna, however, says developing an effective vaccine against dengue is tricky because it is caused by four closely related viruses—DEN-1, DEN-2, DEN-3 and DEN-4—called serotypes. Each one interacts differently with antibodies in human blood. A person infected with DEN-1 is then protected against it for life, but not against the other three serotypes. An ideal vaccine must target all serotypes.

Targeted trial

The team led by NCBS conducted a sequencing study in 2017 and found that all four dengue serotypes circulate in India, but DEN-2 is dominant. Hence, to design the vaccine, the researchers targeted two proteins: one is a part of the genetic material of all four serotypes, and the other is from DEN-2.

Previous research suggested these proteins simulate host immunity responses. The team attached them to a plasmid DNA, which carries them to cells once the vaccine is injected.

The plasmid DNA enters the cell nucleus and is copied to create messenger RNA (mRNA), which then travels to the cytoplasm of the cell. The mRNA is then copied to create the proteins which elicit immune response.

In a study published in the journal Molecular Therapy in May 2022, the researchers say inoculation of the vaccine in mice generated humoral or B cells that create antibodies and T cells that protect from infection.

They also performed a challenge study, in which they collected blood serum from a laboratory-bred strain of mice injected with the DNA vaccine and transferred it to immunocompromised mice susceptible to dengue.

On exposure, immunocompromised mice showed 50 per cent better survival rate than unvaccinated mice, says Sreekumar E, a scientist at Rajiv Gandhi Centre for Biotechnology. The challenge study was done in his laboratory in Kerala.

Encouraged by preliminary results, Sankaradoss plans to collaborate with the industry and other research institutes to evaluate the vaccine in non-human primates. If the results are positive, the team will move on to clinical trials. Sankaradoss also plans to conduct experiments by tweaking the vaccine design for better response.

One caveat with DNA vaccines is that they generate weaker immune response in humans than in mice. This means humans must take high doses or multiple boosters.

There is another concern with dengue viruses—antibody-dependent enhancement (ADE). Typically, vaccines trigger production of antibodies that prevent the virus from binding to cells at later exposure. But with dengue, antibodies help the virus replicate and cause severe disease, says Shashank Tripathi, assistant professor at the Indian Institute of Science, Bengaluru.

This happens because antibodies generated after vaccination or natural infection may be of low quality and quantity and bind to the virus, resulting in a virus-antibody complex that attaches itself to immune cells. Once inside the cells, the virus makes multiple copies, increasing the viral load.

ADE may have contributed to the partial failure of Dengvaxia, the first and only approved dengue vaccine, which contains a live attenuated (weakened) virus developed by Sanofi Pasteur.

The World Health Organization says Dengvaxia proved effective and safe in clinical trials in people with prior infection, but increased disease severity among those who got their first natural infection after the shot. The US Food and Drug Administration recommends Dengvaxia for children above nine years and those with prior infection. India has not approved it.

For the DNA vaccine candidate, Sanakaradoss says the team plans to test for ADE in future trials. He adds that earlier studies show one of the proteins already part of the design may eliminate ADE in mice.

Consortium is key

The DNA vaccine candidate is not the only one NCBS is testing. Raghavan is testing on mice an mRNA vaccine, which is known to provoke better immune responses than DNA.

Two live-attenuated vaccines by the US National Institutes of Health are also being tested. Delhi-based Panacea Biotec Ltd has done phase 1 and 2 clinical trials of the first candidate in Belgavi, Puducherry and Lucknow with positive results. Hyderabad’s India Immunologicals Limited plans to begin phase 1 trials of the second candidate soon.

The team at NCBS also plans to work on building a research consortium for dengue, to adopt a holistic approach for research. “Close to 10 research groups worked with us on our DNA vaccine. We were already working informally in consortium mode. But we need to firm up and make the collaborations formal,” says Krishna.

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This was first published in the February 16-28, 2023 print edition of Down To Earth

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