Development of effective vaccines against SARS-CoV-2 and HIV

Researchers led by Raghavan Varadarajan, a professor at the Molecular Biophysics Unit, Indian Institute of Science (IISc), are working on developing effective vaccination strategies against two viruses: SARS-CoV-2 and HIV.

In two studies published last week, they report the design of a “heat tolerant” COVID-19 vaccine candidate and a rapid method for identifying specific regions on the HIV envelope protein that are targeted by antibodies, which can help. to design effective vaccines. The studies were published in Journal of Biological Chemistry and the Proceedings of the National Academy of Sciences respectively.

The COVID-19 vaccine candidate contains a part of the new coronavirus spike protein called the receptor binding domain (RBD), the region that helps the virus adhere to the host cell. It was developed by the Varadarajan laboratory in collaboration with Mynvax, a startup co-founded by him and incubated at IISc, as well as several other institutes. When tested in guinea pig models, the vaccine candidate activated a strong immune response.

Surprisingly, it also remained stable for a month at 37 ° C, and the freeze-dried versions could tolerate temperatures up to 100 ° C. Such “hot” vaccines can be stored and transported without expensive cooling equipment to remote areas for mass vaccination. – most vaccines should be stored between 2-8 degrees C or even lower temperatures to avoid losing their potency. Compared to newer types like mRNA vaccines, the production of a protein-based vaccine like this one can easily be expanded even in India, where manufacturers have been making similar vaccines for decades.

There is another difference between the vaccine candidate developed by the Varadarajan team and many other COVID-19 vaccines in the works: it uses only a specific part of the RBD, a string of 200 amino acids, instead of the entire spike protein. The team inserted genes that code for this part via a carrier DNA molecule called a plasmid into mammalian cells, which then churned out copies of the RBD section. They found that the RBD formulation was as good as the full spike protein in triggering an immune response in guinea pigs, but much more stable at high temperatures for prolonged periods: the full spike protein rapidly lost its activity at temperatures above 50 degrees C .

“We now need to raise funds to take this process forward in clinical development,” says Varadarajan. This would include safety and toxicity studies in rats along with process development and GMP production of a clinical trial batch before they are tested in humans. “These studies can cost around 10 million rupees. Unless the government funds us, we may not be able to carry them out.”

The second study focused on HIV, the virus that causes AIDS, a disease for which there is no vaccine despite decades of research. The team, which included researchers from multiple institutes, sought to pinpoint which parts of the HIV envelope protein are targeted by neutralizing antibodies – the ones that actually block the virus from entering cells, not just signaling it for other cells. immune. According to the authors, vaccines based on these regions could induce a better immune response. To map these regions, the researchers use methods such as X-ray crystallography and cryo-electron microscopy, but these are time-consuming, complicated and expensive. Therefore, Varadarajan and his team explored alternative approaches and eventually came up with a simpler but effective solution.

First, they mutated the virus so that an amino acid called cysteine ​​appeared in different places in the envelope protein. They then added a chemical label that would attach to these cysteine ​​molecules, and finally treated the virus with neutralizing antibodies. If the antibodies fail to bind to crucial virus sites because they were blocked by the cysteine ​​label, the virus could survive and cause infections. These sites were then identified by sequencing the genes of the surviving mutant viruses.

“This is a quick way to understand where antibodies bind and is useful for vaccine design,” says Varadarajan. It could also help test how serum samples from different people – portions of their blood containing antibodies – simultaneously react to the same candidate vaccine or virus, he says. “In principle, researchers could adapt this methodology to any virus, including SARS-CoV-2.”