The prospect of a next-generation COVID-19 vaccine that could offer protection against future virus variants took a step closer to reality at now.

The Coalition for Epidemic Preparedness Innovations (CEPI) has agreed to provide $20.6 million in funding to a six-year-old biotechnology company called Gritstone, based in Emeryville, Calif., to help it test a “universal” COVID-19 vaccine.

CEPI is a global partnership of governments and nongovernmental organizations dedicated to creating mechanisms for quickly combating pandemics. COVID-19 has been the first real test for the organization, which was established in 2016.

“COVID-19 variants are already rendering some of our vaccines less effective, so it is critical that we don’t let our guard down. We must continue to invest in critical vaccine R&D if we are to stay one step ahead of this deadly virus,” Richard Hatchett, CEPI’s chief executive officer, said.

The latest funding for Gritstone will help it conduct an initial human clinical trial of its COVID-19 vaccine in South Africa. The company said in an announcement on August 17 that the trial would begin before the end of the year.

The money will also help Gritstone conduct preclinical studies, increase its research and manufacturing capacity, and help it develop a more stable vaccine, the company said. The company has previously received backing for its research from the U.S. National Institute of Allergy and Infectious Diseases (NIAID), as well as the La Jolla Institute for Immunology and the Bill & Melinda Gates Foundation.

As part of the latest CEPI funding deal, Gritstone has agreed that if it is successful in developing a universal COVID-19 vaccine, it will be made available globally through the COVAX facility, which is sponsored by CEPI, the vaccine funding body Gavi, and the World Health Organization, meaning that developing countries ought to be able to gain access to the vaccine.

Gritstone is one of several biotechnology research groups around the world pursuing a universal coronavirus vaccine. Others include Belgian startup myNEO as well as separate academic teams from the Walter Reed Army Institute of Research, Duke University, and the University of North Carolina at Chapel Hill. Each is betting on a slightly different strategy and technology to achieve the goal of a vaccine that is more robust to future coronavirus mutations. But CEPI’s funding of Gritstone’s clinical trial is an important endorsement of its progress so far.

Gritstone’s messenger RNA (mRNA) technology is similar to that used by both Pfizer and Moderna in their COVID-19 vaccines. But there are a few crucial differences: The existing mRNA vaccines prompt the body’s cells to manufacture just a single coronavirus protein—the spike protein that the virus uses to infect cells. That has made these existing vaccines vulnerable to mutations in the spike protein seen in new variants of SARS-CoV-2, such as the Delta variant.

In addition to that spike protein, Gritstone’s vaccine would instruct cells to make other proteins associated with the virus, especially targeting ones that seem not to show much variation across the whole family of coronaviruses. Although their function is not entirely understood in many cases, these “well-conserved” proteins are thought to be essential for the virus’s survival and thus may not be as susceptible to mutations that would enable the virus to elude a vaccine. Plus, by targeting multiple proteins at the same time, it becomes far less likely that any one variant would have enough mutations in all of those proteins to enable it to escape the vaccine.

Another key difference is that Gritstone is investigating the use of what is known as a “self-augmenting mRNA” (or SAM) vaccine. While existing mRNA vaccines can prompt a cell to make only a limited number of virus proteins, SAM vaccines trick the cell into producing many more copies of a particular protein. This means a smaller amount of vaccine can potentially create a more robust immune response, potentially obviating the need for second doses and booster shots.

Some researchers, however, are skeptical of Gritstone’s approach. For one thing, the only antibodies proven to prevent infection from SARS-CoV-2 form in response to the spike protein. While training the body’s B cells and T cells to recognize other virus proteins too might help a person mount an immune response, it isn’t clear how effective that response is without antibodies that can also prevent the virus from using its spike to infect cells.

In addition, some researchers worry that SAM vaccines, unless very carefully engineered and administered with other molecules, overstimulate a part of the immune system that can degrade mRNA and reduce the cell's production of the virus proteins, ultimately rendering the vaccine less effective.

Finally, there is some concern that this approach, by prompting cells to display many virus proteins at once, could exhaust the B cell and T cell response, spreading the body's defenses too thin, which would also make the vaccine less effective.

Gritstone said that as part of its COVID-19 vaccine development platform, which it calls CORAL, it will experiment with whether a universal COVID-19 vaccine could be delivered with a chimpanzee adenovirus vector technology that is similar to the one used in AstraZeneca’s current COVID-19 vaccine, or whether a combination of adenovirus and SAM technologies could be used.

“Together with the CEPI-supported study, this set of clinical trials will test four different vaccine candidates and establish optimal dosing and antigenic content for the CORAL program in young individuals, the elderly, the previously vaccinated, and the immunocompromised,” the company said.

Gritstone, whose shares are publicly traded on Nasdaq, has primarily been developing its SAM technology for use in cancer therapies. The company currently has two oncology drugs—one for use in colorectal cancer and another for lung cancer—in Phase II human trials. But it has recently broadened the scope of its research to include infectious diseases, such as HIV and SARS-CoV-2.