Mar 1, 2021
How to Make a Variant-Proof Vaccine
T-cell vaccines involve a different kind of immune response
As the coronavirus mutates, a central question is whether our current vaccines will still be effective against emerging variants of the virus that are cropping up around the world. Some scientists are trying to get ahead of a changing coronavirus and build vaccines that would be virtually variant-proof.
The current Covid-19 vaccines in use — and the vast majority of those in development — are designed to spur neutralizing antibodies against the spike protein. This protein sits on the surface of the coronavirus and allows it to gain entry into our cells.
But as SARS-CoV-2 evolves, so too could the spike protein. Changes to the spike protein’s appearance could make it harder for an immunized person’s antibodies to recognize it, rendering the vaccine they received less effective. Already, the Moderna and Pfizer vaccines appear less effective against the highly transmissible South African variant.
Some scientists think we can avoid this problem by designing a vaccine that doesn’t rely on antibodies to the spike protein. Instead, they want to enlist another type of immunity: T cells. In recent years, researchers have studied the role that T cells play in protection against pathogens. Whereas antibodies recognize and take out the virus before it enters cells, T cells help destroy cells once the virus has already infected them.
“It’s a relatively new idea,” Andrew Allen, MD, PhD, CEO and co-founder of Gritstone Oncology of Emeryville, California, tells the Medium Coronavirus Blog. “Over the last 10 years or so, there’s been a concerted effort to drive towards stronger T-cell vaccines. Making antibodies does not seem to be so hard; it’s T cells that are the problem.”
Figuring out how to spur T cells into action is the challenge. Whereas antibodies recognize proteins on the outside of the virus — like the spike protein — T cells need to recognize the virus once it’s already inside of our cells.
Every day, cells chew up proteins into little fragments and present the pieces on their surface. The immune system generally ignores them because they’re just normal proteins. But when a cell gets infected by a virus, the cell starts making viral proteins. When viral proteins get chewed up by the cell and its fragments get displayed on the cell’s surface, the immune system recognizes them as foreign and activates killer T cells, which then destroy the infected cells. A T-cell vaccine would need to recognize these protein fragments to stimulate those killer T cells.
“What’s tricky is trying to figure out which bits of the viral proteins end up being processed and presented on the surface of the infected cell,” Allen says. “That’s one of the core problems in the field.”
Allen’s company has identified protein fragments from areas on the coronavirus that don’t seem to mutate. Gritstone has designed a vaccine incorporating these fragments, plus the spike protein, and is beginning an early-stage clinical trial to test its efficacy against SARS-CoV-2. The company thinks this strategy could provide protection across many variants of the virus. The idea being that T cells would essentially provide backup protection if a person’s antibody response isn’t enough to neutralize the virus.
As for their role in Covid-19 immunity, a paper published in Nature in December found that T cells help protect against SARS-CoV-2 and may be especially important to long-term protection and reinfection.
The researchers, from Beth Israel Deaconess Medical Center, first used a drug to deplete T cells in five monkeys that had recovered from SARS-CoV-2. Then they reexposed the animals to the virus. The researchers found evidence of reinfection in the nose of all the monkeys and in the lungs of one monkey. A group of monkeys with their T cells intact, meanwhile, successfully fought off reinfection. This means that for long-term protection against the coronavirus, a vaccine may need to generate both antibodies and T cells.
