RARE , NATURALLY OCCURRING T CELLS that are capable of targeting a protein found in SARSCoV- 2 and a range of other coronaviruses have been identified by researchers at the Eli and Edythe Broad Center of Regenerat ive Medicine and Stem Cell Research at UCLA. The study findings suggest that a component of this protein, cal led viral polymerase, could potentially be added to COVID-19 vaccines to create a longer-last ing immune response and increase protection against new variants of the virus.
More than 6 million people have died from COVID-19 worldwide. Current vaccines provide signi f icant protect ion against severe disease. However, newer variants — such as delta and omicron — carry mutations to the coronavirus spike protein, which can make them less recognizable to the immune cells and antibodies stimulated by vaccination. Researchers say that a new generation of vaccines will likely be needed to create a more robust and wideranging immune response capable of beating back current variants and those that may arise in the future.
One way to accomplish this is by adding a fragment of a different viral protein to vaccines — one that is less prone to mutations than the spike protein and that will activate the immune system’s T cells. T cells are equipped with molecular receptors on their surfaces that recognize foreign protein fragments called antigens. When a T cell encounters an antigen its receptor recognizes, it selfreplicates and produces additional immune cells, some of which target and kill infected cells immediately and others that remain in the body for decades to fight that same infection should it ever return.
The researchers, including graduate student Pavlo Nesterenko and Owen Witte, MD, University Professor of Microbiology, Immunology and Molecular Genetics and President’s Chair in Developmental Immunology, focused on the viral polymerase protein. Viral polymerases serve as engines that coronaviruses use to make copies of themselves, enabling infection to spread. Unlike the spike protein, viral polymerases are unlikely to change or mutate, even as viruses evolve.
To determine whether or not the human immune system has T-cell receptors capable of recognizing viral polymerase, the researchers exposed blood samples from healthy human donors (collected prior to the COVID-19 pandemic) to the viral polymerase antigen. They found that certain T-cell receptors did, in fact, recognize the polymerase. They then used a method they developed ca lled CLInt-Seq to genetically sequence these receptors. Next, the researchers engineered T cells to carry these polymerase-targeting receptors, which enabled them to study the receptors’ ability to recognize and kill SARS-CoV-2 and other coronaviruses.
The new UCLA findings point toward a strategy that may help increase protection and long-term immunity, wi th resea rcher s now conducting further studies to evaluate viral polymerase as a potential new vaccine component.
— Tiare Dunlap
“HLA-A*02:01 Restricted T Cell Receptors Against the Highly Conserved SARS-CoV-2 Polymerase Cross-React with Human Coronaviruses,” Cell Reports, December 9, 2021