Instead of focusing exclusively on the spike protein, COVID-19 vaccines could also attend to another viral protein, the RNA polymerase that coronaviruses use to make copies of themselves. This dual approach, which is being proposed by UCLA researchers, could help COVID-19 vaccines offer longer-lasting protection.

The UCLA researchers reason that COVID-19 vaccine protection slips because the spike protein is, well, slippery. That is, the spike protein keeps changing its shape as the SARS-CoV-2 virus evolves, which means the spike protein gets better at evading the grasp of the antibodies that are produced in response to COVID-19 vaccines.

Unlike the spike protein, the RNA polymerase is highly conserved. It keeps its shape. So, if the immune system could be primed to recognize the RNA polymerase, the immune system might well stay primed.

To explore the potential advantages of focusing on RNA polymerase, the UCLA researchers studied the cross-reactivity and direct killing of target cells by SARS-CoV-2 specific CD8+ T cells. This work allowed the researchers to identify rare, naturally occurring T cells that are capable of targeting the RNA polymerase, a protein that is found not just in SARS-CoV-2, but in a range of other coronaviruses, including those that cause SARS, MERS, and the common cold.

Details from the study appeared December 10 in Cell Reports, in an article titled, “HLA-A*02:01 restricted T cell receptors against the highly conserved SARS-CoV-2 polymerase cross-react with human coronaviruses.” In this article, the authors noted that isolation of T-cell receptors (TCRs) and overexpression in allogeneic cells allows for extensive T-cell reactivity profiling. The authors also observed that SARS-CoV-2 RNA-dependent RNA-polymerase (RdRp/NSP12) is highly conserved.

“We perform single-cell TCRαβ sequencing in HLA-A*02:01 restricted, RdRp specific T cells from SARS-CoV-2 unexposed individuals,” the article’s authors wrote. “Human T cells expressing these TCRαβ constructs kill target cell lines engineered to express full length RdRp. Three TCR constructs recognize homologous epitopes from common cold coronaviruses, indicating CD8+ T cells can recognize evolutionarily diverse coronaviruses.”

The researchers used a method they developed called CLInt-Seq to genetically sequence the TCRs. 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.

“Analysis of individual TCR clones may help define vaccine epitopes that can induce long-term immunity against SARS-CoV-2 and other coronaviruses,” concluded the article’s authors, who were led by Owen Witte, MD, the founding director of the UCLA Broad Stem Cell Research Center.

The new findings uncovered by the UCLA team point toward a strategy that may help increase the protection and long-term immunity offered by COVID-19 vaccines. The researchers are now conducting further studies to evaluate viral polymerase as a potential new vaccine component.

Graphical abstract of Cell Reports article about SARS-CoV-2-specific CD8+ T cells that recognize viral polymerase.

Newer COVID-19 variants—such as delta and omicron—carry mutations to the 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 wide-ranging 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 self-replicates and produces additional immune cells, some of which target and kill infected cells immediately and others which remain in the body for decades to fight that same infection should it ever return.