Looking beyond COVID-19's spike protein for the next wave of vaccines

Most ongoing vaccine development efforts against the novel coronavirus use the spike protein on the surface of SARS-CoV-2 in the hopes of inducing neutralizing antibodies that can directly block the virus from infecting healthy cells. But there could be one major caveat to that approach: The antibody response to the virus, mediated by B cells of the immune system, appears to wane quickly.

That’s why a research team led by immuno-oncology biotech TScan Therapeutics turned to another key component of the immune response—T cells—in the hopes of informing the future development of vaccines, treatments and diagnostics.

By studying memory CD8+ T cells from patients who recovered from COVID-19, the team pinpointed the dominant targets of T cells during the natural cellular response. The majority of the targets they found resided outside of the spike protein, according to data published on journal preprint site medRxiv.

Several companies have reported encouraging early-phase clinical data from their vaccine trials, reporting that the candidates induced neutralizing antibodies against SARS-CoV-2 at levels comparable to or above those of recovered COVID-19 patients. However, it remains unclear whether these antibodies can protect people from an infection or how long the protection, if any, will last.

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Previous studies of two other coronaviruses—SARS and MERS—showed that the increases in antibodies could drop quickly to almost undetectable concentrations in recovered patients, whereas memory CD8+ T cells persisted for years. These T cells are able to recognize specific antigens and can launch an immediate immune attack upon re-encountering a pathogen.

A recent non-peer-reviewed paper by researchers at King’s College London reported a rapid decline in neutralizing antibody titers in most COVID-19 patients within three months after COVID-19 symptom onset.

Such findings suggest that T cells might play a more important role in long-term immunity against the novel coronavirus, the TScan-led team figured. So the researchers used a genomewide screening technology to look for sites in SARS-CoV-2 that are recognized by the memory CD8+ T cells of convalescent patients. TScan has been utilizing the same platform to identify new antigens in cancer for the design of T-cell receptor cell therapies. It recently inked a $30 million upfront deal with Novartis to work on such therapies for solid tumors.

The team focused on six most prevalent human leukocyte antigen (HLA) types. HLA regulates the cell surface molecules that present antigenic proteins to the receptors on T cells.

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For each HLA type, the COVID-19 patients' T cells largely recognized the same three- to eight-most targeted sites, called “immunodominant epitopes,” on the virus, the researchers found. Strikingly, of the 29 epitopes the researchers identified, only three resided in the spike protein, which is the target of most vaccines currently in development.

What’s more, these immunodominant targets were mostly absent in four commonly circulating coronaviruses, indicating that prior infection with these less serious coronaviruses might not provide T-cell-based immunity to SARS-CoV-2, the researchers wrote in the study.

Identifying the most critical T-cell targets “could form the basis of a second-generation vaccine, potentially an important follow-on approach to the spike protein vaccines that are currently being developed,” TScan’s chief scientific officer, Gavin MacBeath, said in a statement. The discoveries may also guide the development of novel therapeutic agents and T-cell-based diagnostic tests to determine immunity, the company said.