Study: Immune Cells Crucial for Vaccination Efficacy

A study has provided fresh information on a vital subset of immune system cells required for successful vaccination against the SARS-CoV-2 pandemic virus.

The study, led by researchers at NYU Grossman School of Medicine and the New York Genome Centre, focused on T cells, which, along with B cells, form the human immune system's response to invading viruses and bacteria. T lymphocytes labelled with the surface protein CD8 generate chemicals that kill infected cells directly. B cells secrete antibodies, which neutralise and mark contaminated cells for removal from the body.’

Vaccines expose patients to a bit of an invading bacterium in order to generate responses such as B and T cell activation so that the system is ready for the invader if it is met again. The COVID-19 mRNA vaccines were based on RNA, a genetic material utilised to encode the spike protein required by the virus to adhere to human cells. When mRNA instructions are injected, the spike is generated, and the immune response is activated.

In the rush to create vaccines against SARS-CoV-2, clinical trials relied mostly on antibody levels, when efficient diagnostics were available, to determine whether patients' immune responses to mRNA vaccine candidates were protective. However, clinical protection was observed as early as ten days following the initial vaccine dose, well before neutralising antibodies could be produced. T cells were thought to be at least as significant in this protection, but normal methods for tracking them were too sluggish, so careful examinations of CD8+ T cell responses were put on hold.

The study published in Nature Immunology describes a quick (high-throughput) approach for tracking T cell responses, demonstrates that they are critical to the early protection afforded by mRNA vaccines against COVID-19, and identifies the T cell subsets most responsible for it.

“Our study identified markers for the CD8+ T cells that arise from mRNA vaccination and that track closely with successful vaccination, which had previously been difficult to quantify on the population level,” said co-first study author Rabi Upadhyay, MD, assistant professor in the Department of Medicine at NYU Langone Health, and faculty in its Perlmutter Cancer Center.

“Although our study looks at mRNA vaccination against coronavirus, the antigen-specific CD8+ T cell subpopulations we uncover represent key features of immune responses more broadly, and may help us to study T cells in other disease settings.”

For the current study, the research team analyzed gene expression over time in single T cells collected before and after immunization with the mRNA vaccine produced by BioNTech and Pfizer against SARS-CoV-2.

The researchers found distinct subsets of CD8+ T cells that reliably multiplied (proliferated) 21 days after the original vaccination, specifically targeting and attacking key proteins (antigens) that make up the pandemic virus.

In looking at the genetic makeup of the most effective T cells, the researchers observed that cells lacking a surface protein called KLRG1, which stands for co-inhibitory receptor killer-cell lectin-like receptor G1, were the most likely to multiply quickly after mRNA vaccination and specifically attack.

When study authors checked for these profiles in hospitalized COVID-19 patients, those with the most “properly programmed” T cells – lacking KLRG1 but expressing other markers such as CD38 and HLA-DR – were the most likely to successfully recover from their infections.

In the years since the pandemic began, mRNA vaccines, first used against the virus, are now in clinical trials wherein they direct the body’s immune system to attack cancerous cells.

By clarifying T cell markers (e.g. KLRG1, CD38, HLA-DR), and the timeline for when CD8+ T cells arise in the blood after vaccination, the new work may enable clinical teams to tell which patients are responding to the vaccines within days or weeks, say the authors.

That compares to the more than two months that oncologists must currently wait after mRNA vaccination to perform CT scans and assess whether their lung, breast, or prostate cancer patients responded to an mRNA vaccine.

If they are validated in this setting and dramatically shorten such wait times, the new profiling methods promise to help patients pivot more quickly to other treatments if necessary, the researchers say.

Furthermore, the study authors refer to a recent study led by a different research team which found that T cells with very similar attributes, again involving KLRG1, CD38, and HLA-DR, were the most effective at attacking cancer cells after treatment with an immune system-triggering drug (immunotherapy), just as they were the most effective at attacking the SARS-CoV-2 virus in the current study.

“It is remarkable that T cell attributes found after treatment with an effective immunotherapy mirrored those that we found to track with patient recovery from COVID-19,” said co-corresponding author Dan Littman, MD, PhD, the Helen L. and Martin S. Kimmel Professor of Molecular Immunology in the Department of Cell Biology at NYU Langone. “This pattern suggests that the close monitoring of antigen-specific CD8+ T cell subpopulations will be central to future efforts to design treatments and vaccines against either viruses or tumours.”