A Little Bit of Good News About the SARS-CoV-2 Virus!

Transmission electron micrograph of SARS-CoV-2 virus particles, isolated from a patient. Image captured and color-enhanced at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland.

Credit: NIAID

T cells can mount attacks against many SARS-CoV-2 targets—even on new virus variant

The good news is that research by scientists at La Jolla Institute of Immunology (LJI), La Jolla, California, USA has shown that our T cells are capable of recognising many targets on the surface of the virus (known as epitopes) and so can mount an attack against the new variants.

The bad news is that this is so for naturally-acquired immunity (in people who have recovered from the infection). It is not clear that this applies to immunity acquired by vaccination. All the vaccines approved for general use so far are based on mRNA technology that produces antibodies to the surface 'spike' proteins only, not to other surface proteins.

The research and its importance is explained in an LJI News release by Madeline McCurry-Schmidt:

The immune system is very flexible. By re-scrambling genetic material, it can make T cells that respond to a huge range of targets, or epitopes, on a pathogen. Some T cell responses will be stronger against some epitopes than others. Researchers call the targets that prompt a strong immune cells response “immunodominant.”

For the new study, the researchers examined T cells from 100 people who had recovered from SARS-CoV-2 infection. They then took a close look at the genetic sequence of the virus to separate the potential epitopes from the epitopes that these T cells would actually recognize.

Their analysis revealed that not all parts of the virus induce the same strong immune response in everyone. In fact, T cells can recognize dozens of epitopes on SARS-CoV-2, and these immunodominant sites also change from person to person. On average, each study participant had the ability to recognize about 17 CD8+ T cells epitopes and 19 CD4+ T cell epitopes.

This broad immune system response serves a few purposes. The new study shows that while the immune system often mounts a strong response against a particular site on the virus’s “spike” protein called the receptor binding domain, this region is actually not as good at inducing a strong response from CD4+ helper T cells.

Without a strong CD4+ T cell response, however, people may be slow to mount the kind of neutralizing immune response that quickly wipes out the virus. Luckily, the broad immune response comes in handy, and most people have immune cells that can recognize sites other than the receptor binding domain.

Among the many epitopes they uncovered, the researchers identified several additional epitopes on the SARS-CoV-2 spike protein. Grifoni says this is good news. By targeting many vulnerable sites on the spike protein, the immune system would still be able to fight infection, even if some sites on the virus change due to mutations.

“The immune response is broad enough to compensate for that,” Grifoni says.

Since the announcement of the fast-spreading UK variant of SARS-CoV-2 (called SARS-CoV-2 VUI 202012/01), the researchers have compared the mutated sites on that virus to the epitopes they found. Sette notes that the mutations described in the UK variant for the spike protein affect only 8% of the epitopes recognized by CD4+ T cells in this study, while 92% of the responses is conserved.

The T cells referred to are white blood cells which are part of the immune system and are mobilised in response to infections. They are produced in the bone marrow then migrate to the thymus gland where they mature and differentiate into several different types, each with a different function:

T cells are born from hematopoietic stem cells,^[1] found in the bone marrow. Then, developing T cells migrate to the thymus gland to mature. T cells derive their name from this organ where they develop (or mature).^[2] After migration to the thymus, the precursor cells mature into several distinct types of T cells. T cell differentiation also continues after they have left the thymus. Groups of specific, differentiated T cell subtypes have a variety of important functions in controlling and shaping the immune response. One of these functions is immune-mediated cell death, and it is carried out by two major subtypes: CD8+ "killer" and CD4+ "helper" T cells. (These are named for the presence of the cell surface proteins CD8 or CD4.) CD8+ T cells, also known as "killer T cells", are cytotoxic – this means that they are able to directly kill virus-infected cells, as well as cancer cells. CD8+ T cells are also able to use small signaling proteins, known as cytokines, to recruit other types of cells when mounting an immune response. A different population of T cells, the CD4+ T cells, function as "helper cells". Unlike CD8+ killer T cells, these CD4+ helper T cells function by indirectly killing cells identified as foreign: they determine if and how other parts of the immune system respond to a specific, perceived threat. Helper T cells also use cytokine signaling to influence regulatory B cells directly, and other cell populations indirectly.

Source: Wikipedia

The teams findings were published open access in Cell Reports Medicine yesterday:

Graphical Abstract

Highlights

1. T cell responses recognize at least 30-40 epitopes in each donor.
2. Immunodominance is correlated with HLA binding.
3. Immunodominant regions for CD4+T cells have minimal overlap with antibody epitopes.
4. CD8+T cells responses depend on the repertoire of HLA class I alleles

Summary

T cells are involved in control of SARS-CoV-2 infection. To establish the patterns of immunodominance of different SARS-CoV-2 antigens, and precisely measure virus-specific CD4+ and CD8+ T cells, we study epitope-specific T cell responses of 99 convalescent COVID-19 cases. The SARS-CoV-2 proteome is probed using 1,925 peptides spanning the entire genome, ensuring an unbiased coverage of HLA alleles for class II responses. For HLA class I, we study an additional 5,600 predicted binding epitopes for 28 prominent HLA class I alleles, accounting for wide global coverage. We identify several hundred HLA-restricted SARS-CoV-2-derived epitopes. Distinct patterns of immunodominance are observed, which differ for CD4+ T cells, CD8+ T cells, and antibodies. The class I and class II epitopes are combined into epitope megapools to facilitate identification and quantification of SARS-CoV-2-specific CD4+ and CD8+ T cells.

Tarke, Alison; Sidney, John; Kidd, Conner K.; Dan, Jennifer M.; Ramirez, Sydney I.; Yu, Esther Dawen; Mateus, Jose; da Silva Antunes, Ricardo; Moore, Erin; Rubiro, Paul; Methot, Nils; Phillips, Elizabeth; Mallal, Simon; Frazier, April; Rawlings, Stephen A.; Greenbaum, Jason A.; Peters, Bjoern; Smith, Davey M.; Crotty, Shane; Weiskopf, Daniela; Grifoni, Alba; Sette, Alessandro
Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases
Cell Reports Medicine Volume 0, Issue 0, 100204 DOI:10.1016/j.xcrm.2021.100204

Copyright: © 2021 The Authors. Published by Elsevir
Open access
Reprinted under a Creative Commons Attribution 4.0 – NonCommercial – NoDerivs License (CC BY-NC-ND 4.0)

As I said at the start, the bad news is that this study looked at patients who had acquired their immunity by becoming infected, not by being vaccinated, so it's not clear that this broad-scope immunity applies to vaccinated people. However, by identifying 'new' epitopes to which T cells can respond, this raises the possibility of vaccines being produced to more than just the spike proteins, maybe as a cocktail giving a broad range of responses, so minimising any risk of the virus evolving complete resistance to our antibodies.

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