Current COVID-19 vaccines induce neutralizing antibodies that can inhibit viral entry, but their efficiency decreases when new variations arise. On the basis of short peptide epitopes that stimulate CD8+ and CD4+ T cell responses, scientists have created a new mRNA-LNP (Lipid nanoparticle) vaccine called MIT-T-COVID. Researchers evaluated this novel vaccination on mice infected with the virus’s Beta variant. They discovered that the vaccine significantly increased the amount of T cells in the mice’s lungs. The vaccination does not rely on the production of antibodies, therefore, it may be effective for individuals who cannot produce antibodies or who have Long COVID.
Strategy for protection against future variants
Modern COVID-19 vaccine development techniques rely mostly on portions of the SARS-CoV-2 Spike protein to stimulate the generation of neutralizing antibodies capable of preventing viral entry into cells. Unfortunately, this strategy is restricted since the Spike protein is prone to changes, leading to novel viral variants that may avoid current vaccines. While existing multivalent Spike vaccinations and booster injections can give protection against certain known variants of the virus, they may not be effective against future variants that have not yet been identified.
To address this issue, a novel vaccine strategy is being developed that employs conserved T cell epitopes from the whole viral proteome to defend against future variants. T cell epitopes are small protein fragments that can activate T cells, which then kill infected cells. These epitopes can be isolated from any immunogenic and stable portion of the virus. Stability can be anticipated by evaluating historical data from hundreds of viral variants, by structural analysis, or by analyzing lethal mutations.
The novel vaccine approach chooses a group of very stable epitope candidates for the development of a T cell vaccine that can protect against a wide variety of human MHC class I and class II haplotypes. This technique tries to enhance population coverage by guaranteeing that every vaccinated individual would, on average, experience numerous immunogenic peptide-HLA hits, where HLA is the human leukocyte antigen, a protein that helps the immune system distinguish between self- and non-self proteins.
T cell response in transgenic mice
The immunogenicity of MIT-T-COVID was investigated in HLA-A*02:01 transgenic mice. The researchers discovered that immunization with MIT-T-COVID increased CD8+ and CD4+ T lymphocytes that released interferon-gamma (IFN-ฮณ) or tumor necrosis factor-alpha (TNF-ฮฑ) in response to vaccine epitopes. In contrast, immunization with Comirnatyยฎ, a COVID-19 vaccine presently in use, did not result in substantial T-cell responses to vaccine epitopes.
The study also revealed that the immunogenicity of MIT-T-COVID epitopes differed between convalescent COVID patients and transgenic mice, providing evidence for the utilization of several epitopes per MHC diplotype for n-fold coverage. The MIT-T-COVID vaccine dramatically enhanced CD8+ T cells that are activated by the CD8-4 and CD8-8 epitopes and CD4+ T cells that are activated by the CD4-2 epitope.
The study found no significant increase of regulatory T cells (Treg) in either MIT-T-COVID- or Comirnatyยฎ-immunized mice, suggesting that immunization did not enlarge Treg cells that could induce tolerance.
Comirnatyยฎ and MIT-T-COVID
To evaluate the effectiveness of various vaccinations in guarding against the virus, mice were infected with SARS-CoV-2 and then studied. Animals were placed into three groups: those inoculated with the Comirnatyยฎ vaccine, those immunized with the MIT-T-COVID vaccine, and those given a placebo (PBS).
When mice were exposed to the virus, both the Comirnatyยฎ and MIT-T-COVID vaccinations provided protection against weight loss and poor clinical performance. The MIT-T-COVID-immunized mice began to recover on day 4, but the PBS control group did not. The Comirnatyยฎ vaccine protected the mice from severe weight loss and poor clinical ratings.
When the quantity of infectious progeny virus was evaluated at two days post-infection, the mice inoculated with the MIT-T-COVID vaccine had a 3.6-fold reduction in viral replication compared to the PBS control, but the Comirnatyยฎ vaccine fully stopped the reproduction of the infectious virus. At seven days post-infection, however, the infectious virus titer was not significant for any of the test items.
All Comirnatyยฎ and MIT-T-COVID-immunized mice survived to 7 days post-infection before the trial was terminated, with the difference in clinical ratings between the two vaccine groups becoming inconsequential. In comparison, four out of five PBS control mice were terminated due to weight reduction > 20%. Compared to the PBS-inoculated control, the survival of all five mice immunized with Comirnatyยฎ and the MIT-T-COVID was significantly higher.
Immune responses among the mice
The researchers analyzed lung samples from mice from all three categories and conducted immunohistochemistry staining to detect the presence of the SARS-CoV-2 spike protein and CD8+ and CD4+ T cells.
The results demonstrated that both the PBS and MIT-T-COVID vaccines initially caused large viral infections in the lungs, but by seven days after immunization, the viral infection had considerably decreased in both extent and intensity. In contrast, the Comirnatyยฎ vaccine dramatically decreased viral infections at both 2 and 7 days after immunization, with viral antigen unreported at both time points in Comirnatyยฎ-immunized animals.
Mice immunized with the MIT-T-COVID vaccine had substantial lymphocytic infiltrations in perivascular areas, whereas mice immunized with Comirnatyยฎ or PBS displayed fewer infiltrations. In addition, congestion, bleeding, and thromboembolism were seen only in the lungs of mice inoculated with Comirnatyยฎ.
The Comirnatyยฎ vaccine was, to some extent, the most efficient at preventing viral infection in the lungs. Nevertheless, it also induced congestion, bleeding, and thrombosis in the lungs and less CD8+ T cell infiltration than the MIT-T-COVID vaccine.
Conclusion
The researchers developed a T cell vaccine dubbed “MIT-T-COVID” that has 11 short T cell epitopes that are identical across 22 known variants of the COVID-19 virus. They tested the vaccine on mice and found that it gave significant protection against severe COVID-19 illness induced by the Beta version of the virus. The vaccine resulted in a considerable infiltration of immune cells in the lungs following infection, which is a positive indicator of immunity. The researchers believe that T-cell vaccines may be more successful than spike-based vaccinations, which rely on the virus’s spike protein. Even in those with compromised antibody responses, T-cell vaccinations may offer protection against the virus.
Article Source: Reference Paper
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Sejal is a consulting scientific writing intern at CBIRT. She is an undergraduate student of the Department of Biotechnology at the Indian Institute of Technology, Kharagpur. She is an avid reader, and her logical and analytical skills are an asset to any research organization.
