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The COVID-19 pandemic is still creating economic and health-related impact over the world. A new study published on the preprint server bioRxiv in August 2020 shows that a gp96-Ig-secreting vaccine candidate based on the expression of full-length spike protein generates a potent T cell response. The spike or S protein of SARS-CoV-2 is still the best choice for a COVID-19 vaccine as it is both abundantly present and highly immunogenic. Antibodies against this protein neutralize the binding of the virus to the mammalian host cell. However, the presence of glycosylated residues shields the antibody from being able to neutralize the virus properly. Moreover, antibody decay has been shown to occur in recovering individuals, even more rapidly than with the earlier SARS outbreak. T cells are responsible for robust and long-lasting immunity as they induce the formation of memory cells to protect against viral infection, and these cells persist for years rather than the short-lived memory B-cells induced by SARS-CoV-2. Most recovered COVID-19 patients show specific CD8+ T cells. There is a specific subpopulation of tissue-resident memory (TRM) cells, which can respond rapidly to tissue infection without being primed in the lymph nodes. These have the marker molecules CD69 and CXCR620, while interactions between CXCR6-CXCL16 regulate the localization and number of these specific T cells in the lungs. These cells are essential in virus clearance. The researchers, therefore, aimed to generate TRM, since their persistence may lead to improved immunity compared to antibody-only responses.
The Novel Vaccine Candidate
The researchers used a genetically engineered gp96 construct, called the fusion protein gp96-Ig. Here, they replaced the C-terminal KDEL-retention sequence with the Fc portion of immunoglobulin G1 (IgG1). This fusion protein was encoded inside a plasmid vector that is transfected into a cell line for study. The cell line secretes the gp96-Ig. This protein complexes with the antigenic peptides so that the antigens derived from the cell are specifically cross-presented by gp96-Ig in vivo. The most significant benefit of this approach is its ability to allow any viral peptide that is bound to gp96 to produce a durable and potent response.
T Cell Induction
Previous research by the same team has shown, over 20 years, the immunogenic potential of gp96-Ig, whether from an allogeneic or xenogeneic cell primed with the specific antigen, to produce potent and specific T cells against multiple viral antigens. They adapted this technology to show its suitability for vaccine production to induce T cell immunity in lungs, airways, and other relevant epithelial sites Secondly, this technology can work in synchrony with other therapies or vaccines, either as a booster or as a second line of defense, and is amenable to large-scale manufacture. This technology has already been validated in animal and human experiments. This induces protein-specific CD8+ and CD4+ T helper 1 (Th1) responses against tumors, various viruses like HIV and Zika, and malaria, in various models. It not only delays virus infection but also improves the survival of patients with non-small cell lung cancer in clinical trials.
How the gp96-Ig Vaccine Works
The principle of this cell-based vaccine is that gp96-Ig can chaperone protein antigens for efficient endocytosis, allowing them to be cross-presented by activated antigen-presenting dendritic cells to CD8+ T cells, which causes an avid, specific T cell response. This technology was used to create a vaccine that actually brings the spike protein straight to the dendritic cells.
As a result of such a presentation, the primed and activated T cells, specifically targeting the viral S protein can now detect and kill the lung epithelial cells that are infected by SARS-CoV-2.
The gp96-Ig platform is an endoplasmic reticulum chaperone protein that participates in the transfer of antigenic peptides from the cytosol to MHC class I molecules in an orderly fashion. The complexes formed by gp96-antigen binding are mostly internalized by subsets of antigen-presenting cells that have the CD91 receptor on the surface. Once gp96 is internalized, it can present the complex antigens to MHC I and II molecules, helping to activate specific CD4 and CD8 T cells...
Preprint available in bioRxiv (August 24, 2020):
