Chimeric Polyepitope RNA Vaccine for CD8+ T Cell Activation
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Solution Overview
Problem
Existing vaccines against SARS-COV-2 and related coronaviruses often induce antibody-dependent enhancement (ADE) and do not effectively stimulate long-lasting cellular immune responses, particularly CD8+ T cell responses, which are crucial for protection against severe disease.
Innovation Solution
A chimeric nucleotide sequence encoding a polyepitope comprising multiple epitopes from non-structural proteins of SARS-COV-2, aligned with a modified form of glycoprotein D (gD) of herpes simplex type 1, designed to induce both humoral and cellular immune responses, including CD8+ T cell activation, using expression vectors and RNA constructs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing vaccines target the spike protein to induce humoral immunity, then antibody response is improved, but antibody-dependent enhancement (ADE) occurs and cellular immune response is insufficient
Solution Approach 1:
The vaccine divides the immunogenic components into multiple distinct epitopes from different coronavirus proteins (spike, envelope, membrane, nucleocapsid, and non-structural proteins) rather than using a single spike protein antigen. This segmentation allows the vaccine to induce broad humoral immunity against multiple viral proteins while reducing the risk of ADE that occurs with spike protein-only vaccines.
Solution Approach 2:
The vaccine merges multiple epitopes from different coronavirus proteins into a single chimeric nucleotide sequence that encodes a polyepitope. This combination approach enables simultaneous induction of humoral immunity against multiple viral antigens and cellular immunity through CD8+ T cell activation, while avoiding the ADE phenomenon associated with spike protein-only vaccines.
2Reliability
If vaccines focus on inducing antibody response, then humoral immunity is improved, but long-lasting cellular immune response (CD8+ T cell) is insufficient
Solution Approach 1:
The vaccine combines multiple epitopes from both structural and non-structural coronavirus proteins into a single chimeric construct. This merging strategy enables simultaneous induction of humoral immunity through antibody production and long-lasting cellular immunity through CD8+ T cell activation, as evidenced by the presence of epitopes from proteins involved in different viral functions and cellular pathways.
Solution Approach 2:
The vaccine changes the immunogenic parameters by including epitopes from non-structural proteins (ORF1ab replicase polyprotein) in addition to structural proteins. This parameter change expands the immune response profile to include both humoral immunity and sustained cellular immunity, as non-structural proteins elicit different immune pathways compared to traditional spike protein-only vaccines.
3Adaptability or versatility
If vaccines use multiple epitopes from different coronavirus proteins, then broad-spectrum immune protection is improved, but vaccine complexity increases
Solution Approach 1:
The vaccine merges multiple epitopes from different coronavirus proteins (spike, envelope, membrane, nucleocapsid, and non-structural proteins) into a single chimeric nucleotide sequence. This merging approach achieves broad-spectrum immune protection against multiple viral antigens while simplifying the vaccine structure compared to using separate vaccine components for each protein, as all epitopes are encoded in one integrated construct.
4Reliability
If vaccines target non-structural proteins like replicase polyprotein, then cellular immune response is improved, but manufacturing complexity increases
Solution Approach 1:
The vaccine combines epitopes from non-structural proteins (ORF1ab replicase polyprotein) with structural proteins in a single chimeric nucleotide sequence. This merging strategy enables the production of a vaccine that induces strong cellular immune responses through non-structural protein epitopes while maintaining ease of manufacture, as the entire polyepitope is encoded in one integrated genetic construct that can be produced using standard recombinant DNA technology.
Data Source
AI summary
A chimeric nucleotide sequence that corresponds to an encoded fusion protein comprising a polyepitope resulting from selecting and juxtaposing multiple epitopes from a coronavirus protein to induce an immune response in mammals. In one embodiment, said fusion protein comprises: a) a first peptide consisting of epitopes found in the amino acid sequence of replicase polyprotein 1ab (PR1ab); b) a first spacer; c) a modified form of herpes simplex virus type 1 (HSV-1) glycoprotein D (gD). In one embodiment, the replicase polyprotein is defined by SEQ ID NO: 96 flanked by a gD fragment comprising the amino acid sequence defined by SEQ ID NO: 98 in the N-terminal portion and another gD fragment comprising the amino acid sequence defined by SEQ ID NO: 100 in the C-terminal region. Use of the fusion protein has surprising results in inducing cellular and humoral immune responses against coronavirus, SARS-COV-2, and related viruses.