Spike Fusion Polypeptides for Durable SARS-CoV-2 Immunity
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Solution Overview
Problem
Current SARS-CoV-2 vaccines face challenges with waning immunity, limited durability of protection, and inadequate response against emerging variants, while also struggling with manufacturing and distribution complexities, particularly affecting immunocompromised individuals and regions with limited accessibility.
Innovation Solution
Development of fusion polypeptides comprising a SARS-CoV-2 Spike polypeptide fragment, including the receptor binding domain (RBD) with additional domains and a heterologous N- or C-terminal tag, which are expressed in host cells and used in pharmaceutical compositions, optionally with adjuvants, to generate long-lasting antibody responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If mRNA vaccines are used to elicit high antibody titers, then initial immune response is improved, but immunity wanes quickly requiring multiple boosters
Solution Approach 1:
The patent modifies the spike protein immunogen by truncating it to specific domains (S1, S2, or CTD) and fusing it to stable protein scaffolds (GB1, fibronectin type III, or IgG Fc). These parameter changes in the protein structure enable sustained antigen presentation without the rapid waning observed with full-length mRNA spike vaccines, achieving both high initial titers and durable immunity
Solution Approach 2:
The invention creates composite protein structures by fusing spike protein fragments with stable structural domains (GB1, fibronectin type III, or IgG Fc). These composite constructs combine the immunogenicity of spike RBD with the stability and sustained expression characteristics of the scaffold proteins, resolving the contradiction between high antibody response and durable protection
2Duration of action of moving object
If viral vectored vaccines are used to provide sustained antigen levels, then durability of protection is improved, but initial antibody response is reduced
Solution Approach 1:
The patent optimizes the balance between antigen quantity and durability by selecting specific spike domains (S1, S2, or CTD) and controlling their expression from plasmid DNA. The fusion to stable scaffolds ensures sustained antigen levels while the optimized domain selection maintains high immunogenicity, achieving both strong initial response and durable protection in a single vaccine formulation
3Ease of manufacture
If full-length spike protein is used as immunogen, then manufacturing is simplified, but immune response is less potent compared to RBD-based vaccines
Solution Approach 1:
The patent segments the full-length spike protein into specific functional domains (S1, S2, or CTD) that can be independently expressed and fused to stable scaffolds. This segmentation concentrates the immune response on the most immunogenic regions (particularly RBD-containing domains) while maintaining manufacturing feasibility through modular expression systems
Solution Approach 2:
The invention modifies the spike protein by truncating it to specific domains and fusing to stable scaffolds, changing the physical and immunological parameters of the immunogen. This produces a more potent vaccine that elicits higher neutralizing antibody responses while remaining manufacturable through standard protein expression and purification techniques
4Reliability
If multiple booster doses are administered to combat waning immunity, then protection against variants is improved, but vaccine hesitancy and accessibility issues persist
Solution Approach 1:
The patent incorporates durability-enhancing features directly into the single-dose vaccine formulation through the use of stable protein scaffolds and optimized spike domains. This preliminary design ensures long-lasting immunity from the first dose, eliminating the need for multiple boosters and simplifying the vaccination regimen while maintaining robust protection against variants
Data Source
AI summary
The present disclosure describes, inter alia, fusion polypeptides comprising a SARS-CoV-2 Spike polypeptide fragment comprising at least a portion of the N-terminal domain, domains CD1, RBM, and CD2, and at least a portion of CTD1, wherein the N- or C-terminus of the Spike polypeptide fragment is fused to a heterologous N- or C-terminal tag comprising at least two, at least three, or at least four amino acids, as well as polynucleotides and vectors expressing such fusion polypeptides, pharmaceutical compositions comprising the polypeptides or polynucleotides encoding them, host cells for their production, and methods of using such pharmaceutical compositions as vaccines or for generation of antibodies.