Stabilized Spike Antigen Using CS-DVA for Fixed RBD Conformation
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Solution Overview
Problem
Current COVID-19 vaccines based on the Spike glycoprotein face challenges due to the flexible and dynamic nature of the RBD, which affects immunogenicity and neutralization potential, necessitating the development of a stable and effective vaccine that can induce robust immune responses.
Innovation Solution
Development of a stabilized spike antigen that forces the RBD into a 100% all-up conformation, utilizing Conformational Shifting by Distance and Volume Analysis (CS-DVA) to alter glycoprotein dynamics, combined with nucleic acid molecules encoding the stabilized spike antigen, which can be administered with or without nanoparticles and adjuvants to enhance immunogenicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the Spike glycoprotein is used as an immunogen, then the vaccine can mediate receptor recognition and host cell entry, but the flexible and dynamic nature of the RBD reduces immunogenicity and neutralization potential
Solution Approach 1:
The patent applies parameter changes by modifying the RBD sequence at specific positions (e.g., Q494K, L497F, L498F) to alter the conformational dynamics of the protein. These sequence parameter changes force the RBD into a stable 'up' conformation, transforming the flexible dynamic structure into a stable immunogen that maintains consistent binding geometry for enhanced immune recognition and neutralization.
Solution Approach 2:
The patent implements preliminary action by pre-stabilizing the RBD in the desired 'up' conformation before it is presented to the immune system. The engineered mutations are designed in advance to lock the RBD in the optimal binding pose, so that when the vaccine is administered, the RBD is already in the correct conformation for effective neutralization, eliminating the need for conformational selection during the immune response.
2Adaptability or versatility
If the RBD is kept flexible to maintain dynamic configurations, then the virus can adapt to different host cells, but the immune system cannot effectively neutralize the virus
Solution Approach 1:
The patent applies the inversion principle by reversing the natural dynamic behavior of the RBD. Instead of allowing the RBD to fluctuate between multiple conformations to adapt to different host cells, the invention locks the RBD into a single stable 'up' conformation. This inverted approach sacrifices viral adaptability to gain immune system effectiveness, as the fixed conformation provides consistent epitopes for neutralizing antibodies.
Solution Approach 2:
The patent applies local quality by making specific localized changes to the RBD sequence at critical positions while maintaining the overall structure. The mutations are targeted specifically at residues involved in conformational dynamics (e.g., positions 494, 497, 498), allowing local stabilization without affecting the global function of the Spike protein. This localized modification creates a stable RBD that maintains its binding capability while resisting neutralization.
3Ease of manufacture
If conventional Spike proteins are used in vaccines, then the vaccine development process is straightforward, but the immunogenicity is insufficient due to RBD dynamics
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid mutations at defined positions in the RBD sequence. These changes are made during the protein expression process, allowing the stabilized RBD to be produced using standard recombinant protein technology. The mutations are incorporated into the coding sequence, and the resulting protein is expressed and folded normally, maintaining ease of manufacture while enhancing immunogenicity through the stabilized conformation.
Data Source
AI summary
Disclosed herein is a new method referred to as Conformational Shifting by Distance and Volume Analysis (CS-DVA) which can be employed to change the dynamics of multi-state glycoproteins for altered immune responses. Also disclosed are stabilized spike antigens and methods of use thereof for SARS-COV-2 vaccines.