Stabilized Rabies Glycoprotein Trimer for Durable Immunity
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Solution Overview
Problem
Current rabies vaccines do not elicit long-term immune responses due to the heterogeneity of rabies virus glycoprotein (RabvG) conformations, leading to frequent booster shots and high costs, especially in low-income countries where treatment is often unavailable or unaffordable.
Innovation Solution
Development of a recombinant rabies virus glycoprotein with specific mutations (His20Met, His261Gln, Tyr77Ala, and Ser289Leu) that stabilizes the pre-fusion conformation, allowing for the formation of a glycoprotein trimer recognized by neutralizing antibodies, which is used in vaccine compositions to induce a robust and lasting immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If inactivated rabies virus vaccines are used, then antibody response is elicited, but the immune response is not long-lasting requiring frequent boosters
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid substitutions (H20M, H261Q, Y77A, S289L) into the RabvG protein sequence. These mutations stabilize the pre-fusion conformation of the glycoprotein, preventing conformational heterogeneity and enabling the immune system to generate a more durable antibody response that persists longer without requiring booster shots.
Solution Approach 2:
The invention applies local quality by making targeted modifications at specific positions within the RabvG protein structure. Rather than changing the entire protein, precise amino acid substitutions are introduced at key locations (positions 20, 77, 261, and 289) to stabilize the pre-fusion conformation locally, which then propagates to enhance the overall immunogenicity and durability of the vaccine response.
2Reliability
If multiple vaccine doses and antiviral antibodies are administered, then effective protection is achieved, but the cost becomes prohibitively expensive
Solution Approach 1:
By changing the amino acid parameters of RabvG to stabilize the pre-fusion conformation, the vaccine requires fewer doses to achieve effective protection. The enhanced stability and immunogenicity of the mutated glycoprotein reduce the need for multiple administrations and expensive antiviral antibody cocktails, thereby lowering the overall quantity of substances required and reducing costs.
3Adaptability or versatility
If RabvG transitions between pre-fusion and post-fusion conformations, then natural immune response occurs, but heterogeneity prevents long-lasting immunity
Solution Approach 1:
The patent changes the structural parameters of RabvG through specific amino acid mutations that lock the protein in the pre-fusion conformation. This prevents the natural transition to post-fusion states and eliminates conformational heterogeneity, allowing the immune system to focus on generating antibodies against a single, stable antigenic structure, thereby producing long-lasting immunity.
Solution Approach 2:
Instead of allowing the natural conformational transition from pre-fusion to post-fusion that occurs in wild-type RabvG, the invention inverts the approach by stabilizing the pre-fusion state through mutations. This prevents the harmful conformational switching and maintains the antigen in its most immunogenic form throughout the vaccine's persistence in the body.
Data Source
AI summary
Provided herein are, inter alia, methods and compositions for treating and preventing rhabdoviridae infection, including rabies virus. Compositions include recombinant rabies virus glycoproteins that are able to form glycoprotein trimers. The glycoprotein trimers are contemplated to be effective for preventing and/or treating rabies virus infections, including for use in the formulation of rabies virus vaccine compositions.