Humanized Animal Models for B Cell Lineage Immunogen Design
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Solution Overview
Problem
Current methods are inadequate for developing effective vaccines against human pathogens as they fail to induce immunity in humans due to the mismatch between epitopes recognized by broadly neutralizing antibodies and those present on early B cell receptors, making it challenging to design suitable immunogens that can prime the human immune system to produce protective antibodies.
Innovation Solution
The use of non-human animals with humanized immunoglobulin loci to iteratively develop immunogens that can drive B cell clonal selection and mature B cells to produce broadly neutralizing antibodies, employing a process of priming and boosting with immunogen variants to identify epitopes that can induce protective immune responses in humans.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If epitopes from broadly neutralizing antibodies are used as immunogens, then antibody binding affinity is improved, but vaccine effectiveness is worsened
Solution Approach 1:
The patent applies preliminary action by using non-human animals with humanized immunoglobulin loci to pre-screen and identify immunogen variants that can effectively prime naïve B cells before human vaccination. This preliminary testing in humanized animals allows selection of immunogens that have been proven to drive B cell maturation and produce broadly neutralizing antibodies, thereby resolving the contradiction between high binding affinity and actual vaccine effectiveness
Solution Approach 2:
The patent uses non-human animals with humanized immunoglobulin loci as an intermediary system to bridge the gap between in vitro antibody binding assays and in vivo human immune responses. This intermediary model allows testing of immunogen effectiveness in a human-like immune system without exposing human subjects to potentially ineffective or unsafe immunogens, thus resolving the contradiction by identifying truly effective immunogens through the intermediary animal model
2Loss of information
If human subjects are exposed to pathogen-derived immunogens for vaccine design, then human immunogenicity data is obtained, but ethical and practical problems arise
Solution Approach 1:
The patent applies copying by creating non-human animals with humanized immunoglobulin loci that replicate the human immune response to pathogen-derived immunogens. These animal models serve as copies of the human immune system, allowing researchers to obtain human immunogenicity data without exposing actual human subjects to potentially harmful pathogens or incomplete vaccine candidates, thus resolving the ethical and practical dilemmas while preserving the ability to gather critical immunogenicity information
3Object-affected harmful factors
If non-human animal systems are used for vaccine design, then ethical safety is improved, but human immunogenicity relevance is worsened
Solution Approach 1:
The patent applies parameter changes by modifying the immunoglobulin loci of non-human animals to express human immunoglobulin genes, thereby changing the fundamental parameter of antibody specificity and immune response characteristics. This transformation makes the animal immune system more similar to the human immune system, allowing ethically safe animal studies to produce data that is highly relevant to human immunogenicity, thus resolving the contradiction between ethical safety and human relevance
Data Source
AI summary
Non-human animals with humanized immunoglobulin loci and methods of using them in vaccine design are described, as well as methods for making broadly neutralizing antibodies against infectious agents and pathogens are provided. Non-human animals with humanized immunoglobulin loci used in B-cell-lineage immunogen design in vaccine development are provided, as are methods of carrying out such design.