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Genetically Engineered Mice for Pre-clinical Evaluation of HIV Vaccine Candidates


Fast Track Proposals will be accepted. Direct to Phase II will not be accepted. Number of anticipated awards: 1-3 Budget (total costs): Phase I: $300,000 for up to 1 year; Phase II: $2,000,000 for up to 3 years. Background The development of novel HIV candidate vaccines generally requires preclinical testing in animal models before proceeding to Phase I clinical trials. Multiple efforts have focused on developing and evaluating innovative platforms and formulations of HIV envelope (Env) immunogens for the induction and generation of a durable and broadly neutralizing antibody (bNAb) response. Progress has been hampered, in part, due to the lack of an iterative, physiologically relevant, small animal model to test novel HIV vaccine candidates, concepts, and formulations that elicit bnAbs. Human immunoglobulin (IgG) gene knockin (KI) technology has been used to engineer mice with relevant pre-rearranged V(D)J exons of mature bnAbs or unrearranged human V, D, and J segments to generate the desired bNAb lineage. There is a need for methodological improvements of existing KI models and creation of new lines using current state-of-the-art, e.g., genome editing technologies. Several limitations due to immune tolerance mechanisms in mice need to be overcome. Humanized mice may express B cell precursors of the desired bNAb germline lineage at more variable frequencies than found in humans; other germline genes may not be functionally expressed due to the inability to overcome B cell tolerance mechanisms, yet others may be lethal to the mouse line. Existing mouse lines and novel improved second-generation human immunoglobulin KI mice or those generated by crossbreeding to other transgenic mice expressing relevant immunological receptors may Page 105 expedite translation of HIV vaccine concepts. Such strains could be used to rapidly test, for instance, HIV vaccination strategies, contribution of B cell precursor frequencies to elicit a robust bNAb response, factors that modulate B cell dominance and sub-dominance, affinity maturation (AM), somatic hypermutations (SHM), and factors that drive germinal center responses. This topic will focus on evaluating proof-of-concept HIV vaccine strategies in existing KI models or in newly created next-generation KI and transgenic mice to accelerate translation of HIV vaccine candidates for testing in Phase I clinical trials. Project Goal The goal of this project is to utilize genetically engineered mouse models, such as human immunoglobulin KI or other transgenic mice expressing relevant human genes, to accelerate testing and development of HIV vaccine candidates. Genetically engineered mice expressing human genes, for example, V(D)J immunoglobulin genes, Fc receptors, and/or other protein receptors on diverse cell types and further modified with gene-editing technologies, such as CRISPR-Cas, should offer an iterative, robust, small animal platform for rapidly testing HIV vaccine immunogens and formulations. Such models may lead to the generation of a flexible preclinical model that more accurately reflects the human humoral immune response. Ultimately, development of a predictive in vivo small animal model could accelerate testing of novel HIV vaccine concepts into Phase I clinical trials. Phase I activities may include, but are not limited to: • Investigation of proof-of-concept HIV vaccine studies in existing KI models that express human IgG germline genes of bnAbs, e.g., unmutated common ancestors of HIV bnAbs lineage • Modulation of the human B cell repertoire in existing KI models to elicit a bNAb response to HIV vaccine immunogens and particle-based HIV vector platforms • Determination of mechanism(s) required to elicit a bNAb response to HIV vaccine candidates • Determination of in vivo factors contributing to a weak humoral response, e.g., B cell tolerance, anergy, clonal deletion, sub-dominance • Identification of immunogen platforms that will elicit a rapid, robust, and durable humoral response in the mouse model • Measurement of neutralizing bnAbs of B cell lineages and other functions (e.g., non-neutralizing) of antibodies in response to HIV immunogens • Testing antibody-antigen and adjuvant formulations that promote successful B cell responses during vaccination • Evaluating the performance, effectiveness, and toxicity of particulate HIV vaccine candidates versus soluble antigens in KI models • Investigating the effects of route of immunization, dose, dosage form, and dose-sparing capacity of particulate formulations on the particle distribution and kinetics of the immune response to the immunogen Phase II activities may include, but are not limited to: • Creation and development of next-generation pre-clinical genetically engineered mouse model(s) for the rapid evaluation of HIV vaccine candidates and testing immunogen-guided bNAb lineage HIV vaccine concepts • Rapid creation of novel lines of human IgG KI models by crossbreeding with other transgenic mice expressing relevant human genes to enhance bnAbs to HIV immunogens • Testing proof of concept studies, outlined as Phase I activities, in next-generation, novel KI models • Characterization, genotyping, and detailed phenotyping of new mouse models associated with existing mouse strains and made publicly available, if applicable • Ensure availability of the newly created mouse models to academic, government, and private sector scientists, for example through NIH-supported mouse repositories • Creation of the cryopreserved archive for all new strains of mice, to enable storage of strains, for which there is no immediate need and serve as a backup supply of pathogen-free and genetically stable genetically engineered strains • Establishment of a live, specific pathogen-free colony for research use and distribution for a mouse strain upon request (Animal genotype should be verified, and health and disease status should be assessed.) • Maintenance of the breeding colonies to be conducted using standard breeding schemes appropriate to the strain, with maintenance of pedigree records • Maintenance as a live breeding colony for several months, if needed, after which it is retired to the cryopreserved archive if no further use or interest is expressed or if no orders are received. This SBIR will not support: • The design and conduct of clinical trials (see for the NIH definition of a clinical trial) • Testing non-HIV immunogens or studies unrelated to HIV vaccine development efforts • Humanized mouse models engrafted with human cells or human fetal tissue (such as hu-PBL, hu-CD34, and BLT mice) Page 106 • Investigation of transplantation, autoimmune diseases, allergic diseases, other immune-mediated diseases, and cancer
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