Accelerating Malaria Vaccines with a Custom Preclinical Humanized Mouse Model Platform

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Project Abstract There were 229 million cases of malaria in 2019, leading to 409,000 deaths; effective vaccines are a global health priority. Animal models capable of prefiguring the human immune response are a vital component of the preclinical testing of vaccines. The major goal of this proposal is to apply the Batista lab's technical innovations in the rapid generation of mice with B cells bearing human B cell receptors (BCRs) to create new platforms for malaria immunogen screening and development. Vaccines targeting the infectious sporozoite stage could inhibit the establishment of clinical malaria, and sporozoite surfaces are densely covered by circumsporozoite protein (CSP); the most advanced current vaccines in human trials display regions of this protein, and we intend to use our mouse platforms to improve their targeting. For Aim 1, we will use our existing mouse model, which expresses the inferred germline version of a potent monoclonal antibody (mAb) currently in clinical trials, CIS43. Using an immunofocused approach, presenting a conserved junctional epitope between the N-terminus and the central repeat region of CSP, we have not only recapitulated the ontogeny of this potent mAb, but have also elicited variant antibodies that are even more effective in malaria challenge experiments. We intend to deep mine this effective platform with immunizations by variable-length junctional epitope peptides to 1) identify the most promising candidate junctional epitope immunogens for inclusion in vaccine design and 2) identify protective matured antibodies with potential clinical utility. In our models, B cells bearing humanized BCRs are titrated to low levels to mimic human physiological conditions. For Aim 2, we will use the CSP full-length and partial probes we have developed for characterizing our mouse models, in tandem with single-cell sequencing, to explore the frequencies of precursor B cells in humans. We will use these numbers to improve the precision of our mouse platform, titrating the humanized cells to more exactingly accurate levels. Finally, in Aim 3, we will take this immunofocusing approach to other regions of the CSP protein by creating a new series of mice expressing the precursor sequences of human antibodies to other subdomains of CSP. We will use this mouse platform to study the immunogenicity of peptides consisting of various sections of the CSP protein, with the goal of identifying the ideal epitope, or combination of epitopes, to elicit robust immune responses. We will enhance our models by moving multiple strains of KI B cells to the same host to try immunogens against “mini-repertoires” of humanized B cells. By creating these new precision platforms for malaria, we intend to cut the time needed to validate potential vaccine candidates.