Accelerating malaria vaccines with a custom preclinical humanized mouse model platform

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. 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, the project will use the 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, this project has not only recapitulated the ontogeny of this potent mAb, but has also elicited variant antibodies that are even more effective in malaria challenge experiments. The intention is 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 this models, B cells bearing humanized BCRs are titrated to low levels to mimic human physiological conditions. For Aim 2, the project 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. These numbers will be used to improve the precision of our mouse platform, titrating the humanized cells to more exactingly accurate levels. Finally, in Aim 3, the immunofocusing approach will be taken 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. This mouse platform will be used 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. Our models will be enhanced 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, the intention is to cut the time needed to validate potential vaccine candidates.

Project details

Vaccines (Immune Correlates)

Mar 2022 — Feb 2027

$1.41M

United States