Accelerating Malaria Vaccines with a Custom Preclinical Humanized Mouse Model Platform

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.

Grant Number: 5R01AI168114-05
NIH Institute/Center: NIH
Principal Investigator: Facundo Batista