Rational design and characterization of a conformationally stabilized next-generation immunogen against Malaria

Malaria is a global health concern and increasing resistance to current interventions has amplified the need for a potent vaccine. Antibodies (Abs) targeting circumsporozoite protein (CSP), a protein coating the surface of malaria parasites that mediates infection, facilitate protection in animal models against malaria. In fact, the current leading malaria vaccine candidate induces protective human Abs against CSP upon vaccination. However, this vaccine provided only 30-50% short-lived protection against malaria in children. Thus, a better vaccine is needed. One strategy to improve the potency of the antibody response elicited by a vaccine is to computationally design proteins that will display antibody-binding targets such that these segments are readily accessible for the immune system to mount an antibody response against them. This strategy has been used and tested against respiratory syncytial virus (RSV) whereby monkeys were protected from infection by protective Abs induced by computationally designed proteins presenting a site of vulnerability from the viral particle. To improve the duration of the antibody response, these molecules can be linked to the surface of a spherical delivery platform such that numerous copies are readily presented to the immune system. The plan is to apply these techniques to malaria by developing proteins that display the protective antibody-binding targets of CSP to the immune system and linking them to a spherical delivery platform. This will be achieved using Rosetta, a robust computational software that was also used to design the aforementioned RSV-targeted proteins. Based on computer-generated scores and manual inspection, after selecting promising candidates to be produced and tested in the lab to ensure that antibody binding occurs as intended during the design. Finally, our international team will evaluate our top designed proteins in immunization experiments and an in-depth study of the immune response elicited in mice.

Enabling Technologies & Assays
Product Development

May 2021 — Apr 2024

$79,000

Canada