Rational design of next-generation snakebite antivenoms using cryoEM polyclonal epitope mapping

The 2024/25 application process is now closed

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Abstract	Snakebite kills >100,000 people each year and antivenom is the only effective treatment. There is an urgent need to improve these therapeutics as they exhibit low dose efficacy, limited snake species cross-reactivity and high incidences of adverse reactions. In this project, we will apply a new technological approach, called cryoEM polyclonal epitope mapping to identify, for the first time, the conserved, conformational epitopes on venom toxins that mediate cross-reactivity of antivenoms. Using Echis saw-scaled vipers as a model, we will then perform antibody discovery against consensus toxins that contain these identified conformational epitopes. We will use phage-display approaches to discover nanobodies against the most pathogenic toxin families, and then we will test the ability of the recovered nanobodies to bind to and inhibit the venom toxins. We anticipate the antibodies recovered in this project will have desirable dose efficacy compared with existing antivenom therapy, and could form the basis of future snakebite treatments.
Where does the project lie on the Translational Pathway?	T1 – Basic Research
Expected Outputs	Aside from the technical skills training, the expected outputs for this project will be high-impact papers due to the novelty of the project, potentially intellectual property leading to patent applications relating to the future design of a diagnostic device, and new tools that could be readily impactful for measuring snakebite envenoming in future clinical trials and studies.
Training Opportunities	The student will be exposed to a wide variety of research training opportunities, as they will join a well-funded, multi-disciplinary and dynamic team of post docs, students and technicians. Thus, they will have an opportunity to acquire additional clinical and lab skill sets to those described below: Full training in a range of in vitro and in in vivo antibody discovery and validation techniques Training in recombinant engineering of bacteria and mammalian cells for protein production will be provided Training in in vitro assays of toxin activity Training in cryoEM to solve structures of venom toxins and epitope mapping
Skills Required	We expect the student to possess strong organisational and project solving aptitude. The student would benefit from basic skills in molecular biology and in vitro assays. Skills in protein production, antibody discovery and/or structural biology would be beneficial, however, these are not essential as we will provide in-depth training in all techniques.
Key Publications associated with this project	Ahmadi et al (2020) An in vitro methodology for discovering broadly-neutralizing monoclonal antibodies DOI: 10.1038/s41598-020-67654-7
	Casewell et al (2010) Pre-clinical assays predict pan-African Echis viper efficacy for a species-specific antivenom https://doi.org/10.1371/journal.pntd.0000851
	Hooft van Huijsduijnen R, Kojima S, Carter D, Okabe H, Sato A, et al. (2020) Reassessing therapeutic antibodies for neglected and tropical diseases. PLOS Neglected Tropical Diseases 14(1): e0007860. https://doi.org/10.1371/journal.pntd.0007860
	Antanasijevic et al (2022) From structure to sequence: Antibody discovery using cryoEM DOI: 10.1126/sciadv.abk2039
	Antanasijevic et al (2021) Polyclonal antibody responses to HIV Env immunogens resolved using cryoEM DOI: 10.1038/s41467-021-25087-4
LSTM Themes and Topics – Key Words	Neglected tropical diseases and Snakebite