Ricin toxin (RT) is classified by the National Institute of Allergy and Infectious Diseases (NIAID) as an Emerging Infectious Disease Priority Pathogen. NIAID and the Department of Defense are each supporting efforts to develop an effective RT subunit vaccine. A major roadblock to developing RT vaccines is the absence of a functional preclinical assay to predict efficacy in humans. While it is well established that immunity to RT is mediated by antibodies, the immune response against ricin toxin A subunit (RTA)-based antigens consists predominantly (>90%) of non-neutralizing antibodies. Indeed, detailed functional and structural analyses of RTA-specific murine and camelid monoclonal antibodies (MAbs) has revealed that toxin-neutralizing activity (TNA) is associated a very limited number of B epitope ?clusters? on the surface of RTA. Conventional cell-based cytotoxicity assays are not sufficiently sensitive to detect the small fraction of toxin-neutralizing antibodies responsible for protective immunity. From the standpoint of vaccine development, it is critical to develop a more sensitive and direct assay to measure serum antibodies against the key protective epitopes. Therefore, the goal of this program is to develop a preclinical ELISA-based competition assay that will predict the efficacy of RT subunit vaccines in humans.
Aim 1 will e stablish a prototype competition ELISA-based assay that identifies a serum antibody profile associated with protective immunity against RT.
Aim 2 will qualify the competition ELISA-based assay in a NHP model to define antibody profile that is associated with protection against aerosolized RT. Finally, Aim 3 will validate the competition ELISA using human sera from Phase I and II studies. As part of this program we will establish the link between MAb competition and protective immunity, with the expectation that the ability to measure epitope-specific neutralizing antibody responses will constitute a major advance in assessing the efficacy of candidate RT subunit vaccines in humans.

Public Health Relevance

The proposed research program will advance technologies required for the development of vaccines for protection against bioterrorism agents and toxins, which constitute a threat to the United States public and the military.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI125190-03
Application #
9477455
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Baqar, Shahida
Project Start
2016-05-01
Project End
2021-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Wadsworth Center
Department
Type
DUNS #
153695478
City
Menands
State
NY
Country
United States
Zip Code
12204
Westfall, Jennifer; Yates, Jennifer L; Van Slyke, Greta et al. (2018) Thermal stability and epitope integrity of a lyophilized ricin toxin subunit vaccine. Vaccine 36:5967-5976