The National Institute of Allergy and Infectious Diseases (NIAID) is supporting efforts to develop a recombinant subunit vaccine against the Category B agent ricin toxin. The current focus is on the toxin's 267- amino acid enzymatic A subunit (RTA). To date, vaccine design has been aimed at making point mutations and site-specific deletions in RTA to attenuate its enzymatic activity so that it is safe for use in humans. Very little attention has been paid to how these mutations may affect B-cell epitopes on RTA that are critical for eliciting protective immunity. It is known that neutralizing antibodies consttute only a very small fraction of the total antibody pool elicited by RTA immunization. The overwhelming antibody response is made up of non- neutralizing and toxin-enhancing antibodies. This fact may explain the relative ineffectiveness of the current lead vaccine candidate to elicit detectable serum neutralizing activity despite high titer anti-toxin antibodies Because serum neutralizing antibody titers are the singular correlate of immunity to ricin, it is essential that RTA-based subunit vaccine stimulate measurable serum neutralizing activities. Unfortunately, in the absence of a comprehensive B-cell epitope map of RTA it is not possible to engineer derivatives RTA in which key protective B-cell epitopes are preserved, while epitopes that give rise to non-neutralizing (or even deleterious) antibodies are eliminated. This applicatio proposes to generate a comprehensive and high-resolution B-cell epitope map of RTA. This will be accomplished using a unique collection of resources, including a large panel of RTA-specific mAbs, as well as a collection of RTA derivatives with mutations in all of the known immunodominant regions of the protein. The proposed research project is significant in that the resulting B-cell epitope map will be used in conjunction with the available structural information about RTA to design novel antigens in which targets of neutralizing antibodies are preserved and presented in a context designed to most effectively elicit protective immunity.

Public Health Relevance

The proposed project will aid in the development of a vaccine against ricin toxin, one of the most deadly toxins known to mankind, and a potential biothreat agent.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Research Grants (R03)
Project #
1R03AI097688-01A1
Application #
8301906
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
Baqar, Shahida
Project Start
2012-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
1
Fiscal Year
2012
Total Cost
$67,754
Indirect Cost
$17,754
Name
Wadsworth Center
Department
Type
DUNS #
153695478
City
Menands
State
NY
Country
United States
Zip Code
12204
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Herrera, Cristina; Vance, David J; Eisele, Leslie E et al. (2014) Differential neutralizing activities of a single domain camelid antibody (VHH) specific for ricin toxin's binding subunit (RTB). PLoS One 9:e99788
O'Hara, Joanne M; Kasten-Jolly, Jane C; Reynolds, Claire E et al. (2014) Localization of non-linear neutralizing B cell epitopes on ricin toxin's enzymatic subunit (RTA). Immunol Lett 158:7-13
Yermakova, Anastasiya; Klokk, Tove Irene; Cole, Richard et al. (2014) Antibody-mediated inhibition of ricin toxin retrograde transport. MBio 5:e00995
Yermakova, Anastasiya; Mantis, Nicholas J (2013) Neutralizing activity and protective immunity to ricin toxin conferred by B subunit (RTB)-specific Fab fragments. Toxicon 72:29-34
O'Hara, Joanne M; Mantis, Nicholas J (2013) Neutralizing monoclonal antibodies against ricin's enzymatic subunit interfere with protein disulfide isomerase-mediated reduction of ricin holotoxin in vitro. J Immunol Methods 395:71-8
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