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Endpoint and Epitope-specific Antibody Responses as Correlates of Vaccine-mediated Protection of Mice against Ricin Toxin

Greta Van Slyke, Dylan J Ehrbar, Jennifer Doering, Jennifer L. Yates, Ellen S.Vitetta, Oreola Donini, View ORCID ProfileNicholas J Mantis
doi: https://doi.org/10.1101/2020.05.06.081174
Greta Van Slyke
1Division of Infectious Disease, Wadsworth Center, New York State Department of Health, Albany, NY 12208
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Dylan J Ehrbar
1Division of Infectious Disease, Wadsworth Center, New York State Department of Health, Albany, NY 12208
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Jennifer Doering
1Division of Infectious Disease, Wadsworth Center, New York State Department of Health, Albany, NY 12208
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Jennifer L. Yates
1Division of Infectious Disease, Wadsworth Center, New York State Department of Health, Albany, NY 12208
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Ellen S.Vitetta
2Department of Immunology and Microbiology, University of Texas Southwestern Medical School, Dallas, TX
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Oreola Donini
3Soligenix, Inc., Princeton, NJ, 08540
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Nicholas J Mantis
1Division of Infectious Disease, Wadsworth Center, New York State Department of Health, Albany, NY 12208
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  • ORCID record for Nicholas J Mantis
  • For correspondence: nicholas.mantis@health.ny.gov
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ABSTRACT

The successful licensure of vaccines for biodefense is contingent upon the availability of well-established correlates of protection (CoP) in at least two animal species that can then be applied to humans, without the need to assess efficacy in the clinic. In this report we describe a multivariate model that combines pre-challenge serum antibody endpoint titers (EPT) and values derived from an epitope profiling immune-competition capture (EPICC) assay as a predictor in mice of vaccine-mediated immunity against ricin toxin (RT), a Category B biothreat. EPICC is a modified competition ELISA in which serum samples from vaccinated mice were assessed for their ability to inhibit the capture of soluble, biotinylated (b)-RT by a panel of immobilized monoclonal antibodies (mAbs) directed against four immunodominant toxin-neutralizing regions on the enzymatic A chain (RTA) of RT. In a test cohort of mice (n=40) vaccinated with suboptimal doses of the RTA subunit vaccine, RiVax®, we identified two mAbs, PB10 and SyH7, which had EPICC inhibition values in pre-challenge serum samples that correlated with survival following a challenge with 10 x LD50 of RT administered by intraperitoneal (IP) injection. Analysis of a larger cohort of mice (n=645) revealed that a multivariate model combining endpoint titers and an epitope-profiling immune-competition capture (EPICC) assay values for PB10 and SyH7 as predictive variables had significantly higher statistical power than any one of the independent variables alone. Establishing the correlates of vaccine-mediated protection in mice represents an important steppingstone in the development of RiVax® as a medical countermeasure under the United States Food and Drug Administration’s “Two Animal Rule.”

Competing Interest Statement

OD is an employee of Soligenix, Inc. which holds the license for RiVax.

  • Abbreviations

    ELISA
    Enzyme-linked immunosorbent assay
    EPICC
    epitope profiling immune-competition capture
    mAb
    Monoclonal antibody
    b
    biotinylated
    RT
    ricin toxin
    RTA
    RT A chain
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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    Posted May 08, 2020.
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    Endpoint and Epitope-specific Antibody Responses as Correlates of Vaccine-mediated Protection of Mice against Ricin Toxin
    Greta Van Slyke, Dylan J Ehrbar, Jennifer Doering, Jennifer L. Yates, Ellen S.Vitetta, Oreola Donini, Nicholas J Mantis
    bioRxiv 2020.05.06.081174; doi: https://doi.org/10.1101/2020.05.06.081174
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    Endpoint and Epitope-specific Antibody Responses as Correlates of Vaccine-mediated Protection of Mice against Ricin Toxin
    Greta Van Slyke, Dylan J Ehrbar, Jennifer Doering, Jennifer L. Yates, Ellen S.Vitetta, Oreola Donini, Nicholas J Mantis
    bioRxiv 2020.05.06.081174; doi: https://doi.org/10.1101/2020.05.06.081174

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