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Vaccines, Blood & Biologics

Plague Vaccine Efficacy: Development of New Assays to Better Assess Vaccine Efficacy

Principal Investigator: Karen Meysick, PhD
Office / Division / Lab: OVRR / DBPAP / LRSP


Public Health Issue: Yersinia pestis is the causative agent of plague and there is the potential for this organism to be used as a bioterrorist weapon. Two forms of the disease exist: bubonic plague, a systemic disease that is usually acquired from the bite of an infected flea, and pneumonic plague, a rapidly progressive and fatal broncho-pneumonia that occurs after inhalation of vegetative organisms. Although killed whole-cell plague vaccines have been shown to confer protection against bubonic plague in animal models these vaccines do not appear effective in combating the more lethal pneumonic form of the disease. Furthermore, these vaccines are no longer being manufactured in the US. Thus, there is an urgent need to develop and license new plague vaccines that can provide protection against both forms of the disease.

Regulatory Contribution: The goal of this progarm is to facilitate the development of new biological assays for high-priority public health threats, namely plague. New plague vaccines will be licensed under the "Animal Rule " ( Application of this rule requires that there is a reasonably well understood mechanism of the disease and its prevention as well as the capacity to translate correlates of protection between animals and humans. To help meet the requirements of the "Animal Rule" and expedite vaccine licensure, this program focuses on the development of assays that can measure the critical immune parameters across species and thereby bridge correlates of protection. Specifically, the assays under development will be designed to measure "functional" antibody responses to the two plague vaccine candidate antigens F1 and LcrV as well as any newly identified vaccine candidates.

Research Approach: Currently, new plague vaccines under development are composed of two antigens: F1, a plasmid-encoded, thermo-regulated proteinaceous capsule and LcrV, a plasmid-encoded, thermo-regulated component of the Yersinia Ysc type III secretion system. With regard to plague vaccines, protection against disease is considered to be predominantly antibody-mediated. Moreover, antibody titers, as measured by ELISA, appear to correlate with protection. Unfortunately, ELISAs are only capable of measuring antibody/antigen binding and are not designed to quantify "functional" antibodies, namely those antibodies that can directly neutralize the biological activity associated with each of these proteins. Additionally, ELISAs are chiefly species specific which limits their use when trying to effectively translate correlates of protection across species. Functional assays are much more applicable to the assessment and quantitation of functional antibodies and in general are non-species specific. Unfortunately, functional assays for either F1 or LcrV have been slow to develop and at this time the only functional assay available is passive transfer and challenge studies which are costly, time-consuming and require containment facilities. Therefore, the overall goal of this research project is to design relevant functional assays for both F1 and LcrV antigens based on their unique biological properties in order to establish whether these assays correlate with protection.

Mission Relevance & Outcomes: This research program is highly relevant to CBER's public health mission specifically related to the licensure of new plague vaccines under the "Animal Rule". The development of new biological assays that can be used to evaluate the immune responses elicited by plague vaccines will be critical in providing the most accurate translation of correlates of protection between animals and humans.


Infect Immun 2009 Jan;77(1):170-9
Cytotoxic necrotizing factor type 1-neutralizing monoclonal antibody NG8 recognizes three amino acids in a C-terminal region of the toxin and reduces toxin binding to HEp-2 cells.
Grande KK, Meysick KC, Rasmussen SB, O'Brien AD

Infect Immun 2007 Nov;75(11):5095-104
Two domains of cytotoxic necrotizing factor type 1 bind the cellular receptor, laminin receptor precursor protein.
McNichol BA, Rasmussen SB, Carvalho HM, Meysick KC, O'Brien AD

Mol Microbiol 2006 May;60(4):939-950
A single amino acid substitution in the enzymatic domain of cytotoxic necrotizing factor type 1 of Escherichia coli alters the tissue culture phenotype to that of the dermonecrotic toxin of Bordetella spp.
McNichol BA, Rasmussen SB, Meysick KC, O'Brien AD

Contact FDA

(800) 835-4709
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Office of Communication, Outreach and Development

Food and Drug Administration

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Building 71 Room 3103

Silver Spring, MD 20993-0002

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