Synergistic Protection of Mice against Plague with Monoclonal Antibodies Specific for the F1 and V Antigens of Yersinia pestis

Defence Science and Technology Laboratory, Porton Down, Wiltshire SP4 OJQ, United Kingdom.
Infection and Immunity (Impact Factor: 3.73). 05/2003; 71(4):2234-8. DOI: 10.1128/IAI.71.4.2234-2238.2003
Source: PubMed


Monoclonal antibodies specific for Yersinia pestis V antigen and F1 antigen, administered singly or in combination, protected mice in models of bubonic and pneumonic plague. Antibodies showed synergy when administered prophylactically and as a therapy 48 h postinfection. Monoclonal antibodies therefore have potential as a treatment for plague.

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Available from: Ethel Diane Williamson, Aug 12, 2014
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    • "Scientists and regulatory authorities have for many years been looking for a functional assay which will enable measurement of a correlate of protection against pneumonic plague. Passive immune protection studies in animals, using antibodies isolated from vaccinated individuals, may provide this assay [14] [15] [25] [26]. "
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    ABSTRACT: New vaccines against biodefense-related and emerging pathogens are being prepared for licensure using the US Federal Drug Administration's "Animal Rule." This allows licensure of drugs and vaccines using protection data generated in animal models. A new acellular plague vaccine composed of two separate recombinant proteins (rF1 and rV) has been developed and assessed for immunogenicity in humans. Using serum obtained from human volunteers immunised with various doses of this vaccine and from immunised cynomolgus macaques, we assessed the pharmacokinetic properties of human and cynomolgus macaque IgG in BALB/c and the NIH Swiss derived Hsd:NIHS mice, respectively. Using human and cynomolgus macaque serum with known ELISA antibody titres against both vaccine components, we have shown that passive immunisation of human and nonhuman primate serum provides a reproducible delay in median time to death in mice exposed to a lethal aerosol of plague. In addition, we have shown that Hsd:NIHS mice are a better model for humoral passive transfer studies than BALB/c mice.
    Research Journal of Immunology 07/2014; 2014:807564. DOI:10.1155/2014/807564
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    • "A strong humoral immune response to the individual subunits F1 or V or combined subunits (F1-V or F1+V), or an altered V-antigen (V10) was initially believed to be sufficient to provide protection against a lethal Y. pestis challenge in both mouse and nonhuman primate models of plague [2] [3] [4] [5] [6] [7] [8]. Both murine and human monoclonal antibodies against the subunit components of the plague vaccine have been shown to mediate protection against a lethal plague challenge in mice [9] [10] [11] [12]. There is evidence to suggest that cell mediated immune responses are also important for protection against Y. pestis infection [13] [14] [15]. "
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    ABSTRACT: The current candidate vaccine against Yersinia pestis infection consists of two subunit proteins: the capsule protein or F1 protein and the low calcium response V protein or V-antigen. Little is known of the recognition of the vaccine by the host's innate immune system and how it affects the acquired immune response to the vaccine. Thus, we vaccinated Toll-like receptor (Tlr) 2, 4, and 2/4-double deficient, as well as signal adaptor protein Myd88-deficient mice. We found that Tlr4 and Myd88 appeared to be required for an optimal immune response to the F1-V vaccine but not Tlr2 when compared to wild-type mice. However, there was a difference between the requirement for Tlr4 and MyD88 in vaccinated animals. When F1-V vaccinated Tlr4 mutant (lipopolysaccharide tolerant) and Myd88-deficient mice were challenged by aerosol with Y. pestis CO92, all but one Tlr4 mutant mice survived the challenge, but no vaccinated Myd88-deficient mice survived the challenge. Spleens from these latter nonsurviving mice showed that Y. pestis was not cleared from the infected mice. Our results suggest that MyD88 appears to be important for both an optimal immune response to F1-V and in protection against a lethal challenge of Y. pestis CO92 in F1-V vaccinated mice.
    Research Journal of Immunology 06/2014; 2014:341820. DOI:10.1155/2014/341820
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    • "In animal models, the administration of monoclonal antibodies (Mab's) with specificity for F1 and V, has been shown to protect mice infected with Y. pestis, even when the Mab's were administered at 48 h post-exposure [37]. However, the protective effect of the anti-V Mab 7.3 was abrogated by the coadministration of anti-TNFα and anti-IFNγ indicating that a cellular proinflammatory response is also contributing to protection [38]. "
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    ABSTRACT: One of the difficulties in developing countermeasures to biothreat agents is the challenge inherent in demonstrating their efficacy in man. Since the first publication of the Animal Rule by the FDA, there has been increased discussion of potential correlates of protection in animal models and their use to establish surrogate markers of efficacy in man. The latter need to be relatively easy to measure in assays that are at least qualified, if not validated, in order to derive a quantitative assessment of the clinical benefit conferred. The demonstration of safety and clinical benefit is essential to achieve regulatory approval for countermeasures for which clinical efficacy cannot be tested directly, as is the case for example, for biodefence vaccines. Plague is an ancient, serious infectious disease which is still endemic in regions of the modern world and is a potential biothreat agent. This paper discusses potential immune correlates of protection for plague, from which it may be possible to derive surrogate markers of efficacy, in order to predict the clinical efficacy of candidate prophylaxes and therapies.
    01/2012; 2012(2090-3480):365980. DOI:10.1155/2012/365980
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