Synergistic protection of mice against plague with monoclonal antibodies specific for the F1 and V antigens of Y. pestis

Defence Science and Technology Laboratory, Porton Down, Wiltshire SP4 OJQ, United Kingdom.
Infection and Immunity (Impact Factor: 4.16). 05/2003; 71(4):2234-8. DOI: 10.1128/IAI.71.4.2234-2238.2003
Source: PubMed

ABSTRACT 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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    • "The ability of anti-F1 antibodies to provide effective protection against bubonic and pneumonic plague was previously demonstrated [32] [33]. To investigate the role of humoral anti-F1 defense mechanisms in greater detail, we used a previously developed mouse model for post-exposure passive therapy [34]. "
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    ABSTRACT: Plague, which is initiated by Yersinia pestis infection, is a fatal disease that progresses rapidly and leads to high mortality rates if not treated. Antibiotics are an effective plague therapy, but antibiotic-resistant Y. pestis strains have been reported and therefore alternative countermeasures are needed. In the present study, we assessed the potential of an F1 plus LcrV-based vaccine to provide protection shortly pre- or post-exposure to a lethal Y. pestis infection. Mice vaccinated up to one day before or even several hours after subcutaneous challenge were effectively protected. Mice immunized one or three days pre-challenge were protected even though their anti-F1 and anti-LcrV titers were below detection levels at the day of challenge. Moreover, using B-cell deficient μMT mice, we found that rapidly induced protective immunity requires the integrity of the humoral immune system. Analysis of the individual contributions of vaccine components to protection revealed that rF1 is responsible for the observed rapid antibody-mediated immunity. Applying anti-F1 passive therapy in the mouse model of bubonic plague demonstrated that anti-F1 F(ab')(2) can delay mortality, but it cannot provide long-lasting protection, as do intact anti-F1 molecules. Fc-dependent immune components, such as the complement system and (to a lesser extent) neutrophils, were found to contribute to mouse survival. Interestingly, T cells but not B cells were found to be essential for the recovery of infected animals following passive anti-F1 mediated therapy. These data extend our understanding of the immune mechanisms required for the development of a rapid and effective post-exposure therapy against plague.
    Vaccine 07/2011; 29(40):6866-73. DOI:10.1016/j.vaccine.2011.07.059 · 3.49 Impact Factor
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