Recombinant (F1+V) vaccine protects cynomolgus macaques against pneumonic plague

Williamson, E. Diane; Packer, P.; Waters, Emma; Simpson, Andrew; Dyer, David; Hartings, Justin M.; Twenhafel, Nancy; Pitt, M. Louise M.

doi:10.1016/j.vaccine.2011.04.084

Cited by 56 publications

(36 citation statements)

References 34 publications

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“…Promising recombinant subunit plague vaccines, which are under clinical investigation, consist of a low-calcium-response V (LcrV [V]) antigen, a component of the type 3 secretion system (T3SS), as well as an effector and the capsular antigen F1. These vaccines elicit high antibody titers in rodents; however, their potential as efficacious vaccines has been debated because of varied responses in nonhuman primates (NHPs) (12)(13)(14)(15)(16). Specifically, African green monkeys (AGMs), in which the symptoms of plague mimic those in humans and represent an ideal model with which to study Y. pestis infection (17)(18)(19)(20)(21), exhibit highly varied protective responses to pneumonic plague (despite similar antibody titers).…”

mentioning

confidence: 99%

Deletion of Braun Lipoprotein and Plasminogen-Activating Protease-Encoding Genes Attenuates Yersinia pestis in Mouse Models of Bubonic and Pneumonic Plague

et al. 2014

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f Currently, there is no FDA-approved vaccine against Yersinia pestis, the causative agent of bubonic and pneumonic plague. Since both humoral immunity and cell-mediated immunity are essential in providing the host with protection against plague, we developed a live-attenuated vaccine strain by deleting the Braun lipoprotein (lpp) and plasminogen-activating protease (pla) genes from Y. pestis CO92. The ⌬lpp ⌬pla double isogenic mutant was highly attenuated in evoking both bubonic and pneumonic plague in a mouse model. Further, animals immunized with the mutant by either the intranasal or the subcutaneous route were significantly protected from developing subsequent pneumonic plague. In mice, the mutant poorly disseminated to peripheral organs and the production of proinflammatory cytokines concurrently decreased. Histopathologically, reduced damage to the lungs and livers of mice infected with the ⌬lpp ⌬pla double mutant compared to the level of damage in wild-type (WT) CO92-challenged animals was observed. The ⌬lpp ⌬pla mutant-immunized mice elicited a humoral immune response to the WT bacterium, as well as to CO92-specific antigens. Moreover, T cells from mutant-immunized animals exhibited significantly higher proliferative responses, when stimulated ex vivo with heat-killed WT CO92 antigens, than mice immunized with the same sublethal dose of WT CO92. Likewise, T cells from the mutant-immunized mice produced more gamma interferon (IFN-␥) and interleukin-4. These animals had an increasing number of tumor necrosis factor alpha (TNF-␣)-producing CD4 ؉ and CD8 ؉ T cells than WT CO92-infected mice. These data emphasize the role of TNF-␣ and IFN-␥ in protecting mice against pneumonic plague. Overall, our studies provide evidence that deletion of the lpp and pla genes acts synergistically in protecting animals against pneumonic plague, and we have demonstrated an immunological basis for this protection.

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confidence: 99%

Deletion of Braun Lipoprotein and Plasminogen-Activating Protease-Encoding Genes Attenuates Yersinia pestis in Mouse Models of Bubonic and Pneumonic Plague

et al. 2014

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“…Indeed, F1 and LcrV antigens must be used in a specific ratio during immunization to demonstrate optimal protection in animals (5,6,47). We were able to demonstrate that OmpA, Pla, and Ail/OmpX were all protective in either bubonic or pneumonic Y. pestis challenges in either mouse or rat models of infection.…”

Section: Fig 8 (A)mentioning

confidence: 82%

“…Indeed, we, and other investigators, have shown that F1 does not contribute to Y. pestis pathogenesis during pneumonic plague but does participate in contributing to virulence during bubonic plague in mice (38,45). However, vaccines composed of either F1 or F1 and V antigens, as well as the V-F1 fusion protein contribute to developing protection against pneumonic plague in nonhuman primates (6,46,47). In earlier studies, protection was shown in a mouse model against both bubonic and pneumonic plague by passive immunization with monoclonal antibodies to F1 (48) and the recombinant F1-V antigen fusion vaccine (12).…”

Section: Fig 8 (A)mentioning

confidence: 88%

Evaluation of Protective Potential of Yersinia pestis Outer Membrane Protein Antigens as Possible Candidates for a New-Generation Recombinant Plague Vaccine

Erova

Rosenzweig

Sha

et al. 2013

Clin Vaccine Immunol

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؊ strains or those which harbor variants of LcrV is a significant concern. Here, we show that the passive transfer of hyperimmune sera from rats infected with the plague bacterium and rescued by levofloxacin protected naive animals against pneumonic plague. Furthermore, 10 to 12 protein bands from wild-type (WT) Y. pestis CO92 reacted with the aforementioned hyperimmune sera upon Western blot analysis. Based on mass spectrometric analysis, four of these proteins were identified as attachment invasion locus (Ail/OmpX), plasminogen-activating protease (Pla), outer membrane protein A (OmpA), and F1. The genes encoding these proteins were cloned, and the recombinant proteins purified from Escherichia coli for immunization purposes before challenging mice and rats with either the F1 ؊ mutant or WT CO92 in bubonic and pneumonic plague models. Although antibodies to Ail and OmpA protected mice against bubonic plague when challenged with the F1 ؊ CO92 strain, Pla antibodies were protective against pneumonic plague. In the rat model, antibodies to Ail provided protection only against pneumonic plague after WT CO92 challenge. Together, the addition of Y. pestis outer membrane proteins to a new-generation recombinant vaccine could provide protection against a wide variety of Y. pestis strains.Yersinia pestis, the causative agent of bubonic, septicemic, and pneumonic plague, is a Gram-negative zoonotic pathogen, and human infections are often acquired through the infected-flea vector carried by domestic and/or wild animals (1). The microorganism possesses multiple virulence determinants that are both chromosomally and extrachromosomally encoded on its three plasmids: pCD1, pMT1/pFra, and pPCP1/pPla (2). Although bubonic plague, inflicted by flea bites, in humans represents the most common form worldwide (http://www.gov.mb.ca/health /publichealth/cdc/protocol/plague.pdf), it can lead to secondary septicemic and pneumonic plague, with a nearly 100% mortality rate. Primary pneumonic plague results by inhaling aerosolized droplets charged with Y. pestis, and the organism can then rapidly spread from person to person, possibly leading to mass causalities (http://www.cdc.gov/ncidod/dvbid/plague/info.htm).Presently, there is no licensed plague vaccine in the United States (3), which is alarming in the light of epidemics and potential bioterrorism threats associated with this lethal pathogen. The current subunit vaccines under investigation include the capsular antigen F1 and the low-calcium-response V antigen (LcrV). LcrV is part of the type 3 secretion system (T3SS) and is encoded by the pCD1 plasmid (3). F1 and LcrV vaccines are tested as either purified individual antigens or as a fusion of these proteins (F1-V or V-F1) (4-6; see also reference 3 and references therein). Although efficacious in rodents and some nonhuman primate models (4-6; see also reference 3 and references therein), these recombinant vaccines would not be as efficacious against F1Ϫ strains of Y. pestis that exist in nature and are as virulent as the wild-typ...

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“…Neutralization of TNF-and IFN-interfered with the protective efficacy of F1-or LcrV-specific antibodies against the fully virulent pgm-positive Y. pestis strain CO92 (Lin et al, 2010). Recently, a recombinant rF1+rV vaccine provided protection in Cynomolgus macaques against pneumonic plague following inhalational challenge with a clinical isolate of Y. pestis (CO92) (Williamson et al, 2011).…”

Section: Subunit Vaccines Based On the F1 Lcrv And Yscf Proteinsmentioning

confidence: 99%

Recent Advancement in the Development of Vaccines Against Y. pestis - A Potential Agent of Bioterrorism

Ali¹,

Rao²

2012

Bioterrorism

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Recombinant (F1+V) vaccine protects cynomolgus macaques against pneumonic plague

Cited by 56 publications

References 34 publications

Deletion of Braun Lipoprotein and Plasminogen-Activating Protease-Encoding Genes Attenuates Yersinia pestis in Mouse Models of Bubonic and Pneumonic Plague

Deletion of Braun Lipoprotein and Plasminogen-Activating Protease-Encoding Genes Attenuates Yersinia pestis in Mouse Models of Bubonic and Pneumonic Plague

Evaluation of Protective Potential of Yersinia pestis Outer Membrane Protein Antigens as Possible Candidates for a New-Generation Recombinant Plague Vaccine

Recent Advancement in the Development of Vaccines Against Y. pestis - A Potential Agent of Bioterrorism

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