Postexposure Immunization with Modified Vaccinia Virus Ankara or Conventional Lister Vaccine Provides Solid Protection in a Murine Model of Human Smallpox

Paran, Nir; Suezer, Yasemin; Lustig, Shlomo; Israely, Tomer; Schwantes, Astrid; Melamed, Sharon; Katz, L. J.; Preuß, Thomas G.; Hanschmann, Kay-Martin; Kalinke, Ulrich; Erez, Noam; Levin, Reuven; Velan, Baruch; Löwer, Johannes; Shafferman, Avigdor; Sutter, Gerd

doi:10.1086/595565

Cited by 55 publications

(107 citation statements)

References 47 publications

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“…In ⌬m01-17ϩm144-158-MCMV, immuneevasive genes were deleted to increase the antiviral immune response and thereby to attenuate the virus. The combination of both approaches in the future, namely, the deletion of at least one essential gene combined with the deletion of selected Ϫ/Ϫ mice were protected against an otherwise lethal challenge, similar to results from other infection models (9,48). Although recent work revealed the capacity of MCMV to efficiently induce type I interferon (26), the efficacy of the spread-deficient MCMV vaccine in IFN␣␤R Ϫ/Ϫ mice implies that type I interferon-dependent immunity is not essential for the protection conferred by short-term vaccination.…”

Section: Discussionsupporting

confidence: 69%

A Spread-Deficient Cytomegalovirus for Assessment of First-Target Cells in Vaccination

Mohr

Arapović

Mühlbach

et al. 2010

J Virol

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Human cytomegalovirus (HCMV) is a human pathogen that causes severe disease primarily in the immunocompromised or immunologically immature individual. To date, no vaccine is available. We describe use of a spread-deficient murine CMV (MCMV) as a novel approach for betaherpesvirus vaccination. To generate a spread-deficient MCMV, the conserved, essential gene M94 was deleted. Immunization with MCMV-⌬M94 is apathogenic and protective against wild-type challenge even in highly susceptible IFN␣␤R ؊/؊ mice. MCMV-⌬M94 was able to induce a robust CD4؉ and CD8 ؉ T-cell response as well as a neutralizing antibody response comparable to that induced by wild-type infection. Endothelial cells were identified as activators of CD8 ؉ T cells in vivo. Thus, the vaccination with a spread-deficient betaherpesvirus is a safe and protective strategy and allows the linkage between cell tropism and immunogenicity. Furthermore, genomes of MCMV-⌬M94 were present in lungs 12 months after infection, revealing first-target cells as sites of genome maintenance.

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Section: Discussionsupporting

confidence: 69%

A Spread-Deficient Cytomegalovirus for Assessment of First-Target Cells in Vaccination

Mohr

Arapović

Mühlbach

et al. 2010

J Virol

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“…Comparisons with other small animal models, (1,2,50) show that the pathogenesis of MPXV in prairie dogs is more similar to systemic OPXV infection in humans than other small animal models in both the route of transmission of challenge virus and length of viral incubation period. This 7-to 9-day incubation period is especially important, as it potentially makes the MPXV-infected prairie dog an ideal model for testing postexposure therapies, as have recently been tested in ECTV-infected mice (55). In addition, unlike the recently described MPXV-infected STAT1 Ϫ/Ϫ mice (71) and inbred mouse models (2), the prairie dog is an immunocompetent and natural host for MPXV.…”

Section: Discussionmentioning

confidence: 99%

Establishment of the Black-Tailed Prairie Dog (Cynomys ludovicianus) as a Novel Animal Model for Comparing Smallpox Vaccines Administered Preexposure in both High- and Low-Dose Monkeypox Virus Challenges

Keckler

Carroll

Gallardo-Romero

et al. 2011

J Virol

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The 2003 monkeypox virus (MPXV) outbreak and subsequent laboratory studies demonstrated that the black-tailed prairie dog is susceptible to MPXV infection and that the ensuing rash illness is similar to human systemic orthopoxvirus (OPXV) infection, including a 7-to 9-day incubation period and, likely, in some cases a respiratory route of infection; these features distinguish this model from others. The need for safe and efficacious vaccines for OPVX in areas where it is endemic or epidemic is important to protect an increasingly OPXV-naïve population. In this study, we tested current and investigational smallpox vaccines for safety, induction of anti-OPXV antibodies, and protection against mortality and morbidity in two MPXV challenges. Although smallpox has been eradicated (5), orthopoxviruses (OPXVs), such as variola virus (VARV) (6, 32), monkeypox virus (MPXV) (3, 10, 57), vaccinia virus (VACV) (4, 76), and others (53,68,77), are a continuing public health concern (61, 67). Due to cellular and humoral protective effects (7,15,16,46,73), the traditional live VACV-based smallpox vaccines provide cross-protection against multiple OPXV threats (48). Unfortunately, the cessation of routine vaccination (37) has left much of the global population fully susceptible to OPXV infections (34), and the adverse effects of first-and secondgeneration vaccines (78) coupled with increases in the global immunocompromised population (59) underline the need for continued development and testing of safer smallpox vaccines (30).Testing of smallpox vaccines requires the development of relevant animal models. Current smallpox vaccine testing animal models include ectromelia virus (ECTV) infection of mice (75), VACV infection of mice (63), rabbitpox virus (RPXV) and VACV infection of rabbits (1, 18), VARV and MPXV infection of nonhuman primates (NHP) (13,19,21,25,26,31), and others (65, 74). Limitations of current models include abbreviated disease incubation periods and/or differences from human systemic orthopoxvirus disease presentation and progression The validation of alternative animal models for smallpox vaccine testing is an ongoing effort (2, 19, 39).The MPXV outbreak in the United States in 2003 (3) identified a potential alternative model as it established that MPXV can be transmitted to black-tailed prairie dogs (Cynomys ludovicianus) (42). Investigations of the MPXV outbreak and epidemiological, immunological, and pathological studies of prairie dogs infected with MPXV (8,12,27,28,35,38,43,57,58,64,69,74,80) determined that this rodent species can manifest MPXV infection similar to human systemic OPXV disease. This disease model shares a respiratory route of infection, similar disease incubation period, and similar rash illness (20,29,38,42,80) with human MPXV and VARV infections, thus making it a potentially useful small animal model for testing vaccines and therapeutics (29,70). A particular strength of this model is its 7-to 9-day incubation period, which is more similar to that seen in human disease than many other a...

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“…Importantly, in comparison to the VACV-based mouse challenge model, ECTV infection of BALB/c or C57BL/6 mice is characterized by an extended asymptomatic incubation period. 109,110 This rather long disease free period seems vital to allow for the demonstration of protective post-exposure vaccination with VACV. 109,111 In contrast, respiratory challenge infection with VACV produces a fulminant acute disease which appears to hamper the feasibility of therapeutic immunization.…”

Section: Animal Modelsmentioning

confidence: 99%

“…109,110 This rather long disease free period seems vital to allow for the demonstration of protective post-exposure vaccination with VACV. 109,111 In contrast, respiratory challenge infection with VACV produces a fulminant acute disease which appears to hamper the feasibility of therapeutic immunization. 112 Additional parameters including the increase in hemagglutination inhibiting or neutralizing antibodies were not tested in all vaccinees, yet neutralizing antibodies appeared to better correlate with "vaccine take".…”

Section: Animal Modelsmentioning

confidence: 99%

“…Recently, the efficacy of vaccination shortly before or post exposure was demonstrated in animal models. 60,109,111 Future research needs to carefully address the evaluation of immune correlates for rapid protection and to investigate the usefulness of new approaches and schedules for emergency immunization in human clinical trials. These activities should be supplemented by the evaluation of other options for therapeutic intervention.…”

Section: Animal Modelsmentioning

confidence: 99%

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Smallpox vaccines: New formulations and revised strategies for vaccination

Paran¹,

Sutter²

2009

Human Vaccines

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Postexposure Immunization with Modified Vaccinia Virus Ankara or Conventional Lister Vaccine Provides Solid Protection in a Murine Model of Human Smallpox

Abstract: ECTV infection in mice models the course of human smallpox. Our data provide evidence to substantiate historical data on the usefulness of postexposure vaccination with conventional VACV and the new candidate MVA to protect against fatal orthopoxvirus infections.

Cited by 55 publications

References 47 publications

A Spread-Deficient Cytomegalovirus for Assessment of First-Target Cells in Vaccination

A Spread-Deficient Cytomegalovirus for Assessment of First-Target Cells in Vaccination

Establishment of the Black-Tailed Prairie Dog (Cynomys ludovicianus) as a Novel Animal Model for Comparing Smallpox Vaccines Administered Preexposure in both High- and Low-Dose Monkeypox Virus Challenges

Smallpox vaccines: New formulations and revised strategies for vaccination

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