Recombinant A27 protein synergizes with modified vaccinia Ankara in conferring protection against a lethal vaccinia virus challenge.
ABSTRACT Highly attenuated modified vaccinia virus Ankara (MVA) is being considered as a safer alternative to conventional smallpox vaccines such as Dryvax or ACAM 2000, but it requires higher doses or more-frequent boosting than replication-competent Dryvax. Previously, we found that passive transfer of A27 antibodies can enhance protection afforded by vaccinia immune globulin (VIG), which is derived from Dryvax immunized subjects. Here we investigated whether protective immunity elicited by MVA could be augmented by prime-boost or combination immunizations with a recombinant A27 (rA27) protein. We found that a prime/boost immunization regimen with rA27 protein and MVA, in either sequence order, conferred protection to mice challenged with a lethal dose of vaccinia virus strain Western Reserve (VV-WR), compared to no protection after immunizations with a similar dose of either MVA or rA27 alone. Moreover, protection was achieved in mice primed simultaneously with combination of both MVA and rA27 in different vaccination routes, without any boost, even though MVA or rA27 alone at the same dose gave no protection. These findings show that rA27 can synergize with MVA to elicit robust protection that has a dose-sparing effect on MVA and can accelerate protection by eliminating the need for a booster dose.
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ABSTRACT: Significant adverse events are associated with vaccination with the currently licensed smallpox vaccine. Candidate new-generation smallpox vaccines such as the replication-defective modified vaccinia virus Ankara (MVA) produce very few adverse events in experimental animals and in limited human clinical trials conducted near the end of the smallpox eradication campaign. Efficacy evaluation of such new-generation vaccines will be extraordinarily complex, however, since the eradication of smallpox precludes a clinical efficacy trial and the correlates of protection against smallpox are unknown. A combination of relevant animal efficacy studies along with thorough comparative immunogenicity studies between traditional and new-generation smallpox vaccines will be necessary for vaccine licensure. In the present study, a variety of immune responses elicited by MVA and the licensed smallpox vaccine Dryvax in a murine model were compared, with a focus on mimicking conditions and strategies likely to be employed in human vaccine trials. Immunization of mice with MVA, using several relevant vaccination routes including needle-free delivery, elicited humoral and cellular immune responses qualitatively similar to those elicited by vaccination with Dryvax. Similar levels of vaccinia-specific IgG and neutralizing antibody were elicited by Dryvax and MVA when higher doses (approximately 1 log) of MVA were used for immunization. Antibody levels peaked at about 6 weeks post-immunization and remained stable for at least 15 weeks. A booster immunization of either MVA or Dryvax following an initial priming immunization with MVA resulted in an enhanced IgG titer and neutralizing antibody response. In addition, both Dryvax and various MVA vaccination protocols elicited antibody responses to the extracellular enveloped form of the virus and afforded protection against a lethal intranasal challenge with vaccinia virus WR.Virology 10/2005; 339(2):164-75. · 3.37 Impact Factor
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ABSTRACT: Vaccination with live vaccinia virus affords long-lasting protection against variola virus, the agent of smallpox. Its mode of protection in humans, however, has not been clearly defined. Here we report that vaccinia-specific B-cell responses are essential for protection of macaques from monkeypox virus, a variola virus ortholog. Antibody-mediated depletion of B cells, but not CD4+ or CD8+ T cells, abrogated vaccine-induced protection from a lethal intravenous challenge with monkeypox virus. In addition, passive transfer of human vaccinia-neutralizing antibodies protected nonimmunized macaques from severe disease. Thus, vaccines able to induce long-lasting protective antibody responses may constitute realistic alternatives to the currently available smallpox vaccine (Dryvax).Nature Medicine 08/2005; 11(7):740-7. · 22.86 Impact Factor
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ABSTRACT: Modified vaccinia virus Ankara (MVA), developed >30 years ago as a highly attenuated candidate smallpox vaccine, was recloned from a 1974 passage and evaluated for safety and immunogenicity. Replication of MVA is impaired in most mammalian cells, and we found that mice with severe combined immunodeficiency disease remained healthy when inoculated with MVA at 1,000 times the lethal dose of vaccinia virus derived from the licensed Dryvax vaccine seed. In BALB/c mice inoculated intramuscularly with MVA, virus-specific CD8+ T cells and antibodies to purified virions and membrane protein components of the intracellular and extracellular infectious forms of vaccinia virus were induced in a dose-dependent manner. After one or two inoculations of MVA, the T cell numbers and antibody titers equaled or exceeded those induced by percutaneous injection of Dryvax. Antibodies induced by MVA and Dryvax were neutralizing and inhibited virus spread in cultured cells. Furthermore, vaccinated mice were protected against lethal intranasal challenge with a pathogenic vaccinia virus. B cell-deficient mice unable to generate antibodies and beta2-microglobulin-deficient mice unable to express MHC class I molecules for a CD8+ T cell response were also protectively vaccinated by MVA. In contrast, mice with decreased CD4 or MHC class II expression and double-knockout mice deficient in MHC class I- and II-restricted activities were poorly protected or unprotected. This study confirmed the safety of MVA and demonstrated that the overlapping immune responses protected normal and partially immune-deficient animals, an encouraging result for this candidate attenuated smallpox vaccine.Proceedings of the National Academy of Sciences 03/2004; 101(13):4590-5. · 9.74 Impact Factor