Highly attenuated smallpox vaccine protects mice with and without immune deficiencies against pathogenic vaccinia virus challenge

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 BALB͞c 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 dosedependent 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 ␤2-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 Iand 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.

Clinical and immunologic responses to multiple doses of IMVAMUNE® (Modified Vaccinia Ankara) followed by Dryvax® challenge

“…Immunodeficient mice given a single dose of MVA survived intranasal challenge with vaccine virus strain Western Reserve (WR) [3] and animals administered intracranial injections of MVA experienced minimal encephalopathic responses [4,5]. MVA was efficacious in animal variola challenge models [6,2] and protected monkeys against a lethal monkeypox challenge [7,8].…”

Dominance and Diversity in the Primary Human CD4 T Cell Response to Replication-Competent Vaccinia Virus

“…In vivo, CD4-depleted, CD4 Ϫ/Ϫ , and MHC II Ϫ/Ϫ mice show delayed viral clearance and increased mortality after vaccinia infection (8,9). Modified vaccinia Ankara (MVA) 3 fails to protect MHC II Ϫ/Ϫ mice against vaccinia challenge (9).…”

“…Modified vaccinia Ankara (MVA) 3 fails to protect MHC II Ϫ/Ϫ mice against vaccinia challenge (9). Vaccinia-specific CD8 T cells in MHC II Ϫ/Ϫ or CD4 Ϫ/Ϫ mice have proliferative and functional protection defects (10 -12) and cannot transition into memory cells (4).…”

Detection of vaccinia virus DNA, but not infectious virus, in the blood of smallpox vaccine recipients

“…We cultured white blood cells, rather than plasma, since orthopoxviruses circulate in primates primarily within leukocytes in the blood [9]. Cell culture of vaccinia is more sensitive than infection of mice; in a study of severely immunodeficient mice, animals developed illness after inoculation with 10 6 plaque forming units (PFU) of vaccinia, but were asymptomatic with 10 5 PFU of virus [10]. Therefore culture of vaccinia is 100,000 times more sensitive than inoculation into immunodeficient mice.…”