The potential use of smallpox as a biological weapon has led to the production and stockpiling of smallpox vaccine and the immunization of some healthcare workers. Another public health goal is the licensing of a safer vaccine that could benefit the millions of people advised not to take the current one because they or their contacts have increased susceptibility to severe vaccine side effects. As vaccines can no longer be tested for their ability to prevent smallpox, licensing will necessarily include comparative immunogenicity and protection studies in non-human primates. Here we compare the highly attenuated modified vaccinia virus Ankara (MVA) with the licensed Dryvax vaccine in a monkey model. After two doses of MVA or one dose of MVA followed by Dryvax, antibody binding and neutralizing titres and T-cell responses were equivalent or higher than those induced by Dryvax alone. After challenge with monkeypox virus, unimmunized animals developed more than 500 pustular skin lesions and became gravely ill or died, whereas vaccinated animals were healthy and asymptomatic, except for a small number of transient skin lesions in animals immunized only with MVA.
We designed, optimized, and extensively tested several sensitive and specific real-time PCR assays for rapid detection of both smallpox and pan-orthopox virus DNAs. The assays are based on TaqMan 3-minor groove binder chemistry and were performed on both the rapid-cycling Roche LightCycler and the Cepheid Smart Cycler platforms. The hemagglutinin (HA) J7R, B9R, and B10R genes were used as targets for the variola virus-specific assays, and the HA and DNA polymerase-E9L genes were used as targets for the pan-orthopox
It is unknown whether smallpox vaccination would protect human immunodeficiency virus type 1 (HIV-1)-infected individuals, because helper CD4(+) cells, the targets of HIV-1 infection, are necessary for the induction of both adaptive CD8(+) cell and B cell responses. We have addressed this question in macaques and have demonstrated that, although smallpox vaccination is safe in immunodeficient macaques when it is preceded by immunization with highly attenuated vaccinia strains, the macaques were not protected against lethal monkeypox virus challenge if their CD4(+) cell count was <300 cells/mm(3). The lack of protection appeared to be associated with a defect in vaccinia-specific immunoglobulin (Ig) switching from IgM to IgG. Thus, vaccination strategies that bypass CD4(+) cell help are needed to elicit IgG antibodies with high affinity and adequate tissue distribution and to restore protection against smallpox in severely immunocompromised individuals.
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