The overarching goal of this proposal is to develop a safe and highly effective single-dose Modified VacciniaAnkara (MVA)-based smallpox vaccine. Despite the historical evidence that protection following smallpoximmunization is strongly associated with the epidermal pox reaction induced by vaccinia virus (W) skin,scarification, in the current clinical trials, MVA are inoculated exclusively by conventional injection routes atmultiple high doses. This is probably due to the assumption that the replication-defective MVA would fail toproduce pox lesions if given by skin scarification. We have recently established a mouse model of MVA skinscarification. Using this model, we showed that MVA skin scarification is superiorly immunogenic andprotective against lethal Western Reserve strain W challenge compared to the injection routes, and at thesame time, less reactogenic than the standard W vaccination. Therefore, we hypothesize that single-doseMVA immunization via skin scarification is both safe and highly effective to prevent natural poxvirus infection,even for immunodeficient individuals. Recently, an ectromelia virus challenge system has been developed atUniversity of Virginia. This system provides an ultimate test for the vaccine protection efficacy against naturalpoxvirus infection. Concurrently, a hu-HSC-DKO model has become available in Dr. Lishan Su's laboratoryat University of North Carolina at Chapel Hill. In this model, human CD34+ hematopoietic stem cells (HSC)are grafted into Rag2-gammaC double knockout mice. Normal human T, B, and dendritic cells are stablypresent in lymphoid tissues of the recipient mice. These mice can be infected by human Iympo-tropic virusessuch as EBV and HIV-1, and viral-specific human T cell response can be detected following the infection.Thus, this model could serve as a surrogate in vivo system to evaluate human vaccine candidates. Takingadvantage of these models, we will test our hypothesis in a rigorous fashion through a series of experiments.
Specific Aims of the project are: (1) Evaluate the protection efficacy of MVA skin scarification to preventectromelia virus infection in wild-type mice; (2) Characterize human immune response in hu-HSC-DKO micefollowing MVA skin scarification; (3) Evaluate protection efficacy of MVA skin scarification in hu-HSC-DKOmice with or without immunodeficiency.Relevance to Public Health: Today, 40% of the US population has never been vaccinated against smallpox.Significant number of immunocompromised individuals are at high risk of severe adverse responses inducedby the current smallpox vaccine. A safe and highly effective smallpox vaccine that can be given to allmembers of the population is urgently needed. If successful, this work will decisively advance strategies ofpoxvirus-based vaccinology and defense against bioterrorism.
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