The purpose of this application is to facilitate the development of the candidate into an independent clinical investigator. The candidate has completed infectious diseases subspecialty training and post-doctoral training in basic immunology and is seeking further mentor-guided training to attain the stated career goals. The overarching goal of this career development proposal is to develop a patient-oriented research program investigating vaccine-elicited host immunity to bioterrorism-associated viral infections, while becoming a successful independent clinician-researcher. The proposed career development plan consists of didactic training that will provide advanced epidemiology and biostatistics training through the Harvard School of Public Health and a mentored research project to be conducted as a collaborative effort between Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, and Harvard Medical School. The goal of the proposed research component is to translate cutting-edge immunology methodology into the design and implementation of clinical trials evaluating experimental vaccine-induced immunity to orthopoxviruses. We hypothesize that the epicutaneous inoculation and subsequent intradermal (ID) replication of wild-type vaccinia virus (VACV) leads to preferential selection of poxvirus-specific T cells which express skin-tropic lymphocyte homing molecules, including the cutaneous lymphocyte-associated antigen (CLA) and specific chemokine receptors such as CCR4 and CCR10. We further hypothesize that vaccination with the experimental smallpox vaccine modified vaccinia Ankara (MVA) by the ID, subcutaneous (SC), and epicutaneous routes has a similar preferential selection for viral-specific dermatotropic T cells as opposed to the common intramuscular (IM) route.
The Specific Aims of the research are therefore to: 1) Investigate the effect that route of administration of MVA has on the induction of dermatotropic orthopoxvirus-specific T cells;2) Determine the kinetics, magnitude, and trafficking marker expression of orthopoxvirus-specific T cells in healthy subjects vaccinated with MVA via epicutaneous scarification;and 3) Determine the kinetics, magnitude, and trafficking marker expression of orthopoxvirus-specific T cells in subjects with eczema or atopic dermatitis vaccinated with MVA. The data generated by these experiments will add significantly to the body of knowledge regarding immune responses elicited by MVA compared with standard VACV vaccination and thus inform biodefense policy-making. By the completion of the comprehensive research and career development plan, the candidate will have obtained the requisite skills to become an independent clinical investigator in vaccinology. Public Health Relevance: Currently available smallpox vaccines have a large number of serious side effects and cannot be used in many people due to the high risk of adverse events. This proposal will investigate whether a new smallpox vaccine is safe to use in people with eczema or atopic dermatitis and determine whether the immune responses induced by the new smallpox vaccine are similar to immune responses induced by traditional smallpox vaccines.
Currently available smallpox vaccines have a large number of serious side effects and cannot be used in many people due to the high risk of adverse events. This proposal will investigate whether a new smallpox vaccine is safe to use in people with eczema or atopic dermatitis and determine whether the immune responses induced by the new smallpox vaccine are similar to immune responses induced by traditional smallpox vaccines.
|Walsh, Stephen R; Wilck, Marissa B; Dominguez, David J et al. (2013) Safety and immunogenicity of modified vaccinia Ankara in hematopoietic stem cell transplant recipients: a randomized, controlled trial. J Infect Dis 207:1888-97|
|Walsh, Stephen R; Seaman, Michael S; Grandpre, Lauren E et al. (2012) Impact of anti-orthopoxvirus neutralizing antibodies induced by a heterologous prime-boost HIV-1 vaccine on insert-specific immune responses. Vaccine 31:114-9|
|Walsh, Stephen R; Dolin, Raphael (2011) Vaccinia viruses: vaccines against smallpox and vectors against infectious diseases and tumors. Expert Rev Vaccines 10:1221-40|