CBER Expertise
Development and Evaluation of New-Generation Smallpox Vaccines
Principal Investigator: M. Merchlinsky, PhD
Office / Division / Lab: OVRR / DVP / LDV
Overview
Public Health Issue: The most effective prophylactic treatment for smallpox, a class A biological weapon threat, is vaccination with vaccinia-based smallpox vaccines. However, because of the known rate of complications that result from vaccination, particularly in certain high-risk populations (e.g., the immunocompromised, the old, or the very young), the development of new-generation smallpox vaccines with improved safety profiles is a high priority. Efficacy evaluation of new-generation smallpox vaccines will depend on relevant animal efficacy studies (using the Animal Efficacy Rule) since the natural disease no longer exists and, thus, vaccines cannot be tested in the natural setting. In addition, biomarkers such as comparative studies of immune responses between traditional smallpox vaccines and new-generation vaccine candidates will need to be developed for use in both clinical trials and small animal models.
Regulatory Contribution: Since standard efficacy trials using smallpox are impossible, the evaluation of new candidate vaccines will require comparing the new vaccine to proven effective smallpox vaccines using biomarkers reflective of the immune response (in humans and animals) and, using animal models, of protection against lethal challenge.
Research Approach: This research program measures biomarkers of the elicited humoral (i.e., antibody) and cellular immune responses of second-generation smallpox vaccines in small animal models and compares these biomarkers to the responses elicited by the licensed vaccine, Dryvax®. This research program compares the ability of the new-generation vaccines to Dryvax® in their ability to protect against lethal challenge after vaccination. Other efforts include the development on new tests to identify the functionally relevant facets of the immune response, the development and validation of tests to ensure maintenance of consistent product quality, e.g., for safety to assure the attenuated phenotype for the new vaccines, and the development and evaluation of new approaches to laboratory-designed smallpox vaccines.
Mission Relevance and Outcomes: These studies will provide the scientific knowledge and tools for evaluating and supporting the development of new-generation safe and effective smallpox vaccines.
Publications
J Infect Dis 2007 Oct 1;196(7):1026-32
Antibodies to the A27 Protein of Vaccinia Virus Neutralize and Protect against Infection but Represent a Minor Component of Dryvax Vaccine-Induced Immunity.
He Y, Manischewitz J, Meseda CA, Merchlinsky M, Vassell RA, Sirota L, Berkower I, Golding H, Weiss CD
Clin Vaccine Immunol 2007 Aug;14(8):1032-44
Characterization and use of mammalian-expressed vaccinia virus extracellular membrane proteins for quantification of the humoral immune response to smallpox vaccines.
Garcia AD, Meseda CA, Mayer AE, Kumar A, Merchlinsky M, Weir JP
J Med Virol 2007 Apr 24;79(6):791-802
Microarray assay for evaluation of the genetic stability of modified vaccinia virus Ankara B5R gene.
Laassri M, Meseda CA, Williams O, Merchlinsky M, Weir JP, Chumakov K
Hepatology 2006 Aug 29;44(3):736-745
CD4+ immune escape and subsequent T-cell failure following chimpanzee immunization against hepatitis C virus.
Puig M, Mihalik K, Tilton JC, Williams O, Merchlinsky M, Connors M, Feinstone SM, Major ME
Virology 2005 Dec 5;343(1):128-40
Identification and preliminary characterization of vaccinia virus (Dryvax) antigens recognized by vaccinia immune globulin.
Jones-Trower A, Garcia A, Meseda CA, He Y, Weiss C, Kumar A, Weir JP, Merchlinsky M
J Virol 2005 Dec;79(24):15084-15090
Vaccinia Virus Nicking-Joining Enzyme Is Encoded by K4L (VACWR035).
Eckert D, Williams O, Meseda CA, Merchlinsky M
Virology 2005 Sep 1;339(2):164-75
Enhanced immunogenicity and protective effect conferred by vaccination with combinations of modified vaccinia virus Ankara and licensed smallpox vaccine Dryvax in a mouse model.
Meseda CA, Garcia AD, Kumar A, Mayer AE, Manischewitz J, King LR, Golding H, Merchlinsky M, Weir JP
Thromb Res 2005;116(4):335-44
Identification of a novel immunodominant cytotoxic T lymphocyte epitope derived from human factor VIII in a murine model of hemophilia A.
Wang W, Merchlinsky M, Inman J, Golding B
Vaccine 2004 Mar 29;22(11-12):1486-93
Mouse neurotoxicity test for vaccinia-based smallpox vaccines.
Li Z, Rubin SA, Taffs RE, Merchlinsky M, Ye Z, Carbone KM