CBER Expertise
Development and evaluation of pre-clinical safety and efficacy disease models for bacterial vaccines: Anthrax and Pertussis (Whooping Cough)
Principal Investigator: Tod Merkel, PhD
Office / Division / Lab: OVRR / DBPAP / LRSP
Overview
Public Health Issue: Anthrax (a Class A Select Agent) and Pertussis (which causes a common childhood illness, whooping cough) vaccines and therapeutics are evaluated for safety and efficacy by the FDA. Critical to this evaluation are the studies performed before testing in patients, i.e., preclinical studies. In the case of Pertussis and Anthrax, clinical efficacy studies may be difficult to perform (i.e., insufficient natural infections to study) or unethical to perform (i.e., it is not ethical to challenge vaccinees with a serious and often lethal infection), and, thus, appropriate animal disease models are needed to provide or support efficacy data (Animal Efficacy Rule). However, for B. anthracis and B. pertussis, appropriate animal models have not yet been developed nor completely evaluated using molecular and immunological techniques.
Regulatory Contribution: The availability of well-defined animal models of disease has direct regulatory impact by provision of critical information required for the pre-clinical evaluation of efficacy and safety of new vaccines and therapies.
Research Approach: Animal models are developed and evaluated to determine the interaction between the host and two important respiratory pathogens, Bordetella pertussis and Bacillus anthracis:: (1) Genetic and molecular studies are used to identify and characterize the bacterial components that are required to establish infection and cause disease, as these bacterial products may represent good targets for vaccines and therapeutic treatments and, (2) Animal models and immunological studies are used to identify and characterize the immune response to the bacterial pathogens to develop biomarkers to indicate vaccine efficacy. Because critical animal and clinical trials designed to demonstrate efficacy will be required in order to move new generation vaccines against these pathogens into clinical trials, an important aspect of our work is the development and refinement of mouse aerosol challenge models for B. anthracis and B. pertussis, a model that mimics the natural route of infection of these agents.
Mission Relevance & Outcomes: This research program provides the new scientific tools and knowledge required for the evaluation of anthrax vaccine efficacy and safety for the evaluation of the next generation of B. anthracis and B. pertussis vaccines.
Publications
Infect Immun 2009 Jan;77(1):255-65
Role of anthrax toxins in dissemination, disease progression, and induction of protective adaptive immunity in the mouse aerosol challenge model.
Loving CL, Khurana T, Osorio M, Lee GM, Kelly VK, Stibitz S, Merkel TJ
Infect Immun 2008 May;76(5):2177-82
Anamnestic Protective Immunity to Bacillus anthracis is Antibody-mediated but Independent of Complement and Fc Receptors.
Harvill ET, Osorio M, Loving CL, Lee GM, Kelly VK, Merkel TJ
Infect Immun 2007 Jun;75(6):2689-98
A Murine Aerosol Challenge Model of Anthrax.
Loving CL, Kennett M, Lee GM, Grippe VK, Merkel TJ
Proc Natl Acad Sci U S A 2006 Dec 19;103(51):19272-7
A fully integrated microfluidic genetic analysis system with sample-in-answer-out capability.
Easley CJ, Karlinsey JM, Bienvenue JM, Legendre LA, Roper MG, Feldman SH, Hughes MA, Hewlett EL, Merkel TJ, Ferrance JP, Landers JP
Infect Immun 2005 Nov;73(11):7535-40
MyD88-dependent signaling contributes to protection following Bacillus anthracis spore challenge of mice: implications for Toll-like receptor signaling.
Hughes MA, Green CS, Lowchyj L, Lee GM, Grippe VK, Smith MF Jr, Huang LY, Harvill ET, Merkel TJ
Infect Immun 2005 Jul;73(7):4420-2
Complement depletion renders C57BL/6 mice sensitive to the Bacillus anthracis Sterne strain.
Harvill ET, Lee G, Grippe VK, Merkel TJ
J Bacteriol 2005 Mar;187(5):1648-58
Activation of the vrg6 Promoter of Bordetella pertussis by RisA.
Croinin TO, Grippe VK, Merkel TJ
Infect Immun 2004 Nov;72(11):6382-9
Cytokine response to infection with Bacillus anthracis spores.
Pickering AK, Osorio M, Lee GM, Grippe VK, Bray M, Merkel TJ
Infect Immun 2004 May;72(5):3069-72
Macrophages release tumor necrosis factor alpha and interleukin-12 in response to intracellular Bacillus anthracis spores.
Pickering AK, Merkel TJ