[CCoE Notice] Seminar: Design of Immunotherapeutics to Prevent & Treat Infectious Diseases

[Grayson, Audrey A]

ChBE Dept. Seminar
10:30am-11:30am, Friday, November 15, 2013
Rm W122
"Design of Immunotherapeutics to Prevent & Treat Infectious Diseases"
Jennifer Maynard
University of Texas at Austin


ABSTRACT: The protein engineering toolbox has been used extensively to develop designer enzymes and antibodies meeting pre-determined biochemical/ biophysical specifications to maximize their industrial or clinical efficacy. However, protein engineering has seen only minor applications in development of therapeutics - including prophylactic vaccines and passive immunization - to prevent infectious diseases. Here, we report our progress in design of antigens and instant immune responses which hinges upon knowledge of protein structure-function relationships.

In spite of near-universal vaccination, whooping cough remains a significant public health problem with no specific therapy for established disease. Indeed, rates have been rising dramatically since the full introduction of the acellular vaccine. To understand this vaccine's limitations and contribute to design of the third generation vaccines, we have examined a number of relevant neutralizing epitopes. We have identified the location of a potently neutralizing epitope on the pertussis toxin and the mechanism by which antibodies binding this epitope can block toxin function. We further show that this epitope is damaged by the vaccine formulation process and that immunization with the current vaccine results in a low level of antibodies binding this epitope relative to natural infection.

The adenylate cyclase toxin (ACT) is an important virulence factor not currently included in any vaccine formulation, with poorly characterized protective epitopes. To better define these, we expressed full-length and individual ACT domains in E. coli and analyzed murine ACT-specific antibody repertoires. Of the four domains, one appears to be a "decoy domain," dominating the antibody response, yet producing non-neutralizing antibodies. In contrast, fewer antibodies were identified binding epitopes in other domains but several of these potently neutralized ACT's adenylate cyclase and hemolytic activities. Immunization with just this domain produces a robust neutralizing antibody response, suggesting it is a candidate for inclusion in future vaccines.

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