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Lookup NU author(s): Dr David Allen Chalton, Dr Heather Lamb, Professor John Robinson, Professor Jeremy LakeyORCiD
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Caf1, a chaperone-usher protein from Yersinia pestis, is a major protective antigen in the development of subunit vaccines against plague. However, recombinant Caf1 forms polymers of indeterminate size. We report the conversion of Caf1 from a polymer to a monomer by circular permutation of the gene. Biophysical evaluation confirmed that the engineered Caf1 was a folded monomer. We compared the immunogenicity of the engineered monomer with polymeric Caf1 in antigen presentation assays to CD4 T-cell hybridomas in vitro, as well as in the induction of antibody responses and protection against subcutaneous challenge with Y. pestis in vivo. In C57BL/6 mice, for which the major H-2 b-restricted immunodominant CD4 T-cell epitopes were intact in the engineered monomer, immunogenicity and protective efficacy were preserved, although antibody titers were decreased 10-fold. Disruption of an H-2 d-restricted immunodominant CD4 T-cell epitope during circular permutation resulted in a compromised T-cell response, a low postvaccination antibody titer, and a lack of protection of BALB/c mice. The use of circular permutation in vaccine design has not been reported previously. Copyright © 2006, American Society for Microbiology. All Rights Reserved.
Author(s): Chalton DA, Musson JA, Flick-Smith H, Walker N, McGregor A, Lamb HK, Williamson ED, Miller J, Robinson JH, Lakey JH
Publication type: Article
Publication status: Published
Journal: Infection and Immunity
Year: 2006
Volume: 74
Issue: 12
Pages: 6624-6631
Print publication date: 01/12/2006
ISSN (print): 0019-9567
ISSN (electronic): 1070-6313
Publisher: American Society for Microbiology
URL: http://dx.doi.org/10.1128/IAI.00437-06
DOI: 10.1128/IAI.00437-06
PubMed id: 16982834
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