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Infection and Immunity, December 2006, p. 6624-6631, Vol. 74, No. 12
0019-9567/06/$08.00+0     doi:10.1128/IAI.00437-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Immunogenicity of a Yersinia pestis Vaccine Antigen Monomerized by Circular Permutation{triangledown}

David A. Chalton,1 Julie A. Musson,2 Helen Flick-Smith,3 Nicola Walker,3 Alistair McGregor,1 Heather K. Lamb,1 E. Diane Williamson,3 Julie Miller,3 John H. Robinson,2 and Jeremy H. Lakey1*

Institute for Cell and Molecular Biosciences, University of Newcastle upon Tyne, Framlington Place, Newcastle NE2 4HH, United Kingdom,1 Musculoskeletal Research Group, Clinical Medical Sciences, University of Newcastle upon Tyne, Framlington Place, Newcastle NE2 4HH, United Kingdom,2 Defence Science and Technology Laboratory, Porton Down, Salisbury, Wiltshire SP4 0JQ, United Kingdom3

Received 17 March 2006/ Returned for modification 24 April 2006/ Accepted 4 September 2006

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-2b-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-2d-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.

* Corresponding author. Mailing address: Institute for Cell and Molecular Biosciences, University of Newcastle upon Tyne, Framlington Place, Newcastle NE2 4HH, United Kingdom. Phone: 44 191 222 8865. Fax: 44 191 222 7424. E-mail: j.h.lakey{at}ncl.ac.uk.

{triangledown} Published ahead of print on 18 September 2006.

Editor: J. B. Bliska

Infection and Immunity, December 2006, p. 6624-6631, Vol. 74, No. 12
0019-9567/06/$08.00+0     doi:10.1128/IAI.00437-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.





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