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Journal of Virology, July 2008, p. 6829-6837, Vol. 82, No. 14
0022-538X/08/$08.00+0     doi:10.1128/JVI.00353-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Differential Antigen Requirements for Protection against Systemic and Intranasal Vaccinia Virus Challenges in Mice {triangledown}

David R. Kaufman,1 Jaap Goudsmit,2 Lennart Holterman,2 Bonnie A. Ewald,1 Matthew Denholtz,1 Colleen Devoy,1 Ayush Giri,1 Lauren E. Grandpre,1 Jean-Michel Heraud,3 Genoveffa Franchini,3 Michael S. Seaman,1 Menzo J. E. Havenga,2 and Dan H. Barouch1*

Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215,1 Crucell Holland BV, 2301 CA, Leiden, The Netherlands,2 National Cancer Institute, National Institutes of Health, Bethesda, Maryland 208923

Received 18 February 2008/ Accepted 24 April 2008

The development of a subunit vaccine for smallpox represents a potential strategy to avoid the safety concerns associated with replication-competent vaccinia virus. Preclinical studies to date with subunit smallpox vaccine candidates, however, have been limited by incomplete information regarding protective antigens and the requirement for multiple boost immunizations to afford protective immunity. Here we explore the protective efficacy of replication-incompetent, recombinant adenovirus serotype 35 (rAd35) vectors expressing the vaccinia virus intracellular mature virion (IMV) antigens A27L and L1R and extracellular enveloped virion (EEV) antigens A33R and B5R in a murine vaccinia virus challenge model. A single immunization with the rAd35-L1R vector effectively protected mice against a lethal systemic vaccinia virus challenge. The rAd35-L1R vector also proved more efficacious than the combination of four rAd35 vectors expressing A27L, L1R, A33R, and B5R. Moreover, serum containing L1R-specific neutralizing antibodies afforded postexposure prophylaxis after systemic vaccinia virus infection. In contrast, the combination of rAd35-L1R and rAd35-B5R vectors was required to protect mice against a lethal intranasal vaccinia virus challenge, suggesting that both IMV- and EEV-specific immune responses are important following intranasal infection. Taken together, these data demonstrate that different protective antigens are required based on the route of vaccinia virus challenge. These studies also suggest that rAd vectors warrant further assessment as candidate subunit smallpox vaccines.

* Corresponding author. Mailing address: Research East Room 213, Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215. Phone: (617) 667-4434. Fax: (617) 667-8210. E-mail: dbarouch{at}bidmc.harvard.edu

{triangledown} Published ahead of print on 30 April 2008.

Journal of Virology, July 2008, p. 6829-6837, Vol. 82, No. 14
0022-538X/08/$08.00+0     doi:10.1128/JVI.00353-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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