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J. Virol. doi:10.1128/JVI.00353-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Differential Antigen Requirements for Protection Against Systemic and Intranasal Vaccinia Virus Challenges in Mice

Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; Crucell Holland BV, 2301 CA, Leiden, The Netherlands; National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

^* To whom correspondence should be addressed. Email: dbarouch{at}bidmc.harvard.edu.

	Abstract

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 intracellular mature virion (IMV) antigens A27L and L1R and extracellular enveloped virion (EEV) antigens A33R and B5R in a murine vaccinia challenge model. A single immunization with the rAd35-L1R vector effectively protected mice against a lethal systemic vaccinia 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 (NAbs) afforded post-exposure prophylaxis following systemic vaccinia infection. In contrast, the combination of rAd35-L1R and rAd35-B5R vectors was required to protect mice against a lethal intranasal vaccinia 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 challenge. These studies also suggest that rAd vectors warrant further assessment as candidate subunit smallpox vaccines.