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Journal of Virology, May 2006, p. 4447-4457, Vol. 80, No. 9
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.9.4447-4457.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Recombinant Vesicular Stomatitis Virus Vectors Expressing Herpes Simplex Virus Type 2 gD Elicit Robust CD4+ Th1 Immune Responses and Are Protective in Mouse and Guinea Pig Models of Vaginal Challenge

Robert J. Natuk,*{dagger} David Cooper,{dagger} Min Guo, Priscilla Calderon, Kevin J. Wright, Farooq Nasar, Susan Witko, Diane Pawlyk, Margaret Lee, Joanne DeStefano, Donna Tummolo, Aaron S. Abramovitz, Seema Gangolli, Narender Kalyan, David K. Clarke, R. Michael Hendry, John H. Eldridge, Stephen A. Udem, and Jacek Kowalski

Department of Vaccines Discovery Research, Wyeth Research, 401 N. Middletown Rd., Pearl River, New York 10965

Received 20 January 2006/ Accepted 10 February 2006

Recombinant vesicular stomatitis virus (rVSV) vectors offer an attractive approach for the induction of robust cellular and humoral immune responses directed against human pathogen target antigens. We evaluated rVSV vectors expressing full-length glycoprotein D (gD) from herpes simplex virus type 2 (HSV-2) in mice and guinea pigs for immunogenicity and protective efficacy against genital challenge with wild-type HSV-2. Robust Th1-polarized anti-gD immune responses were demonstrated in the murine model as measured by induction of gD-specific cytotoxic T lymphocytes and increased gamma interferon expression. The isotype makeup of the serum anti-gD immunoglobulin G (IgG) response was consistent with the presence of a Th1-CD4+ anti-gD response, characterized by a high IgG2a/IgG1 IgG subclass ratio. Functional anti-HSV-2 neutralizing serum antibody responses were readily demonstrated in both guinea pigs and mice that had been immunized with rVSV-gD vaccines. Furthermore, guinea pigs and mice were prophylactically protected from genital challenge with high doses of wild-type HSV-2. In addition, guinea pigs were highly protected against the establishment of latent infection as evidenced by low or absent HSV-2 genome copies in dorsal root ganglia after virus challenge. In summary, rVSV-gD vectors were successfully used to elicit potent anti-gD Th1-like cellular and humoral immune responses that were protective against HSV-2 disease in guinea pigs and mice.

* Corresponding author. Mailing address: Department of Vaccines Discovery Research, Wyeth Research, 401 N. Middletown Rd., Pearl River, NY 10965. Phone: (845) 602-5995. Fax: (845) 602-4941. E-mail: natukr{at}wyeth.com.

{dagger} R.J.N. and D.C. contributed equally to this work.

Journal of Virology, May 2006, p. 4447-4457, Vol. 80, No. 9
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.9.4447-4457.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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