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J Virol, May 1998, p. 4170-4182, Vol. 72, No. 5
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Recombinant Vaccine-Induced Protection against the Highly Pathogenic Simian Immunodeficiency Virus SIVmac251: Dependence on Route of Challenge Exposure

J. Benson,1 C. Chougnet,2 M. Robert-Guroff,1 D. Montefiori,3 P. Markham,4 G. Shearer,2 R. C. Gallo,1,5 M. Cranage,6 E. Paoletti,7 K. Limbach,7 D. Venzon,8 J. Tartaglia,7 and G. Franchini1,*

Basic Research Laboratory,1 Experimental Immunology Branch,2 and Biostatistics and Data Management Section,8 National Cancer Institute, Bethesda, Maryland 20892; Department of Surgery, Center for AIDS Research, Duke University Medical Center, Durham, North Carolina 277103; Advanced Bioscience Laboratories, Inc., Kensington, Maryland 208954; Division of Pathology, Center for Applied Microbiology and Research, Porton Down, Salisbury, Wilshire, United Kingdom6; Virogenetics Corporation, Troy, New York 121807; and Institute of Human Virology, University of Medicine, Baltimore, Maryland 212015

Received 24 September 1997/Accepted 6 February 1998

Vaccine protection from infection and/or disease induced by highly pathogenic simian immunodeficiency virus (SIV) strain SIVmac251 in the rhesus macaque model is a challenging task. Thus far, the only approach that has been reported to protect a fraction of macaques from infection following intravenous challenge with SIVmac251 was the use of a live attenuated SIV vaccine. In the present study, the gag, pol, and env genes of SIVK6W were expressed in the NYVAC vector, a genetically engineered derivative of the vaccinia virus Copenhagen strain that displays a highly attenuated phenotype in humans. In addition, the genes for the alpha  and beta  chains of interleukin-12 (IL-12), as well as the IL-2 gene, were expressed in separate NYVAC vectors and inoculated intramuscularly, in conjunction with or separate from the NYVAC-SIV vaccine, in 40 macaques. The overall cytotoxic T-lymphocyte (CTL) response was greater, at the expense of proliferative and humoral responses, in animals immunized with NYVAC-SIV and NYVAC-IL-12 than in animals immunized with the NYVAC-SIV vaccine alone. At the end of the immunization regimen, half of the animals were challenged with SIVmac251 by the intravenous route and the other half were exposed to SIVmac251 intrarectally. Significantly, five of the eleven vaccinees exposed mucosally to SIVmac251 showed a transient peak of viremia 1 week after viral challenge and subsequently appeared to clear viral infection. In contrast, all 12 animals inoculated intravenously became infected, but 5 to 6 months after viral challenge, 4 animals were able to control viral expression and appeared to progress to disease more slowly than control animals. Protection did not appear to be associated with any of the measured immunological parameters. Further modulation of immune responses by coadministration of NYVAC-cytokine recombinants did not appear to influence the outcome of viral challenge. The fact that the NYVAC-SIV recombinant vaccine appears to be effective per se in the animal model that best mirrors human AIDS supports the idea that the development of a highly attenuated poxvirus-based vaccine candidate can be a valuable approach to significantly decrease the spread of human immunodeficiency virus (HIV) infection by the mucosal route.

* Corresponding author. Mailing address: Basic Research Laboratory, National Cancer Institute, 37 Convent Dr., Bldg. 37, Rm. 6A11, Bethesda, MD 20892. Phone: (301) 496-6007. Fax: (301) 496-8394. E-mail: veffa{at}helix.nih.gov.

J Virol, May 1998, p. 4170-4182, Vol. 72, No. 5
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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