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Journal of Virology, November 2008, p. 10911-10921, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.01129-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Sequential Priming with Simian Immunodeficiency Virus (SIV) DNA Vaccines, with or without Encoded Cytokines, and a Replicating Adenovirus-SIV Recombinant Followed by Protein Boosting Does Not Control a Pathogenic SIVmac251 Mucosal Challenge{triangledown}

Thorsten Demberg,1 Jean D. Boyer,2 Nina Malkevich,1 L. Jean Patterson,1 David Venzon,3 Ebonita L. Summers,1 Irene Kalisz,4 V. S. Kalyanaraman,4 Eun Mi Lee,4 David B. Weiner,2 and Marjorie Robert-Guroff1*

Vaccine Branch, National Cancer Institute, Bethesda, Maryland 20892,1 Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6100,2 Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Maryland 20892,3 Advanced BioScience Laboratories, Inc., Kensington, Maryland 208954

Received 29 May 2008/ Accepted 19 August 2008

Previously, combination DNA/nonreplicating adenovirus (Ad)- or poxvirus-vectored vaccines have strongly protected against SHIV89.6P, DNAs expressing cytokines have modulated immunity elicited by DNA vaccines, and replication-competent Ad-recombinant priming and protein boosting has strongly protected against simian immunodeficiency virus (SIV) challenge. Here we evaluated a vaccine strategy composed of these promising components. Seven rhesus macaques per group were primed twice with multigenic SIV plasmid DNA with or without interleukin-12 (IL-12) DNA or IL-15 DNA. After a multigenic replicating Ad-SIV immunization, all groups received two booster immunizations with SIV gp140 and SIV Nef protein. Four control macaques received control DNA plasmids, empty Ad vector, and adjuvant. All vaccine components were immunogenic, but the cytokine DNAs had little effect. Macaques that received IL-15-DNA exhibited higher peak anti-Nef titers, a more rapid anti-Nef anamnestic response postchallenge, and expanded CD8CM T cells 2 weeks postchallenge compared to the DNA-only group. Other immune responses were indistinguishable between groups. Overall, no protection against intrarectal challenge with SIVmac251 was observed, although immunized non-Mamu-A*01 macaques as a group exhibited a statistically significant 1-log decline in acute viremia compared to non-Mamu-A*01 controls. Possible factors contributing to the poor outcome include administration of cytokine DNAs to sites different from the Ad recombinants (intramuscular and intratracheal, respectively), too few DNA priming immunizations, a suboptimal DNA delivery method, failure to ensure delivery of SIV and cytokine plasmids to the same cell, and instability and short half-life of the IL-15 component. Future experiments should address these issues to determine if this combination approach is able to control a virulent SIV challenge.

* Corresponding author. Mailing address: NIH, NCI, 41 Medlars Drive, Building 41, Room D804, Bethesda, MD 20892-5065. Phone: (301) 496-2114. Fax: (301) 402-0055. E-mail: guroffm{at}mail.nih.gov

{triangledown} Published ahead of print on 27 August 2008.

Journal of Virology, November 2008, p. 10911-10921, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.01129-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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