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40 Durable Long-Term Immune Control of Viremia and Prevention of Clinical AIDS in Rhesus Monkeys by Plasmid Cytokine-Augmented DNA Vaccination
D. H. Barouch*1, S. Santra1, J. E. Schmitz1, M. J. Kuroda1, W. Wagner2, J. Kunstman3, D. C. Montefiori4, S. M. Wolinsky3, M. G. Lewis2, and N. L. Letvin1
1BIDMC, Harvard Med. Sch., Boston, MA, USA; 2Southern Res. Inst., Frederick, MD, USA; 3Northwestern Univ., Chicago, IL, USA; and 4Duke Univ., Durham, NC, USA
Background: Vaccine-elicited cellular immune responses have recently been shown to provide short-term control of viremia and prevent clinical disease progression following pathogenic simian-human immunodeficiency virus (SHIV) challenges in rhesus monkeys. The durability and generalizability of this protection, however, have been uncertain. Here we report the long-term protective efficacy of DNA vaccine-elicited immune responses against pathogenic SHIV-89.6P and SIVsmE660 viral challenges.
Methods: Vaccinated monkeys were challenged and followed prospectively for CD4+ and CD8+ T-cell responses, neutralizing Ab responses, viral loads, viral sequence diversity, CD4+ T-cell counts, and clinical disease progression for 1.5 years.
Results: Monkeys immunized with gag/env DNA vaccines augmented by a plasmid expressing IL-2/Ig maintained potent virus-specific CD4+ and CD8+ T-cell responses, durable control of viral replication, reduced viral sequence diversity, complete preservation of CD4+ T cells, and prevention of clinical AIDS for at least 1.5 years following infection with SHIV-89.6P. Moreover, there was a significant reduction in overall mortality in the vaccinated monkeys as compared with the sham vaccinated controls (p = 0.018 using a Fisher’s exact test). Clinical disease progression occurred in a subset of monkeys immunized with DNA vaccines alone or DNA vaccines augmented by IL-2/Ig protein and correlated with the loss of virus-specific CD4+ T-cell responses or viral escape from CD8+ T-cell recognition. In addition, gag DNA vaccination afforded comparable reductions of viral loads for 1.5 years following SIVsmE660 challenge, suggesting the generalizability of these findings.
Conclusions: We conclude that potent vaccine-elicited cellular immune responses can confer long-term immune control of viremia and durable protection against clinical disease progression for at least 1.5 years following infection with a pathogenic AIDS virus in rhesus monkeys.
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