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37 Replication-Incompetent Recombinant Adenovirus Vector Expressing SIV gag Elicits Robust and Effective Cellular Immune Responses in Rhesus Macaques
T.-M. Fu, W. Trigona*, M.-E. Davies, Z.-Q. Zhang, D. Casimiro, S. Dubey, D. C. Freed, J. Joyce, K. Grimm, W. A. Schleif, N. L. Letvin, E. A. Emini, and J. W. Shiver
Merck Res. Labs, West Point, PA, USA
Background: Accumulating evidence supports the roles for CD4+ and CD8+ T-cell immune responses in controlling HIV-1 infection. Thus, induction of T-cell immunity has been indicated as an important goal for developing effective AIDS vaccines. This study was designed to compare the efficacy of several vaccines for induction of cellular immune response.
Methods: Rhesus macaques, selected for expression of Mamu-A*01 MHC class I allele, were immunized with SIV gag-based plasmid DNA vaccines, an MVA vector, or a replication-incompetent adenovirus vector. The DNA vaccines were formulated either in saline or with 2 experimental adjuvants. The CTL response against an immunodominant CTL epitope restricted by Mamu-A*01 (residues 181(189, p11CM) was quantitatively evaluated with a tetramer (p11CM tetramer). Twelve weeks after the completion of immunization regimens, all monkeys were challenged intravenously with a pathogenic simian-human immunodeficiency virus (SHIV 89.6P).
Results: The most potent T-cell response was elicited by the replication-incompetent adenovirus vector. Concordantly, immunization with adenovirus vector provided the best protection in the rhesus monkeys against challenge. Protection was indicated as prevention of CD4 loss, containment of acute and chronic viremia, and absence of immunodeficiency-related symptoms and death. Protection was also demonstrated to be correlated with pre-challenge CTL response defined by p11CM tetramer staining with statistical significance.
Conclusions: These results provided promising leads to development of effective HIV-1 vaccines, and importantly, provided proof for the concept that vaccine-elicited CTL response alone was capable of mitigating infection of a highly pathogenic virus.
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