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41 Intrarectal Challenge of Macaques Immunized with VEE Replicon Vectors
R. Johnston*1, N. Davis1, M. Collier1, M. Connell2, A. Nielsen1, L. Hensley1, D. Montefiori3, R. Swanstrom1, J. Frelinger1, C. Walker2, and P. Johnson2
1Univ. of North Carolina, Chapel Hill, NC, USA; 2Children's Res. Inst., Columbus, OH, USA; and 3Duke Univ., Durham, NC, USA
Background: Replicon vectors based on Venezuelan equine encephalitis virus (VEE) contain a self-replicating RNA encoding the VEE replicase proteins and expressing a gene of interest substituted for the VEE structural protein genes. The replicon RNA is encapsidated into VEE replicon particles (VRP) by supplying VEE capsid and envelope glycoproteins in trans. VRP expressing immunizing genes from a wide variety of pathogens have proven to be safe and effective vaccines in animal models, including primates. Macaques immunized with these vectors expressing genes of simian immunodeficiency virus (SIV) were examined in an intrarectal challenge experiment with highly pathogenic SIVsm E660.
Methods: A portion of the gag gene, the full-length gp160 gene, and a gene for gp160 truncated immediately prior to the membrane spanning domain (gp140) of the SIVsm H-4i clone were inserted into VEE replicon plasmids and packaged into separate VRP. A cocktail of the 3 VRP was administered to macaques subcutaneously at a dose of 107 infectious units of each VRP at 0, 1, and 4 months. At 5 months the animals were challenged with SIVsm E660 intrarectally.
Results: The immunization induced neutralizing antibodies in 6/6 vaccinees and CTL in 4/6. Upon challenge, the vaccinated group experienced reduced peak virus loads compared with controls, which received VRP expressing influenza HA. Virus load was reduced at set point and at 41 weeks post-challenge, and CD4 counts were preserved and even increased in the vaccinated animals.
Conclusions: Immunization with a VRP-based vaccine formulation provided significant protection from intrarectal challenge with a highly pathogenic SIV strain.
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