John B. Schell, Nina F. Rose, Kapil Bahl, Kathryn Diller, Linda Buonocore, Meredith Hunter, Preston A. Marx, Ratish Gahmbira, Haili Tang, David C. Montefiori, Welkin E. Johnson, and John K. Rose*:
Yale University School of Medicine, New Haven, CT; Tulane National Primate Research Center, Covington, LA; Duke University Medical Center, Durham, NC; New England Regional Primate Research Center, Harvard University, Southborough, MA
* To whom correspondence should be addressed. Email: john.rose@yale.edu.
Abstract
We constructed vaccine vectors based on live recombinant vesicular stomatitis virus (VSV) and a Semliki Forest Virus replicon (SFVG) that propagates through expression of the VSV glycoprotein (G). These vectors expressing SIV Gag and Env proteins were used to vaccinate rhesus macaques in a new heterologous prime-boost regimen designed to optimize induction of antibody. Six vaccinated animals and six controls were then given a high-dose mucosal challenge with the diverse SIVsmE660 quasispecies. All control animals became infected and had peak viral RNA loads of 106-108 copies/ml. In contrast, four of the vaccinees showed significant (p=0.03) apparent sterilizing immunity and no detectable viral load. Subsequent CD8+ T cell depletion confirmed the absence of SIV infection in these animals. The two other vaccinees had peak viral loads of 7 x 105 and 8 x 103 copies/ml, levels below all of the controls, and showed undetectable virus loads by day 42 post-challenge. The vaccine regimen induced high-titer pre-challenge serum neutralizing antibodies (nAb) to some cloned SIVsmE660 Env proteins, but antibodies able to neutralize the challenge virus swarm were not detected. The cellular immune responses induced by the vaccine were generally weak and did not correlate with protection. Although the immune correlates of protection are not yet clear, the heterologous VSV/SFVG prime-boost is clearly a potent vaccine regimen for inducing virus nAbs and protection against a heterogeneous viral swarm.
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