Yale University School of Medicine, 310 Cedar St., New Haven, CT 06510, USA.
J Virol. 2011 Jun;85(12):5764-72. doi: 10.1128/JVI.00342-11. Epub 2011 Apr 13.
We constructed vaccine vectors based on live recombinant vesicular stomatitis virus (VSV) and a Semliki Forest virus (SFV) replicon (SFVG) that propagates through expression of the VSV glycoprotein (G). These vectors expressing simian immunodeficiency virus (SIV) Gag and Env proteins were used to vaccinate rhesus macaques with 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 10(6) to 10(8) copies/ml. In contrast, four of the vaccinees showed significant (P = 0.03) apparent sterilizing immunity and no detectable viral loads. Subsequent CD8(+) T cell depletion confirmed the absence of SIV infection in these animals. The two other vaccinees had peak viral loads of 7 × 10(5) and 8 × 10(3) copies/ml, levels below those of all of the controls, and showed undetectable virus loads by day 42 postchallenge. The vaccine regimen induced high-titer prechallenge serum neutralizing antibodies (nAbs) 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.
我们构建了基于活重组单纯疱疹病毒（VSV）和 Semliki Forest 病毒（SFV）复制子（SFVG）的疫苗载体，该复制子通过表达 VSV 糖蛋白（G）进行复制。这些表达猴免疫缺陷病毒（SIV）Gag 和 Env 蛋白的载体被用于用新的异源初免-加强免疫方案接种恒河猴，旨在优化抗体诱导。然后，用具有多种 SIVsmE660 准种的高剂量黏膜挑战来接种 6 只接种疫苗的动物和 6 只对照动物。所有对照动物均被感染，病毒 RNA 载量达到 10(6)到 10(8)拷贝/ml。相比之下，4 只疫苗接种动物表现出明显的（P = 0.03）、具有统计学意义的绝育性免疫，并且没有检测到病毒载量。随后的 CD8(+)T 细胞耗竭证实了这些动物中不存在 SIV 感染。另外两只疫苗接种动物的病毒载量峰值分别为 7×10(5)和 8×10(3)拷贝/ml，低于所有对照动物的水平，并且在挑战后第 42 天未检测到病毒。该疫苗方案诱导了针对一些克隆 SIVsmE660 Env 蛋白的高滴度预挑战血清中和抗体（nAbs），但未检测到能够中和挑战病毒群的抗体。疫苗诱导的细胞免疫反应通常较弱，与保护无关。尽管保护的免疫相关性尚不清楚，但异源 VSV/SFVG 初免-加强免疫显然是一种有效的疫苗方案，可诱导病毒 nAbs 和对异质病毒群的保护。
