EFFICACY OF A DNA/MVA VACCINE TO PROTECT AGAINST REPEATED VAGINAL SIV CHALLENGE

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。艾滋病毒的自然传播是通过粘膜表面以低效率发生的，但很少有SIV疫苗研究在设计这些条件的条件下检验保护性免疫。我们研究了多基因DNA/MVA PRIME/BOOST免疫方案在诱导SIV黏膜免疫应答和预防反复低剂量阴道SIV攻击方面的有效性。DNA/MVA免疫后2周，6个PBMC的GAG特异性斑点形成细胞(SFC)数超过3500SFCs/10，并诱导出对GAG、Env和Nef的强烈的干扰素-γELISPOT反应。DNA/MVA疫苗中的Gag181-189四聚体结合细胞在MVA加强接种2周后在阴道和直肠活检组织中检测到的频率与在外周血中观察到的频率相似。DNA/MVA初始增强方案可显著减少攻击后的病毒血症。在DNA/MVA疫苗接种的动物中，病毒血症的控制与显著的记忆SIV特异性CD8+T细胞应答有关，A*01/Gag181-189四聚体结合CD8+T细胞的峰值从10.6%到36%，而对照组为1.8%+/-1.2%。在A*01+和A*01-疫苗中观察到，通过保留CD4+T细胞计数，病毒血症的控制得到了改善。我们的结果表明，多基因DNA/MVA Prime/Boost疫苗能够在直肠和阴道组织中诱导CD8+T细胞反应，并在反复低剂量阴道攻击后显著减少病毒血症。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Natural transmission of HIV occurs through mucosal surfaces at low efficiency, but few SIV vaccine studies have examined protective immunity under conditions designed to model these conditions. We investigated the efficacy of a multigenic DNA/MVA prime/boost vaccination regimen to induce mucosal immune responses to SIV and protect against repeated low-dose vaginal SIV challenge. DNA/MVA immunization induced vigorous IFN-gamma ELISPOT responses to Gag, Env and Nef, with Gag-specific spot forming cells (SFC) that exceeded 3500 SFCs/10 to the 6 PBMC 2 weeks after the MVA boost. Gag181-189 tetramer-binding cells in DNA/MVA vaccines were detected in vaginal and rectal biopsies at similar frequencies to those observed in peripheral blood 2 weeks after the MVA boost. The DNA/MVA prime boost regimen resulted in a significant reduction in viremia after challenge. Control of viremia in DNA/MVA vaccinated animals was associated with significant anamnestic SIV-specific CD8+ T cell responses, with peak values of A*01/Gag181-189 tetramer-binding CD8+ T cells ranging from 10.6% to 36%, compared to 1.8 percent +/- 1.2 percent in controls. Improved control of viremia was observed in both A*01+ and A*01- vaccines with preservation of CD4+ T cell counts. Our results demonstrate the ability of a multigenic DNA/MVA prime/boost vaccine to induce CD8+ T cell responses in rectal and vaginal tissues and provide substantial reduction in viremia after repeated low dose vaginal challenge.