Protective CMI mechanisms of a dual-subtype FIV vaccine

描述(由申请人提供)：原型和商用双亚型FIV疫苗，由灭活的A和D亚型毒株组成，对同源亚型、A/B重组亚型和异源B亚型挑战具有灭菌保护作用。双亚型FIV疫苗在猫体内的保护机制将为人类有效的HIV-1/AIDS疫苗的开发提供借鉴。纯化的双亚型FIV疫苗诱导的免疫球蛋白对幼猫的被动抗体免疫可保护受体猫免受同源亚型的攻击，这与疫苗诱导的病毒中和抗体(VNA)的存在有关。相比之下，VNA抗性品系对异源B亚型的攻击不能获得被动保护。此外，从接种疫苗的猫到MHC匹配的猫的T细胞富集群的收养转移(A-T)保护了A-T受体免受同源和异源挑战。使用联合免疫途径(皮下、皮内、经皮和鼻腔)的双亚型疫苗提供了对同源阴道攻击的保护。来自前一个资金周期的这些结果表明，对疫苗诱导的VNA敏感毒株(同源亚型毒株)的保护是由VNA免疫和细胞免疫(CMI)共同介导的，而疫苗对异源亚型毒株的保护是由CMI介导的。竞争性更新赠款中的研究旨在确定T细胞的表型和功能，以及负责双亚型疫苗保护的病毒表位和MHC谱(特定目标1)。建议的研究还将确定最佳的疫苗接种途径(S)和疫苗对来自同源或异源亚型的异源菌株的黏膜-阴道攻击的保护机制(特定目标2)。这些研究的最终目标是深入了解哪些病毒成分、宿主免疫反应、MHC特征和疫苗接种途径对于有效预防人类主要的HIV-1传播方式(粘膜和静脉传播)是重要的。与公共卫生相关：自2002年7月以来，已售出180多万剂商用猫科动物免疫缺陷病毒(FIV)疫苗，无一例疫苗失效。FIV会导致宠物猫患上猫咪艾滋病，在全球范围内的流行与HIV-1类似。这种FIV疫苗的保护机制和对这种保护至关重要的病毒蛋白将在这项赠款的拟议研究中确定。这些研究的发现应该会促进我们对如何在人类身上设计有效的HIV-1疫苗的理解。

DESCRIPTION (provided by applicant): Prototype and commercial dual-subtype FIV vaccines, consisting of inactivated subtype-A and -D strains, conferred sterilizing protection against homologous subtype, subtype-A/B recombinant, and heterologous subtype-B challenges. The mechanisms of dual-subtype FIV vaccine protection in cats should provide insights to the development of effective HIV-1/AIDS vaccine in humans. Passive antibody immunization with purified dual-subtype FIV vaccine-induced immunoglobulin to naive cats afforded protection of the recipient cats against homologous subtype, which correlated with the presence of vaccine-induced virus neutralizing antibodies (VNA). In contrast, passive protection was not achieved against heterologous subtype-B challenge with VNA-resistant strain. Moreover, adoptive transfer (A-T) of T-cell enriched population from vaccinated cats to MHC-matched cats protected the A-T recipient against homologous and heterologous challenges. Dual-subtype vaccination using combined immunization routes (subcutaneous, intradermal, transcutaneous, & intranasal) afforded protection against homologous vaginal challenge. These results from the previous funding cycle suggest that protection against vaccine-induced VNA-susceptible strains (homologous subtype strains) is mediated by both VNA immunity and cell-mediated immunity (CMI), while vaccine protection against heterologous subtype strains is mediated by CMI. The studies in the competitive renewal grant are aimed at identifying the phenotypes and functions of the T cells as well as the viral epitopes and MHC profiles responsible for the dual-subtype vaccine protection (Specific aim 1). The proposed studies will also identify the best vaccination route(s) and the mechanisms of vaccine protection against mucosal-vaginal challenges with heterologous strains from homologous or heterologous subtype (Specific aim 2). The ultimate goal of these studies is to provide insights about which viral components, host immune responses, MHC profiles, and vaccination routes are important for an effective prophylaxis against the predominant transmission modes (mucosal and intravenous) of HIV-1 in humans. PUBLIC HEALTH RELEVANCE: Over 1.8 million doses of commercial feline immunodeficiency virus (FIV) vaccine have been sold since July 2002 without any cases of vaccine failure. FIV causes feline AIDS in pet cats and has worldwide prevalence similar to HIV-1. The mechanisms of this FIV vaccine protection and viral proteins important for such protection will be determined in the proposed studies of this grant. Findings from these studies should advance our understanding about how to design an effective HIV-1 vaccine in humans.