Protective CMI mechanisms of a dual-subtype FIV vaccine

描述（由申请方提供）：原型和市售双亚型FIV疫苗由灭活亚型A和亚型D毒株组成，可对同源亚型、亚型A/B重组和异源亚型B攻毒提供灭菌保护。双亚型FIV疫苗在猫中的保护机制将为开发有效的人类HIV-1/AIDS疫苗提供见解。用纯化的双亚型FIV疫苗诱导的免疫球蛋白对未感染猫进行被动抗体免疫，可保护受体猫免受同源亚型的感染，这与疫苗诱导的病毒中和抗体（VNA）的存在相关。与此相反，被动保护没有实现对异源亚型B的攻击与VNA抗性菌株。此外，将T细胞富集群体从接种疫苗的猫过继转移（A-T）至MHC匹配的猫保护A-T受体免受同源和异源攻击。使用联合免疫途径（皮下、皮内、经皮和鼻内）的双亚型疫苗接种提供了针对同源阴道攻击的保护。上一个资助周期的这些结果表明，针对疫苗诱导的VNA敏感毒株（同源亚型毒株）的保护作用由VNA免疫和细胞介导免疫（CMI）介导，而针对异源亚型毒株的疫苗保护作用由CMI介导。竞争性更新资助中的研究旨在鉴定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（具体目标1）。拟定研究还将确定最佳接种途径和疫苗保护机制，以对抗同源或异源亚型的异源菌株的粘膜-阴道攻毒（具体目的2）。这些研究的最终目标是提供关于哪些病毒组分、宿主免疫应答、MHC谱和疫苗接种途径对于有效预防HIV-1在人类中的主要传播模式（粘膜和静脉内）是重要的见解。公共卫生相关性：自2002年7月以来，已售出180多万剂商业猫免疫缺陷病毒（FIV）疫苗，没有任何疫苗失效的病例。FIV在宠物猫中引起猫艾滋病，在世界范围内的流行率与HIV-1相似。这种FIV疫苗保护机制和对这种保护重要的病毒蛋白将在本补助金的拟议研究中确定。这些研究的结果应该会促进我们对如何设计有效的人类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.