靶向Vγ2Vδ2、CD8和CD4效应T细胞的新型结核病疫苗及其免疫机制

耐多药结核和HIV的流行导致结核病死亡率居传染病之首。疫苗可防控传染病，但目前临床使用的结核疫苗BCG对成人无效，且20多年全球性的结核疫苗研发尚未成功。研发Th1细胞单一靶点的结核疫苗的临床试验最近失败。因此，急需研发多靶点的新型结核疫苗。我们团队20多年的研究证明灵长类独有的磷酸抗原特异性Vγ2Vδ2T细胞对结核感染具有显著的抗结核免疫和治疗作用。我们亦证实灵长类CD4Th细胞和CD8CTL都对结核病具免疫保护作用。然而，Vγ2Vδ2T细胞对低剂量结核菌自然感染的抗感染免疫预防机制和效果尚未阐明。另外，Vγ2Vδ2T细胞能否和CD4Th细胞和CD8CTL一起作为高效多免疫靶点协同预防HIV感染引起的潜伏结核感染发病尚无研究。本研究将应用我们已研发并系统报道的减毒高效李斯特菌载体疫苗以及我们独创的loss-of-function系统在灵长类动物深入研究验证这两大结核病疫苗科学问题。

Tuberculosis (TB), caused by M. tuberculosis (Mtb), remains the top killer among infectious diseases due to epidemics of HIV/AIDS and multi-drug resistance. The current TB vaccine, BCG, only protects young children but not adults. Until now, development of new effective TB vaccine has not been successful. Recent failure in Th1-targeted TB vaccine clinical trials indicate that effective TB vaccine should induce multiple protective immune cell subsets or targets. However, protective components/targets and mechanisms for protective TB vaccine remain unknown. Our seminal publications in Science, PNAS, PLOS Pathogens, Blood, J Immunol, J Infect Dis established immunity mechanisms whereby Vγ2Vδ2 Th1/CTL, CD8+CTL, and CD4+T effector cells protect against high-dose Mtb infection in nonhuman primates(NHP). Particularly, we elucidated that the dominant Vγ2Vδ2 T subset exhibit fast-acting innate/memory features, have multiple functions during infections, and protect against high-dose TB in NHP. Thus, one of the major goals in this project is to examine fast-protecting mechanisms whereby vaccine-elicited Vγ2Vδ2 T effector cells protect against low-dose 5 CFU Mtb infection mimicking human TB exposure. Another goal here in this project is to determine whether TB+HIV antigens’ immunization of protective Vγ2Vδ2 and CD4+ T and CD8+ T subsets can protect against HIV-induced reactivation of latent Mtb infection in NHP. We hypothesize that while immunized Vγ2Vδ2+Th1/CTL protect against TB by fast-protecting mechanisms and act in concert with CD4+Th1 and CD8+CTL to induce stronger synergistic immunity against TB and HIV-related TB. To facilitate mechanistic studies, we developed the innovative tool for in vivo Vγ2Vδ2 T-cell depletion leading to a reduced anti-TB immunity. We also have developed and published the innovative Listeria ΔactA prfA* (LM) vector. Positive findings will provide new and novel concepts/mechanisms for guiding future TB vaccine development.