Adjuvanting a Simian Immunodeficiency Virus Vaccine with Toll-Like Receptor Ligands Encapsulated in Nanoparticles Induces Persistent Antibody Responses and Enhanced Protection in TRIM5α Restrictive Macaques
Adjuvanting a Simian Immunodeficiency Virus Vaccine with Toll-Like Receptor Ligands Encapsulated in Nanoparticles Induces Persistent Antibody Responses and Enhanced Protection in TRIM5α Restrictive Macaques
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DOI：
10.1128/jvi.01844-16
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发表时间：
2017-02-01
影响因子：
5.4
通讯作者：
Pulendran, Bali
中科院分区：
文献类型：
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作者：
Kasturi, Sudhir Pai;Kozlowski, Pamela A.;Pulendran, Bali
我们先前的工作已经表明，用对Toll样受体4（TLR 4）和TLR 7/8特异性的配体辅助的抗原包封在基于聚（乳酸-共-乙醇酸）（PLGA）的纳米颗粒（NP）中，在小鼠和猕猴中诱导稳健和持久的免疫应答。我们研究了这些NP佐剂在诱导针对猴免疫缺陷病毒（SIV）的保护性免疫中的功效。用含有TLR 4和TLR 7/8激动剂与可溶性重组SIVmac 239衍生的包膜（Env）gp 140和Gag p55（蛋白质）混合的NP或含有SIVmac 239 Env和Gag的病毒样颗粒（VLP）免疫恒河猴（RM）。NP佐剂化的疫苗诱导稳健的先天性应答、更大幅度和持久性的抗原特异性抗体应答以及与用明矾佐剂化的疫苗实现的那些相比增强的浆母细胞应答。NP-佐剂疫苗诱导抗原特异性、长寿命的浆细胞（LLPC），其在疫苗接种后在骨髓中持续数月。NP佐剂疫苗诱导的免疫应答与在携带TRIM 5 α限制性等位基因的动物中增强的针对重复低剂量、阴道内用异源SIVsmE 660攻击的保护相关。蛋白质-NP免疫诱导的保护作用与血清和阴道分泌物中Env特异性IgG抗体的攻击前滴度相关。然而，对于用VLP-NP或明矾作为佐剂的免疫，没有这种相关性是明显的。在初次接种后最初几小时至几天内分离的外周血单核细胞的转录谱显示，NP佐剂疫苗诱导的分子特征与黄热病毒减毒活疫苗诱导的分子特征相似。该系统方法鉴定了与阴道分泌物中的Env特异性抗体应答和抗感染保护相关的早期血液转录特征。这些结果表明，佐剂的NP佐剂在诱导持久性和保护性抗体反应对SIV在RM与设计的疫苗对人类免疫缺陷病毒（HIV）的影响。重要RV 144 HIV疫苗试验的结果，这表明随着时间的推移保护性免疫力的快速减弱，强调了需要制定战略，以提高保护性免疫反应的持久性。我们最近在小鼠中的工作突出了纳米颗粒包封的TLR配体（NP）诱导在小鼠中持续一生的有效且持久的抗体应答的能力。在本研究中，我们评估了这些NP佐剂在非人灵长类动物中促进针对SIV的稳健和持久的保护性免疫应答的能力。我们的研究结果表明，用NP佐剂与可溶性SIV Env或病毒样颗粒形式的Env（VLP）混合免疫恒河猴在血清和阴道分泌物中诱导有效和持久的Env特异性抗体应答。这些反应是上级的明矾佐剂诱导的，他们导致增强保护对低剂量阴道内攻击与异源株SIV在动物与TRIM 5a限制性等位基因。这些结果突出了这种NP TLR L佐剂在目前正在开发的下一代HIV免疫原中促进针对HIV的稳健和持久的抗体应答的潜力。
Our previous work has shown that antigens adjuvanted with ligands specific for Toll-like receptor 4 (TLR4) and TLR7/8 encapsulated in poly(lactic-co-glycolic) acid (PLGA)-based nanoparticles (NPs) induce robust and durable immune responses in mice and macaques. We investigated the efficacy of these NP adjuvants in inducing protective immunity against simian immunodeficiency virus (SIV). Rhesus macaques (RMs) were immunized with NPs containing TLR4 and TLR7/8 agonists mixed with soluble recombinant SIVmac239-derived envelope (Env) gp140 and Gag p55 (protein) or with virus-like particles (VLPs) containing SIVmac239 Env and Gag. NPadjuvanted vaccines induced robust innate responses, antigen-specific antibody responses of a greater magnitude and persistence, and enhanced plasmablast responses compared to those achieved with alum-adjuvanted vaccines. NP-adjuvanted vaccines induced antigen-specific, long-lived plasma cells (LLPCs), which persisted in the bone marrow for several months after vaccination. NP-adjuvanted vaccines induced immune responses that were associated with enhanced protection against repeated low-dose, intravaginal challenges with heterologous SIVsmE660 in animals that carried TRIM5 alpha restrictive alleles. The protection induced by immunization with protein-NP correlated with the prechallenge titers of Env-specific IgG antibodies in serum and vaginal secretions. However, no such correlate was apparent for immunization with VLP-NP or alum as the adjuvant. Transcriptional profiling of peripheral blood mononuclear cells isolated within the first few hours to days after primary vaccination revealed that NP-adjuvanted vaccines induced a molecular signature similar to that induced by the live attenuated yellow fever viral vaccine. This systems approach identified early blood transcriptional signatures that correlate with Envspecific antibody responses in vaginal secretions and protection against infection. These results demonstrate the adjuvanticity of the NP adjuvant in inducing persistent and protective antibody responses against SIV in RMs with implications for the design of vaccines against human immunodeficiency virus (HIV).IMPORTANCE The results of the RV144 HIV vaccine trial, which demonstrated a rapid waning of protective immunity with time, have underscored the need to develop strategies to enhance the durability of protective immune responses. Our recent work in mice has highlighted the capacity of nanoparticle-encapsulated TLR ligands (NP) to induce potent and durable antibody responses that last a lifetime in mice. In the present study, we evaluated the ability of these NP adjuvants to promote robust and durable protective immune responses against SIV in nonhuman primates. Our results demonstrate that immunization of rhesus macaques with NP adjuvants mixed with soluble SIV Env or a virus-like particle form of Env (VLP) induces potent and durable Env-specific antibody responses in the serum and in vaginal secretions. These responses were superior to those induced by alum adjuvant, and they resulted in enhanced protection against a low-dose intravaginal challenge with a heterologous strain of SIV in animals with TRIM5a restrictive alleles. These results highlight the potential for such NP TLR L adjuvants in promoting robust and durable antibody responses against HIV in the next generation of HIV immunogens currently being developed.