Enhanced Influenza Virus-Like Particle Vaccination with a Structurally Optimized RIG-I Agonist as Adjuvant
Enhanced Influenza Virus-Like Particle Vaccination with a Structurally Optimized RIG-I Agonist as Adjuvant
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DOI：
10.1128/jvi.01526-15
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发表时间：
2015-10-01
影响因子：
5.4
通讯作者：
Hiscott, John
中科院分区：
文献类型：
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作者：
Beljanski, Vladimir;Chiang, Cindy;Hiscott, John
病毒RNA和胞质传感器RIG-I之间的分子相互作用代表了针对RNA病毒感染的有效免疫应答的发展中的初始触发，导致先天免疫激活和随后的适应性应答的诱导。在本研究中，检测了序列优化的含5 '-三磷酸的RNA（5' pppRNA）RIG-1激动剂（称为M8）与表达H5 N1流感病毒血凝素（HA）和神经氨酸酶（NA）作为免疫原的流感病毒样颗粒（VLP）（M8-VLP）的组合的佐剂性质。与VLP联合使用时，M8增加了对VLP免疫的抗体应答，提供了VLP抗原保留，并保护小鼠免受H5 N1流感病毒的致死性攻击。M8-VLP免疫还导致小鼠中针对流感病毒感染的长期保护性应答。与批准的或实验性佐剂明矾、AddaVax和poly（I. C）相比，VLP的M8佐剂增加了终点和抗体滴度，并抑制了肺中的流感病毒复制。独特的是，用M8-VLP免疫刺激T（H）1偏向的CD 4 T细胞应答，如通过CD 4 T细胞中T（H）1细胞因子水平增加和血清中IgG 2水平增加所确定的。总的来说，这些数据表明序列优化的，RIG-I-特异性激动剂是一种有效的佐剂，可用于增加流感VLP疫苗接种的效力，并显著改善体液和细胞介导的针对流感病毒攻击的保护性应答。重要信息开发新的佐剂以增加疫苗免疫原性是一个重要的目标，其寻求改善疫苗效力并最终预防危及健康的感染。人体健康该原理验证研究使用表达HA和NA的流感病毒样颗粒（VLP）作为免疫原，研究了序列优化的5' pppRNA激动剂（M8）的佐剂特性，其具有增强的刺激抗病毒和炎症基因网络的能力。VLP与M8联合接种可提高抗流感病毒抗体滴度，保护动物免受致命流感病毒攻击，突出了M8作为疫苗开发佐剂的潜在临床用途。总而言之，这些结果描述了一种新型的免疫刺激激动剂，其靶向细胞溶质RIG-I传感器，作为一种有吸引力的疫苗佐剂候选物，可用于提高疫苗效力，这是儿童和老年人群中的一个紧迫问题。
The molecular interaction between viral RNA and the cytosolic sensor RIG-I represents the initial trigger in the development of an effective immune response against infection with RNA viruses, resulting in innate immune activation and subsequent induction of adaptive responses. In the present study, the adjuvant properties of a sequence-optimized 5'-triphosphate-containing RNA (5' pppRNA) RIG-I agonist (termed M8) were examined in combination with influenza virus-like particles (VLP) (M8-VLP) expressing H5N1 influenza virus hemagglutinin (HA) and neuraminidase (NA) as immunogens. In combination with VLP, M8 increased the antibody response to VLP immunization, provided VLP antigen sparing, and protected mice from a lethal challenge with H5N1 influenza virus. M8-VLP immunization also led to long-term protective responses against influenza virus infection in mice. M8 adjuvantation of VLP increased endpoint and antibody titers and inhibited influenza virus replication in lungs compared with approved or experimental adjuvants alum, AddaVax, and poly(I.C). Uniquely, immunization with M8-VLP stimulated a T(H)1-biased CD4 T cell response, as determined by increased T(H)1 cytokine levels in CD4 T cells and increased IgG2 levels in sera. Collectively, these data demonstrate that a sequence-optimized, RIG-I-specific agonist is a potent adjuvant that can be utilized to increase the efficacy of influenza VLP vaccination and dramatically improve humoral and cellular mediated protective responses against influenza virus challenge.IMPORTANCEThe development of novel adjuvants to increase vaccine immunogenicity is an important goal that seeks to improve vaccine efficacy and ultimately prevent infections that endanger human health. This proof-of-principle study investigated the adjuvant properties of a sequence-optimized 5' pppRNA agonist (M8) with enhanced capacity to stimulate antiviral and inflammatory gene networks using influenza virus-like particles (VLP) expressing HA and NA as immunogens. Vaccination with VLP in combination with M8 increased anti-influenza virus antibody titers and protected animals from lethal influenza virus challenge, highlighting the potential clinical use of M8 as an adjuvant in vaccine development. Altogether, the results describe a novel immunostimulatory agonist targeted to the cytosolic RIG-I sensor as an attractive vaccine adjuvant candidate that can be used to increase vaccine efficacy, a pressing issue in children and the elderly population.