Synthetic Toll-Like Receptor 4 (TLR4) and TLR7 Ligands as Influenza Virus Vaccine Adjuvants Induce Rapid, Sustained, and Broadly Protective Responses
Synthetic Toll-Like Receptor 4 (TLR4) and TLR7 Ligands as Influenza Virus Vaccine Adjuvants Induce Rapid, Sustained, and Broadly Protective Responses
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DOI：
10.1128/jvi.03337-14
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发表时间：
2015-03-01
影响因子：
5.4
通讯作者：
Carson, Dennis A.
中科院分区：
文献类型：
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作者：
Goff, Peter H.;Hayashi, Tomoko;Carson, Dennis A.
目前针对流感病毒感染的疫苗依赖于诱导针对病毒血凝素 (HA) 球状头部的中和抗体。防止季节性抗原漂移或零星大流行爆发需要进一步开发疫苗以诱导交叉保护性体液反应，可能针对更保守的 HA 茎区域。在这里，我们提出了一种新型病毒疫苗佐剂，由 Toll 样受体 4 (TLR4) 和 TLR7 的两种合成配体组成。 1Z105 是一种取代的嘧啶并[5,4-b]吲哚，对 TLR4-MD2 复合物具有特异性，1V270 是一种磷脂缀合的 TLR7 激动剂。另外，1Z105 诱导快速 Th2 相关 IgG1 反应，1V270 有效产生 Th1 细胞免疫。 1Z105 和 1V270 与来自 A/Puerto Rico/8/1934 毒株 (rPR/8 HA) 的重组 HA 相结合，可有效诱导快速且持续的体液免疫，从而防止同源病毒的致命攻击。更重要的是，使用组合佐剂和 rPR/8 HA、市售裂解疫苗或嵌合 rHA 抗原进行免疫可显着提高针对异源和异亚型攻击病毒的保护作用。异亚型保护与 HA 茎表位的广泛反应性抗体相关。组织学检查和细胞因子分析表明，肌内 (i.m.) 施用 1Z105 和 1V270 的反应原性低于基于角鲨烯的佐剂 AddaVax。综上所述，1Z105和1V270与重组HA的组合可诱导快速、持久、平衡的Th1和Th2型免疫；证明了在多种鼠流感病毒疫苗模型中测定同源、异源和异亚型攻击病毒的功效；重要性需要新型佐剂来增强免疫原性并增加流感病毒疫苗的保护范围，以减轻季节性疾病负担并确保做好大流行准备。我们在此表明，合成的 Toll 样受体 4 (TLR4) 和 TLR7 配体的组合是重组流感病毒血凝素的有效佐剂，可诱导快速且持续的免疫，从而在同源、异源和异亚型攻击模型中针对流感病毒提供保护。结合 TLR4 和 TLR7 配体可平衡 Th1 和 Th2 型免疫反应，以实现长寿命细胞并中和针对病毒血凝素的体液免疫。这种组合佐剂具有有吸引力的安全性，并有可能扩大季节性疫苗的广度，有助于广泛中和的通用疫苗配方，并改善新出现的大流行病的反应时间。
Current vaccines against influenza virus infection rely on the induction of neutralizing antibodies targeting the globular head of the viral hemagglutinin (HA). Protection against seasonal antigenic drift or sporadic pandemic outbreaks requires further vaccine development to induce cross-protective humoral responses, potentially to the more conserved HA stalk region. Here, we present a novel viral vaccine adjuvant comprised of two synthetic ligands for Toll-like receptor 4 (TLR4) and TLR7. 1Z105 is a substituted pyrimido[5,4-b] indole specific for the TLR4-MD2 complex, and 1V270 is a phospholipid-conjugated TLR7 agonist. Separately, 1Z105 induces rapid Th2-associated IgG1 responses, and 1V270 potently generates Th1 cellular immunity. 1Z105 and 1V270 in combination with recombinant HA from the A/Puerto Rico/8/1934 strain (rPR/8 HA) effectively induces rapid and sustained humoral immunity that is protective against lethal challenge with a homologous virus. More importantly, immunization with the combined adjuvant and rPR/8 HA, a commercially available split vaccine, or chimeric rHA antigens significantly improves protection against both heterologous and heterosubtypic challenge viruses. Heterosubtypic protection is associated with broadly reactive antibodies to HA stalk epitopes. Histological examination and cytokine profiling reveal that intramuscular (i.m.) administration of 1Z105 and 1V270 is less reactogenic than a squalene-based adjuvant, AddaVax. In summary, the combination of 1Z105 and 1V270 with a recombinant HA induces rapid, long-lasting, and balanced Th1- and Th2-type immunity; demonstrates efficacy in a variety of murine influenza virus vaccine models assaying homologous, heterologous, and heterosubtypic challenge viruses; and has an excellent safety profile.IMPORTANCENovel adjuvants are needed to enhance immunogenicity and increase the protective breadth of influenza virus vaccines to reduce the seasonal disease burden and ensure pandemic preparedness. We show here that the combination of synthetic Toll-like receptor 4 (TLR4) and TLR7 ligands is a potent adjuvant for recombinant influenza virus hemagglutinin, inducing rapid and sustained immunity that is protective against influenza viruses in homologous, heterologous, and heterosubtypic challenge models. Combining TLR4 and TLR7 ligands balances Th1- and Th2-type immune responses for long-lived cellular and neutralizing humoral immunity against the viral hemagglutinin. The combined adjuvant has an attractive safety profile and the potential to augment seasonal-vaccine breadth, contribute to a broadly neutralizing universal vaccine formulation, and improve response time in an emerging pandemic.