Superior immunogenicity of inactivated whole virus H5N1 influenza vaccine is primarily controlled by Toll-like receptor signalling.
Superior immunogenicity of inactivated whole virus H5N1 influenza vaccine is primarily controlled by Toll-like receptor signalling.
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DOI：
10.1371/journal.ppat.1000138
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发表时间：
2008-08-29
期刊：
影响因子：
6.7
通讯作者：
Huckriede A
中科院分区：
文献类型：
--
作者：
Geeraedts F;Goutagny N;Hornung V;Severa M;de Haan A;Pool J;Wilschut J;Fitzgerald KA;Huckriede A
一旦发生流感大流行，目前全球流感疫苗产能将无法满足数十亿剂疫苗的需求。因此，H5N1 大流行的持续威胁敦促开发高免疫原性、剂量节省的疫苗配方。在未接种疫苗的个体中，灭活全病毒 (WIV) 疫苗比其他制剂（如裂解病毒 (SV) 或亚单位 (SU) 疫苗）更具免疫原性，并以较低的抗原剂量诱导保护性抗体反应。造成这种免疫原性差异的原因是一个长期存在的谜。在这里，我们表明，与 SV 或 SU 诱导的反应相比，H5N1 WIV 疫苗对先天免疫系统的 Toll 样受体 (TLR) 的刺激，特别是对 TLR7 的刺激，是 WIV 诱导的免疫反应幅度更大和 Th1 极化的主要决定因素。这种 TLR 依赖性在很大程度上解释了 SV 和 SU 疫苗免疫原性的相对丧失。 TLR7 识别的天然病原体相关分子模式 (PAMP) 是病毒基因组 ssRNA。将整个病毒颗粒加工成 SV 或 SU 疫苗会破坏病毒颗粒的完整性，并使病毒 RNA 容易降解或涉及主动去除。我们的结果表明，对于经典疫苗，疫苗接种引起的获得性免疫反应可以由先天免疫系统增强和引导，这是由内在疫苗成分与模式识别受体（PRR）相互作用触发的。本文提出的见解可用于进一步改善 WIV 等经典流感疫苗配方的免疫刺激和剂量节省特性，并将促进开发新的、更强大的疫苗以应对下一次流感大流行。高致病性禽H5N1流感病毒的兴起和传播，严重增加了新一轮流感大流行的风险。然而，以目前的产能生产的疫苗剂量将无法满足大流行时期的需求。使用灭活全病毒（WIV）疫苗在未接种人群中比裂解病毒或亚单位疫苗更具免疫原性，可能有助于剂量节约策略。然而，WIV 疫苗制剂优异的免疫原性背后的机制尚不清楚。在这里，我们证明灭活病毒颗粒中存在的病毒 RNA 对于改善小鼠 WIV 的免疫原性至关重要。通过触发 Toll 样受体 7 (TLR7)，病毒 RNA 激活先天免疫机制，增强并决定随后的适应性反应。裂解病毒和亚单位疫苗中有效的 TLR7 信号传导丢失，其加工步骤导致病毒颗粒完整性破坏并排除 RNA。据我们所知，我们的结果首次证明经典疫苗的免疫增强机制是基于其结构成分之一对先天免疫系统的激活。这些发现可能反映了病毒疫苗的一般原理，并为进一步改进流感疫苗提供了合理依据，而流感疫苗是当前H5N1大流行威胁所迫切需要的。
In the case of an influenza pandemic, the current global influenza vaccine production capacity will be unable to meet the demand for billions of vaccine doses. The ongoing threat of an H5N1 pandemic therefore urges the development of highly immunogenic, dose-sparing vaccine formulations. In unprimed individuals, inactivated whole virus (WIV) vaccines are more immunogenic and induce protective antibody responses at a lower antigen dose than other formulations like split virus (SV) or subunit (SU) vaccines. The reason for this discrepancy in immunogenicity is a long-standing enigma. Here, we show that stimulation of Toll-like receptors (TLRs) of the innate immune system, in particular stimulation of TLR7, by H5N1 WIV vaccine is the prime determinant of the greater magnitude and Th1 polarization of the WIV-induced immune response, as compared to SV- or SU-induced responses. This TLR dependency largely explains the relative loss of immunogenicity in SV and SU vaccines. The natural pathogen-associated molecular pattern (PAMP) recognized by TLR7 is viral genomic ssRNA. Processing of whole virus particles into SV or SU vaccines destroys the integrity of the viral particle and leaves the viral RNA prone to degradation or involves its active removal. Our results show for a classic vaccine that the acquired immune response evoked by vaccination can be enhanced and steered by the innate immune system, which is triggered by interaction of an intrinsic vaccine component with a pattern recognition receptor (PRR). The insights presented here may be used to further improve the immune-stimulatory and dose-sparing properties of classic influenza vaccine formulations such as WIV, and will facilitate the development of new, even more powerful vaccines to face the next influenza pandemic. The rise and spread of the highly pathogenic avian H5N1 influenza virus has seriously increased the risk of a new influenza pandemic. However, the number of vaccine doses that can be produced with today's production capacity will fall short of the demand in times of a pandemic. Use of inactivated whole virus (WIV) vaccines, which are more immunogenic than split virus or subunit vaccines in an unprimed population, could contribute to a dose-sparing strategy. Yet, the mechanisms underlying the superior immunogenicity of WIV vaccine formulations are unknown. Here, we demonstrate that the viral RNA present in inactivated virus particles is crucial for the improved immunogenic properties of WIV in mice. By triggering Toll-like receptor 7 (TLR7), the viral RNA activates innate immune mechanisms that augment and determine subsequent adaptive responses. Efficient TLR7 signalling is lost in split virus and subunit vaccines with the processing steps that lead to disruption of the integrity of the virus particle and exclusion of the RNA. Our results prove for the first time to our knowledge that the immune-potentiating mechanism of a classic vaccine is based on activation of the innate immune system by one of its structural components. These findings may reflect a general principle for viral vaccines and provide a rational basis for further improvement of influenza vaccines, which are urgently needed in the face of the current H5N1 pandemic threat.
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影响因子：
4.4
作者：
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