cGAMP loading enhances the immunogenicity of VLP vaccines
cGAMP loading enhances the immunogenicity of VLP vaccines
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DOI：
10.1101/2020.01.03.893586
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发表时间：
2020-01
期刊：
影响因子：
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通讯作者：
Lise Chauveau;A. Bridgeman;T. Tan;R. Beveridge;Joe N. Frost;I. Pedroza-Pacheco;Thomas Partridge;P. Borrow;H. Drakesmith;A. Townsend;J. Rehwinkel
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作者：
Lise Chauveau;A. Bridgeman;T. Tan;R. Beveridge;Joe N. Frost;I. Pedroza-Pacheco;Thomas Partridge;P. Borrow;H. Drakesmith;A. Townsend;J. Rehwinkel
环GMP-AMP（cGAMP）是由激活STING的cGAS产生的免疫刺激性第二信使。当与抗原一起施用时，可溶性cGAMP充当佐剂。cGAMP也在出芽期间掺入包膜病毒颗粒中。我们假设在病毒疫苗载体内包含佐剂cGAMP将促进针对载体抗原的适应性免疫。我们用含有HIV-1 Gag蛋白和VSV-G的病毒样颗粒（VLP）免疫小鼠。在这些VLP中包含cGAMP增强了脾VLP特异性CD4和CD8 T细胞应答。它还增加了VLP和VSV-G特异性血清抗体滴度，并增强了体外病毒中和作用。上级抗体应答伴随着引流淋巴结中T滤泡辅助细胞数量的增加。用含有血凝素的cGAMP负载的VLP接种诱导高滴度的甲型流感病毒中和抗体，并在随后的甲型流感病毒攻击后赋予保护。总之，这些结果表明，将cGAMP掺入VLP增强了它们的免疫原性，使cGAMP-VLP成为新疫苗接种策略的有吸引力的平台。cGAMP是一种先天性免疫信号分子，可以通过包含在包膜病毒体中在细胞之间传递。本研究证明了含有cGAMP的HIV衍生病毒样颗粒的免疫原性增强。因此，装载有cGAMP的病毒载体可能是有效的疫苗。
Cyclic GMP-AMP (cGAMP) is an immunostimulatory second messenger produced by cGAS that activates STING. Soluble cGAMP acts as an adjuvant when administered with antigens. cGAMP is also incorporated into enveloped virus particles during budding. We hypothesised that inclusion of the adjuvant cGAMP within viral vaccine vectors would promote adaptive immunity against vector antigens. We immunised mice with virus-like particles (VLPs) containing the HIV-1 Gag protein and VSV-G. Inclusion of cGAMP within these VLPs augmented splenic VLP-specific CD4 and CD8 T cell responses. It also increased VLP- and VSV-G-specific serum antibody titres and enhanced in vitro virus neutralisation. The superior antibody response was accompanied by increased numbers of T follicular helper cells in draining lymph nodes. Vaccination with cGAMP-loaded VLPs containing haemagglutinin induced high titres of influenza A virus neutralising antibodies and conferred protection following subsequent influenza A virus challenge. Together, these results show that incorporating cGAMP into VLPs enhances their immunogenicity, making cGAMP-VLPs an attractive platform for novel vaccination strategies. Short summary cGAMP is an innate immune signalling molecule that can be transmitted between cells by inclusion in enveloped virions. This study demonstrates enhanced immunogenicity of HIV-derived virus-like particles containing cGAMP. Viral vectors loaded with cGAMP may thus be potent vaccines.