Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines.
Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines.
复制标题
DOI：
10.1038/s41541-017-0032-6
复制
发表时间：
2017
期刊：
影响因子：
9.2
通讯作者：
Fotin-Mleczek M
中科院分区：
文献类型：
--
作者：
Lutz J;Lazzaro S;Habbeddine M;Schmidt KE;Baumhof P;Mui BL;Tam YK;Madden TD;Hope MJ;Heidenreich R;Fotin-Mleczek M
信使核糖核酸代表了一种很有前途的新型疫苗技术平台，在开发和生产方面具有很高的灵活性。在这里，我们证明了基于序列优化的、未经化学修饰的、在优化的脂质纳米粒(LNPs)中配制的mRNA的疫苗具有高度的免疫原性，并且在非人类灵长类动物(NHP)中具有良好的耐受性。用编码狂犬病或流感病毒抗原的LNP配制的mRNAs单次肌肉接种NHP可诱导保护性抗体滴度，并可在长达1年的观察期内保持稳定。首先，对LNP配制的mRNA疫苗作用模式的机械性洞察表明，注射部位和引流淋巴结(DLN)的先天免疫反应被强烈激活。先天免疫系统的激活通过短暂的促炎细胞因子和趋化因子的诱导以及DLN中大多数免疫细胞的激活来反映。值得注意的是，我们的数据表明，mRNA疫苗可以与基于灭活病毒的特许疫苗竞争，甚至在功能抗体和T细胞反应方面更具优势。重要的是，我们表明，开发的LNP配方的mRNA疫苗可以作为一个免疫平台，允许针对不同的病原体进行多次、连续的疫苗接种。这些结果为发展有效的预防传染病的疫苗提供了有力的证据。基于信使核糖核酸的疫苗在单剂接种后会引起强烈的免疫反应。信使核糖核酸通常被认为是DNA的“遗传信使”表亲，也是蛋白质生产的重要中介。现在，由德国CureVac AG的Mariola Fotin-Mleczek领导的研究表明，可以开发出mRNA来产生称为抗原的病毒片段，这些片段可以为疫苗接种者的免疫系统抵御病原体做好准备。为了测试他们的疫苗平台，研究小组创造了狂犬病和流感抗原的编码信使核糖核酸，并使用肌肉注射给非人类灵长类接种。单剂疫苗可引起强烈的免疫反应，研究小组随后通过加强接种疫苗成功地维持了这一反应，观察期为1年。这些反应超过了获得许可的狂犬病和H3N2型流感疫苗。这项研究表明，信使核糖核酸作为一种多用途、经济有效、快速可扩展的疫苗技术是有希望的。
mRNA represents a promising new vaccine technology platform with high flexibility in regard to development and production. Here, we demonstrate that vaccines based on sequence optimized, chemically unmodified mRNA formulated in optimized lipid nanoparticles (LNPs) are highly immunogenic and well tolerated in non-human primates (NHPs). Single intramuscular vaccination of NHPs with LNP-formulated mRNAs encoding rabies or influenza antigens induced protective antibody titers, which could be boosted and remained stable during an observation period of up to 1 year. First mechanistic insights into the mode of action of the LNP-formulated mRNA vaccines demonstrated a strong activation of the innate immune response at the injection site and in the draining lymph nodes (dLNs). Activation of the innate immune system was reflected by a transient induction of pro-inflammatory cytokines and chemokines and activation of the majority of immune cells in the dLNs. Notably, our data demonstrate that mRNA vaccines can compete with licensed vaccines based on inactivated virus or are even superior in respect of functional antibody and T cell responses. Importantly, we show that the developed LNP-formulated mRNA vaccines can be used as a vaccination platform allowing multiple, sequential vaccinations against different pathogens. These results provide strong evidence that the mRNA technology is a valid approach for the development of effective prophylactic vaccines to prevent infectious diseases. Vaccines based on mRNA provoke strong immune responses after a single dose. mRNA is commonly known as the ‘genetic messenger’ cousin of DNA and a crucial mediator of protein production. Now, research led by Mariola Fotin-Mleczek, of Germany’s CureVac AG, demonstrates that mRNA can be developed to produce virus fragments, called antigens, that can prime a vaccinee’s immune system against a pathogen. Testing their vaccine platform, the team created mRNA coding for rabies and influenza antigens, and used intramuscular injection to inoculate non-human primates. A single dose elicited strong immune responses, which the team then successfully maintained through booster vaccinations for an observation period of 1 year. The responses outperformed those of licensed vaccines against rabies and influenza type H3N2. This research shows that mRNA has promise as a versatile, cost-effective, rapidly scalable vaccine technology.
登录
查看更多内容
影响因子：
11.8
作者：
Plotkin, Stanley A.
通讯作者：
Plotkin, Stanley A.
影响因子：
16.6
作者：
Jayaraman, Muthusamy;Ansell, Steven M.;Mui, Barbara L.;Tam, Ying K.;Chen, Jianxin;Du, Xinyao;Butler, David;Eltepu, Laxman;Matsuda, Shigeo;Narayanannair, Jayaprakash K.;Rajeev, Kallanthottathil G.;Hafez, Ismail M.;Akinc, Akin;Maier, Martin A.;Tracy, Mark A.;Cullis, Pieter R.;Madden, Thomas D.;Manoharan, Muthiah;Hope, Michael J.
通讯作者：
Hope, Michael J.
DOI：
10.1056/nejmra1204186
发表时间：
2013-02-07
期刊：
The New England journal of medicine
影响因子：
--
作者：
Nabel GJ
通讯作者：
Nabel GJ
DOI：
10.1016/j.jconrel.2015.08.007
发表时间：
2015-11-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Pardi N;Tuyishime S;Muramatsu H;Kariko K;Mui BL;Tam YK;Madden TD;Hope MJ;Weissman D
通讯作者：
Weissman D
影响因子：
158.5
作者：
Coelho, Teresa;Adams, David;Suhr, Ole B.
通讯作者：
Suhr, Ole B.