Formulation, inflammation, and RNA sensing impact the immunogenicity of self-amplifying RNA vaccines.
Formulation, inflammation, and RNA sensing impact the immunogenicity of self-amplifying RNA vaccines.
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DOI：
10.1016/j.omtn.2022.11.024
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发表时间：
2023-03-14
期刊：
影响因子：
--
通讯作者：
Shattock, Robin J.
中科院分区：
文献类型：
--
作者：
Tregoning, John S.;Stirling, David C.;Wang, Ziyin;Flight, Katie E.;Brown, Jonathan C.;Blakney, Anna K.;McKay, Paul F.;Cunliffe, Robert F.;Murugaiah, Valarmathy;Fox, Christopher B.;Beattie, Mitchell;Tam, Ying K.;Johansson, Cecilia;Shattock, Robin J.
为了有效，RNA疫苗需要原位翻译和诱导免疫应答以将细胞募集到免疫部位。这些因素可以在相反的方向拉动，炎症减少疫苗抗原的表达。我们研究了制剂如何影响对自扩增RNA（saRNA）疫苗的急性全身性细胞因子应答。我们比较了阳离子聚合物（PABOL），脂肪乳剂（纳米结构脂质载体，NLC），和三个脂质纳米颗粒（LNP）。免疫后，我们测定血清细胞因子，并比较对诱导的流感病毒抗体的反应。诱导更大细胞因子应答的制剂诱导更大的抗体应答，其中IP-10、MCP-1、KC和抗原特异性抗体滴度之间具有显著相关性。然后，我们研究了先天免疫传感和信号传导如何影响对LNP配制的saRNA疫苗接种的适应性免疫反应。缺乏MAVS并且不能通过RIG-I样受体发出信号的小鼠对saRNA疫苗接种具有改变的细胞因子应答，并且具有比野生型小鼠显著更大的抗体应答。这表明，由配制的saRNA疫苗诱导的炎症不仅仅在诱导抗体应答中是有害的，并且靶向RNA疫苗感测的特定方面可能改善应答的质量。RNA疫苗是应对大流行的重要组成部分。但需要进一步的研究来扩大其用途。在目前的研究中，我们研究了RNA疫苗诱导的炎症和下游适应性反应的相互作用。我们表明，免疫后的急性炎症是保护性抗体反应所必需的。
To be effective, RNA vaccines require both in situ translation and the induction of an immune response to recruit cells to the site of immunization. These factors can pull in opposite directions with the inflammation reducing expression of the vaccine antigen. We investigated how formulation affects the acute systemic cytokine response to a self-amplifying RNA (saRNA) vaccine. We compared a cationic polymer (pABOL), a lipid emulsion (nanostructured lipid carrier, NLC), and three lipid nanoparticles (LNP). After immunization, we measured serum cytokines and compared the response to induced antibodies against influenza virus. Formulations that induced a greater cytokine response induced a greater antibody response, with a significant correlation between IP-10, MCP-1, KC, and antigen-specific antibody titers. We then investigated how innate immune sensing and signaling impacted the adaptive immune response to vaccination with LNP-formulated saRNA. Mice that lacked MAVS and are unable to signal through RIG-I-like receptors had an altered cytokine response to saRNA vaccination and had significantly greater antibody responses than wild-type mice. This indicates that the inflammation induced by formulated saRNA vaccines is not solely deleterious in the induction of antibody responses and that targeting specific aspects of RNA vaccine sensing might improve the quality of the response. RNA vaccines were a vital part of the pandemic response. But further research is required to broaden their usage. In the current study, we investigated the interplay of RNA vaccine-induced inflammation and the downstream adaptive response. We show that acute inflammation after immunization is required for protective antibody responses.
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影响因子：
6.7
作者：
Lazear HM;Lancaster A;Wilkins C;Suthar MS;Huang A;Vick SC;Clepper L;Thackray L;Brassil MM;Virgin HW;Nikolich-Zugich J;Moses AV;Gale M Jr;Früh K;Diamond MS
通讯作者：
Diamond MS
影响因子：
32.4
作者：
Alameh MG;Tombácz I;Bettini E;Lederer K;Sittplangkoon C;Wilmore JR;Gaudette BT;Soliman OY;Pine M;Hicks P;Manzoni TB;Knox JJ;Johnson JL;Laczkó D;Muramatsu H;Davis B;Meng W;Rosenfeld AM;Strohmeier S;Lin PJC;Mui BL;Tam YK;Karikó K;Jacquet A;Krammer F;Bates P;Cancro MP;Weissman D;Luning Prak ET;Allman D;Locci M;Pardi N
通讯作者：
Pardi N
影响因子：
9.2
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
通讯作者：
Fotin-Mleczek M
影响因子：
5.4
作者：
Goritzka M;Durant LR;Pereira C;Salek-Ardakani S;Openshaw PJ;Johansson C
通讯作者：
Johansson C
影响因子：
12.4
作者：
Erasmus, Jesse H.;Khandhar, Amit P.;Van Hoeven, Neal
通讯作者：
Van Hoeven, Neal