An RNA-Based Vaccine Platform for Use against Mycobacterium tuberculosis.
An RNA-Based Vaccine Platform for Use against Mycobacterium tuberculosis.
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作者：
结核分枝杆菌（M.tb）是一种引起结核病的细菌病原体，对全球卫生造成了广泛的负担。结核分枝杆菌的复杂性，加上结核病的不同阶段，使得确定保护的免疫相关因素具有挑战性，从而减缓了候选疫苗的进展。在这项工作中，我们利用两种递送平台作为预防性疫苗来评估C57BL/6小鼠对低剂量和超低剂量M.tb H37Rv气溶胶攻击的免疫力和随后的有效性。我们的第二代结核病候选疫苗ID91是一种与合成TLR4激动剂（稳定乳剂中的葡萄糖吡喃酰基脂质佐剂）配制的融合蛋白，或者是在纳米结构脂质载体中配制的新型复制rna （repRNA）。基于蛋白质亚基和rna的疫苗可优先引发针对不同ID91表位的细胞免疫应答。在单次预防性免疫筛查中，与对照组相比，这两个平台都减少了肺部细菌负担。令人兴奋的是，在启动-增强策略中，接受异源rna -启动、蛋白质-增强或联合免疫的组显示出最大的细菌负担减少和独特的体液和细胞免疫反应谱。这些数据首次报告了repRNA平台是一种可行的结核病疫苗系统，应该使用含有CD4+和CD8+ t细胞表位的高优先级结核分枝杆菌抗原。
Mycobacterium tuberculosis (M.tb), a bacterial pathogen that causes tuberculosis disease (TB), exerts an extensive burden on global health. The complex nature of M.tb, coupled with different TB disease stages, has made identifying immune correlates of protection challenging and subsequently slowing vaccine candidate progress. In this work, we leveraged two delivery platforms as prophylactic vaccines to assess immunity and subsequent efficacy against low-dose and ultra-low-dose aerosol challenges with M.tb H37Rv in C57BL/6 mice. Our second-generation TB vaccine candidate ID91 was produced as a fusion protein formulated with a synthetic TLR4 agonist (glucopyranosyl lipid adjuvant in a stable emulsion) or as a novel replicating-RNA (repRNA) formulated in a nanostructured lipid carrier. Protein subunit- and RNA-based vaccines preferentially elicit cellular immune responses to different ID91 epitopes. In a single prophylactic immunization screen, both platforms reduced pulmonary bacterial burden compared to the controls. Excitingly, in prime-boost strategies, the groups that received heterologous RNA-prime, protein-boost or combination immunizations demonstrated the greatest reduction in bacterial burden and a unique humoral and cellular immune response profile. These data are the first to report that repRNA platforms are a viable system for TB vaccines and should be pursued with high-priority M.tb antigens containing CD4+ and CD8+ T-cell epitopes.
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影响因子：
4.6
作者：
Larsen SE;Reese VA;Pecor T;Berube BJ;Cooper SK;Brewer G;Ordway D;Henao-Tamayo M;Podell BK;Baldwin SL;Coler RN
通讯作者：
Coler RN
DOI：
10.4049/jimmunol.1301161
发表时间：
2013-09-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Baldwin SL;Ching LK;Pine SO;Moutaftsi M;Lucas E;Vallur A;Orr MT;Bertholet S;Reed SG;Coler RN
通讯作者：
Coler RN
影响因子：
5.4
作者：
Arlehamn, Cecilia S. Lindestam;Lewinsohn, David;Lewinsohn, Deborah
通讯作者：
Lewinsohn, Deborah
影响因子：
12.4
作者：
Erasmus, Jesse H.;Khandhar, Amit P.;Van Hoeven, Neal
通讯作者：
Van Hoeven, Neal
DOI：
10.1056/nejmoa2035389
发表时间：
2021-02-04
期刊：
The New England journal of medicine
影响因子：
--
作者：
Baden LR;El Sahly HM;Essink B;Kotloff K;Frey S;Novak R;Diemert D;Spector SA;Rouphael N;Creech CB;McGettigan J;Khetan S;Segall N;Solis J;Brosz A;Fierro C;Schwartz H;Neuzil K;Corey L;Gilbert P;Janes H;Follmann D;Marovich M;Mascola J;Polakowski L;Ledgerwood J;Graham BS;Bennett H;Pajon R;Knightly C;Leav B;Deng W;Zhou H;Han S;Ivarsson M;Miller J;Zaks T;COVE Study Group
通讯作者：
COVE Study Group