Induction of Robust B Cell Responses after Influenza mRNA Vaccination Is Accompanied by Circulating Hemagglutinin-Specific ICOS+ PD-1+CXCR3+T Follicular Helper Cells
Induction of Robust B Cell Responses after Influenza mRNA Vaccination Is Accompanied by Circulating Hemagglutinin-Specific ICOS+ PD-1+CXCR3+T Follicular Helper Cells
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DOI：
10.3389/fimmu.2017.01539
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发表时间：
2017-11-13
影响因子：
7.3
通讯作者：
Lore, Karin
中科院分区：
文献类型：
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作者：
Lindgren, Gustaf;Ols, Sebastian;Lore, Karin
修饰的mRNA疫苗已发展成为一种有效且耐受性良好的疫苗平台，可提供可扩展且精确的抗原生产。然而，导致由mRNA疫苗引起的强烈抗体应答的免疫学事件在很大程度上是未知的。在这项研究中，我们证明了在非人灵长类动物中，在脂质纳米颗粒（LNP）中封装的编码流感H10的修饰的非复制mRNA的两次免疫后，诱导了针对血凝素的抗体的保护水平。虽然皮内（ID）和肌内（IM）给药均诱导保护性滴度，但ID给药更快地产生这种反应。循环H10特异性记忆B细胞在每次免疫后扩增，沿着浆母细胞的短暂出现。记忆B细胞池随着时间的推移而减少，但在整个25周的研究中仍然可以检测到。初次免疫后，在骨髓中发现H10特异性浆细胞，并随时间持续存在。随着循环H10特异性ICOS+ PD-1+ CXCR 3 + T滤泡辅助细胞的增加，在疫苗引流淋巴结中沿着形成了生殖中心，该群体显示与人类季节性流感疫苗接种后的高亲合力抗体应答相关。总的来说，这项研究表明，mRNA/LNP疫苗有效地诱导与高强度和高质量抗体的产生相关的免疫库。
Modified mRNA vaccines have developed into an effective and well-tolerated vaccine platform that offers scalable and precise antigen production. Nevertheless, the immunological events leading to strong antibody responses elicited by mRNA vaccines are largely unknown. In this study, we demonstrate that protective levels of antibodies to hemagglutinin were induced after two immunizations of modified non-replicating mRNA encoding influenza H10 encapsulated in lipid nanoparticles (LNP) in non-human primates. While both intradermal (ID) and intramuscular (IM) administration induced protective titers, ID delivery generated this response more rapidly. Circulating H10-specific memory B cells expanded after each immunization, along with a transient appearance of plasmablasts. The memory B cell pool waned over time but remained detectable throughout the 25-week study. Following prime immunization, H10-specific plasma cells were found in the bone marrow and persisted over time. Germinal centers were formed in vaccine-draining lymph nodes along with an increase in circulating H10-specific ICOS+ PD-1+ CXCR3+ T follicular helper cells, a population shown to correlate with high avidity antibody responses after seasonal influenza vaccination in humans. Collectively, this study demonstrates that mRNA/LNP vaccines potently induce an immunological repertoire associated with the generation of high magnitude and quality antibodies.