疫苗引发限于引流淋巴结，并由佐剂介导的抗原摄取控制

StephenW

Vaccine priming is restricted to draining lymph nodes and controlled by adjuvant-mediated antigen uptake

    Frank Liang1,2, Gustaf Lindgren1,2, Kerrie J. Sandgren1,*, Elizabeth A. Thompson1,2, Joseph R. Francica3, Anja Seubert4, Ennio De Gregorio4, Susan Barnett5,†, Derek T. O’Hagan5, Nancy J. Sullivan3, Richard A. Koup3, Robert A. Seder3 and Karin Loré1,2,‡
    1Immunology and Allergy Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    2Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    3Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
    4GSK Vaccines, Siena, Italy.
    5GSK Vaccines, Rockville, MD 20850, USA.

    ↵‡Corresponding author. Email: [email protected]

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Science Translational Medicine  07 Jun 2017:
Vol. 9, Issue 393, eaal2094
DOI: 10.1126/scitranslmed.aal2094



Moving beyond mice for vaccine studies

Vaccine enhancement by adjuvants has been known for decades, but the mechanistic differences in how specific adjuvants influence the immune response are just beginning to be elucidated. Liang et al. sought a model that closely mimics humans, so they intramuscularly immunized nonhuman primates with a prototypical HIV antigen in combination with various adjuvants. They then inspected the muscles and lymph nodes to characterize antigen-presenting cells and resulting adaptive immune responses. Their findings should provide valuable information on adjuvant selection for vaccine development in humans.
Abstract

The innate immune mechanisms by which adjuvants enhance the potency and protection of vaccine-induced adaptive immunity are largely unknown. We introduce a model to delineate the steps of how adjuvant-driven innate immune activation leads to priming of vaccine responses using rhesus macaques. Fluorescently labeled HIV-1 envelope glycoprotein (Env) was administered together with the conventional aluminum salt (alum) adjuvant. This was compared to Env given with alum with preabsorbed Toll-like receptor 7 (TLR7) ligand (alum-TLR7) or the emulsion MF59 because they show superiority over alum for qualitatively and quantitatively improved vaccine responses. All adjuvants induced rapid and robust immune cell infiltration to the injection site in the muscle. This resulted in substantial uptake of Env by neutrophils, monocytes, and myeloid and plasmacytoid dendritic cells (DCs) and migration exclusively to the vaccine-draining lymph nodes (LNs). Although less proficient than monocytes and DCs, neutrophils were capable of presenting Env to memory CD4+ T cells. MF59 and alum-TLR7 showed more pronounced cell activation and overall higher numbers of Env+ cells compared to alum. This resulted in priming of higher numbers of Env-specific CD4+ T cells in the vaccine-draining LNs, which directly correlated with increased T follicular helper cell differentiation and germinal center formation. Thus, strong innate immune activation promoting efficient vaccine antigen delivery to infiltrating antigen-presenting cells in draining LNs is an important mechanism by which superior adjuvants enhance vaccine responses.

StephenW

疫苗引发限于引流淋巴结，并由佐剂介导的抗原摄取控制

Frank Liang1,2，Gustaf Lindgren1,2，Kerrie J. Sandgren1，*，Elizabeth A. Thompson1,2，Joseph R. Francica3，Anja Seubert4，Ennio De Gregorio4，Susan Barnett5，†，Derek T. O'Hagan5，Nancy J 。 Sullivan3，Richard A.Koup3，Robert A. Seder3和KarinLoré1,2，‡
1瑞典斯德哥尔摩Karolinska机构医学系免疫学和过敏单位。
2分子医学中心，Karolinska Institutet，斯德哥尔摩，瑞典。
3Vaccine Research Center，National Institute of Allergy and Infectious Diseases，National Institutes of Health，Bethesda，MD 20892，USA。
4GSK疫苗，锡耶纳，意大利。
5GSK Vaccines，Rockville，MD 20850，USA。

↵‡通讯作者电子邮件：[email protected]


超越小鼠进行疫苗研究

佐剂的疫苗增强已知数十年，但是特定佐剂如何影响免疫应答的机制差异刚刚开始被阐明。梁等买了一个模仿人类的模型，所以他们用各种佐剂与原型HIV抗原肌内免疫非人灵长类动物。他们检查肌肉和淋巴结，以表征抗原呈递细胞和随后的适应性免疫应答。
抽象

佐剂增强疫苗诱导的适应性免疫的效力和保护的先天免疫机制在很大程度上是未知的。我们引入一个模型来描述佐剂驱动的先天免疫激活如何导致使用恒河猴痘苗疫苗引发的步骤。将荧光标记的HIV-1包膜糖蛋白（Env）与常规的铝盐（明矾）佐剂一起施用。将其与用预先吸收的Toll样受体7（TLR7）配体（明矾-TLR7）或乳剂MF59的明矾进行比较，因为它们显示优于明矾以进行定性改善的疫苗反应。所有佐剂诱导快速强大的免疫浸润到肌肉注射部位。这是通过嗜中性粒细胞，单核细胞和骨髓和浆细胞样树突状细胞（DCs）大量吸收Env，并且仅迁移到疫苗引流淋巴结（LN）。尽管中性粒细胞与单核细胞和DCs相比不太熟练，但能够将Env呈递给记忆CD4 + T细胞。与明矾相比，MF59和明矾-TLR7显示更显着的细胞活化和总体更高数量的Env +细胞。这在疫苗引起的LN中更多数量的Env特异性CD4 + T细胞的引发，其与增加的T滤泡辅助细胞分化和生发中心形成相关。因此：强有力的天然风味活化有效的疫苗抗原递送到排泄LN中的浸润性抗原呈递细胞是优势佐剂增强疫苗应答的重要机制