ISCOMATRIX™ adjuvant promotes epitope spreading and antibody affinity maturation of influenza A H7N9 virus like particle vaccine that correlate with virus neutralization in humans
ISCOMATRIX™ adjuvant promotes epitope spreading and antibody affinity maturation of influenza A H7N9 virus like particle vaccine that correlate with virus neutralization in humans
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DOI：
10.1016/j.vaccine.2015.06.047
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发表时间：
2015-07-31
期刊：
影响因子：
5.5
通讯作者：
Khurana, Surender
中科院分区：
文献类型：
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作者：
Chung, Ka Yan;Coyle, Elizabeth M.;Khurana, Surender
在先前报道的I期临床试验中，接种两剂无佐剂H7N9病毒样颗粒（VLP）疫苗的受试者应答较差（45 μ g血凝素（HA）剂量的血清转化率为15.6%）。相比之下，80.6%接受H7N9 VLP疫苗（5 μ g HA）与ISCOMATRIX（TM）佐剂的受试者产生血凝抑制（HI）应答。为了更好地理解佐剂的作用，使用全基因组片段噬菌体展示文库（GFPDL）研究疫苗接种后血清的完整抗体表位库。此外，使用基于真实的时间表面等离子体共振（SPR）的动力学测定，测量接种后针对HA 1和HA 2抗原结构域的抗体亲和力成熟。未加佐剂的H7N9-VLP疫苗主要产生靶向HA 1结构域的C-末端的抗体，预测HA 1结构域的C-末端大部分埋在天然HA刺突上，而加佐剂的VLP疫苗产生针对跨越受体结合结构域（RBD）的HA 1中的大表位的抗体。使用功能性H7-HA 1结构域的SPR分析表明，与来自无佐剂疫苗的血清相比，来自有佐剂的H7N9-VLP疫苗的血清诱导更高的总结合抗体和显著更高的对HA 1的抗体亲和力成熟。总抗体结合和对HA 1（而不是HA 2）结构域的亲和力与HI和中和滴度相关。本研究表明，ISCOMATRIX（TM）佐剂疫苗在未感染的人中促进针对禽流感的更高质量的抗体免疫应答。爱思唯尔有限公司出版
In a previously reported phase I clinical trial, subjects vaccinated with two doses of an unadjuvanted H7N9 virus like particle (VLP) vaccine responded poorly (15.6% seroconversion rates with 45 mu g hemagglutinin (HA) dose). In contrast, 80.6% of subjects receiving H7N9 VLP vaccine (5 mu g HA) with ISCOMATRIX (TM) adjuvant developed hemagglutination-inhibition (HI) responses. To better understand the role of adjuvant, complete antibody epitope repertoires of post-vaccination sera were investigated using Whole Genome Fragment Phage Display Library (GFPDL). In addition, antibody affinity maturation following vaccination was measured against HA1 and HA2 antigenic domains using real time Surface Plasmon Resonance (SPR) based kinetic assays. Unadjuvanted H7N9-VLP vaccine generated primarily antibodies targeting the C-terminus of the HA1 domain, predicted to be mostly buried on the native HA spikes, while adjuvanted VLP vaccine generated antibodies against large epitopes in the HA1 spanning the receptor binding domain (RBD). SPR analysis using a functional H7-HA1 domain demonstrated that sera from adjuvanted H7N9-VLP vaccine induced higher total binding antibodies and significantly higher antibody affinity maturation to HA1 compared to sera from unadjuvanted vaccine. Total antibody binding and affinity to the HA1 (but not HA2) domain correlated with HI and neutralization titers. This study demonstrates that ISCOMATRIX (TM) adjuvanted vaccine promotes higher quality antibody immune response against avian influenza in naive humans. Published by Elsevier Ltd.