H5N1 Virus-Like Particle Vaccine Elicits Cross-Reactive Neutralizing Antibodies That Preferentially Bind to the Oligomeric Form of Influenza Virus Hemagglutinin in Humans
H5N1 Virus-Like Particle Vaccine Elicits Cross-Reactive Neutralizing Antibodies That Preferentially Bind to the Oligomeric Form of Influenza Virus Hemagglutinin in Humans
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DOI：
10.1128/jvi.05406-11
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发表时间：
2011-11-01
影响因子：
5.4
通讯作者：
Golding, Hana
中科院分区：
文献类型：
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作者：
Khurana, Surender;Wu, Jian;Golding, Hana
致病性禽流感病毒（AIV）从野鸟向家禽和人类的传播在世界多个国家仍在继续。为了应对潜在的禽流感大流行，多种候选疫苗正在开发中。就 H5N1 AIV 而言，近年来病毒传播发生了从进化枝 1 到进化枝 2 的明显转变。病毒样颗粒（VLP）代表了一种经济的大流行疫苗开发方法。在当前的研究中，我们评估了接种 Sf9 昆虫细胞制造的 H5N1 A/Indonesia/05/2005（clade 2.1）VLP 疫苗的人类的体液免疫反应。 VLP 由流感病毒血凝素 (HA)、神经氨酸酶 (NA) 和基质 1 (M1) 蛋白组成。在 FDA 批准的 I/II 期人类临床研究中，两剂 H5N1 VLP（15、45 或 90 μg HA/剂量）导致血清转化并产生功能性抗体。此外，使用病毒中和测定证明了针对其他进化枝 2 亚型的交叉反应性。 H5N1 全基因组片段噬菌体展示文库 (GFPDL) 用于阐明接种后人血清中的抗体表位库。 HA1/HA2 和 NA 中的不同表位被两个高剂量组的疫苗接种后血清识别，包括跨越 HA1 受体结合域的大片段。重要的是，与单体 HA1 相比，该疫苗引发的血清优先与寡聚形式的重组 HA1 结合。血清的寡聚体/单体HA1结合比率与病毒中和滴度相关。此外，两个高剂量 VLP 疫苗组产生了 NA 抑制抗体，这些抗体与靠近唾液酸结合位点的 C 末端表位的结合有关。这些发现代表了第一份描述人类 AIV VLP 免疫后抗体反应质量的报告，并支持进一步开发针对新出现的流感病毒株的此类疫苗。
Transmission of pathogenic avian influenza viruses (AIV) from wild birds to domestic poultry and humans is continuing in multiple countries around the world. In preparation for a potential AIV pandemic, multiple vaccine candidates are under development. In the case of H5N1 AIV, a clear shift in transmission from clade 1 to clade 2 viruses occurred in recent years. The virus-like particle (VLP) represents an economical approach to pandemic vaccine development. In the current study, we evaluated the humoral immune response in humans vaccinated with H5N1 A/Indonesia/05/2005 (clade 2.1) VLP vaccine manufactured in Sf9 insect cells. The VLPs were comprised of the influenza virus hemagglutinin (HA), neuraminidase (NA), and matrix 1 (M1) proteins. In an FDA-approved phase I/II human clinical study, two doses of H5N1 VLPs at 15, 45, or 90 mu g HA/dose resulted in seroconversion and production of functional antibodies. Moreover, cross-reactivity against other clade 2 subtypes was demonstrated using virus neutralization assays. H5N1 whole-genome fragment phage display libraries (GFPDL) were used to elucidate the antibody epitope repertoire in postvaccination human sera. Diverse epitopes in HA1/HA2 and NA were recognized by postvaccination sera from the two high-dose groups, including large segments spanning the HA1 receptor binding domain. Importantly, the vaccine elicited sera that preferentially bound to an oligomeric form of recombinant HA1 compared with monomeric HA1. The oligomeric/monomeric HA1 binding ratios of the sera correlated with the virus neutralizing titers. Additionally, the two high-dose VLP vaccine groups generated NA-inhibiting antibodies that were associated with binding to a C-terminal epitope close to the sialic acid binding site. These findings represent the first report describing the quality of the antibody responses in humans following AIV VLP immunization and support further development of such vaccines against emerging influenza virus strains.