A modified vaccinia Ankara vaccine vector expressing a mosaic H5 hemagglutinin reduces viral shedding in rhesus macaques.
A modified vaccinia Ankara vaccine vector expressing a mosaic H5 hemagglutinin reduces viral shedding in rhesus macaques.
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DOI：
10.1371/journal.pone.0181738
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Friedrich TC
中科院分区：
文献类型：
--
作者：
Florek KR;Kamlangdee A;Mutschler JP;Kingstad-Bakke B;Schultz-Darken N;Broman KW;Osorio JE;Friedrich TC
流感病毒的快速抗原进化需要频繁的疫苗重新配制。由于连续疫苗重新配制的经济负担和新的大流行的威胁，人们对开发能够引起对流感病毒的广泛交叉反应性免疫的疫苗有浓厚的兴趣。最近，我们构建了一个“镶嵌”血凝素（HA）的基础上亚型5 HA（H5），旨在刺激细胞和体液免疫多种流感病毒亚型。表达这种H5嵌合体的改良安卡拉牛痘（MVA）（MVA-H5 M）保护小鼠免受多种同型亚型H5 N1毒株和异型亚型H1N1病毒的侵害。为了评估其作为人疫苗的潜力，我们评估了MVA-H5 M在非人灵长类动物模型中提供对流感病毒的异亚型免疫的能力。恒河猴接受初始剂量的MVA-H5 M或编码H5 M的质粒DNA，随后加强MVA-H5 M，然后与未感染对照一起用异亚型病毒A/加州/04/2009（H1N1 pdm）攻击。接受任一疫苗方案的猕猴比未接种疫苗的对照组更快地清除H1N1 pdm攻击。用H5 M疫苗接种引起结合H1N1 pdm HA的抗体，但不中和H1N1 pdm攻击病毒。来自接种疫苗的猕猴的血浆在H1N1 pdm HA的存在下激活NK细胞，表明疫苗接种引起能够介导抗体依赖性细胞介导的细胞毒性（ADCC）的交叉反应性抗体。尽管HA特异性T细胞对MVA-H5 M疫苗的应答较弱，但接种疫苗的猕猴在攻击后的应答比对照动物更强。总之，这些数据表明，镶嵌HA抗原可以提供一种诱导广泛的交叉反应性免疫流感病毒的手段。
The rapid antigenic evolution of influenza viruses requires frequent vaccine reformulations. Due to the economic burden of continuous vaccine reformulation and the threat of new pandemics, there is intense interest in developing vaccines capable of eliciting broadly cross-reactive immunity to influenza viruses. We recently constructed a “mosaic” hemagglutinin (HA) based on subtype 5 HA (H5) and designed to stimulate cellular and humoral immunity to multiple influenza virus subtypes. Modified vaccinia Ankara (MVA) expressing this H5 mosaic (MVA-H5M) protected mice against multiple homosubtypic H5N1 strains and a heterosubtypic H1N1 virus. To assess its potential as a human vaccine we evaluated the ability of MVA-H5M to provide heterosubtypic immunity to influenza viruses in a non-human primate model. Rhesus macaques received an initial dose of either MVA-H5M or plasmid DNA encoding H5M, followed by a boost of MVA-H5M, and then were challenged, together with naïve controls, with the heterosubtypic virus A/California/04/2009 (H1N1pdm). Macaques receiving either vaccine regimen cleared H1N1pdm challenge faster than naïve controls. Vaccination with H5M elicited antibodies that bound H1N1pdm HA, but did not neutralize the H1N1pdm challenge virus. Plasma from vaccinated macaques activated NK cells in the presence of H1N1pdm HA, suggesting that vaccination elicited cross-reactive antibodies capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC). Although HA-specific T cell responses to the MVA-H5M vaccine were weak, responses after challenge were stronger in vaccinated macaques than in control animals. Together these data suggest that mosaic HA antigens may provide a means for inducing broadly cross-reactive immunity to influenza viruses.