Ryder Alex B, Buonocore Linda, Vogel Leatrice, Nachbagauer Raffael, Krammer Florian, Rose John K
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
J Virol. 2015 Mar;89(5):2820-30. doi: 10.1128/JVI.03246-14. Epub 2014 Dec 24.
The emergence of novel influenza viruses that cause devastating human disease is an ongoing threat and serves as an impetus for the continued development of novel approaches to influenza vaccines. Influenza vaccine development has traditionally focused on producing humoral and/or cell-mediated immunity, often against the viral surface glycoproteins hemagglutinin (HA) and neuraminidase (NA). Here, we describe a new vaccine candidate that utilizes a replication-defective vesicular stomatitis virus (VSV) vector backbone that lacks the native G surface glycoprotein gene (VSVΔG). The expression of the H5 HA of an H5N1 highly pathogenic avian influenza virus (HPAIV), A/Vietnam/1203/04 (VN1203), and the NA of the mouse-adapted H1N1 influenza virus A/Puerto Rico/8/34 (PR8) in the VSVΔG vector restored the ability of the recombinant virus to replicate in cell culture, without the requirement for the addition of trypsin. We show here that this recombinant virus vaccine candidate was nonpathogenic in mice when given by either the intramuscular or intranasal route of immunization and that the in vivo replication of VSVΔG-H5N1 is profoundly attenuated. This recombinant virus also provided protection against lethal H5N1 infection after a single dose. This novel approach to vaccination against HPAIVs may be widely applicable to other emerging strains of influenza virus.
Preparation for a potentially catastrophic influenza pandemic requires novel influenza vaccines that are safe, can be produced and administered quickly, and are effective, both soon after administration and for a long duration. We have created a new influenza vaccine that utilizes an attenuated vesicular stomatitis virus (VSV) vector, to deliver and express influenza virus proteins against which vaccinated animals develop potent antibody responses. The influenza virus hemagglutinin and neuraminidase proteins, expressed on the surface of VSV particles, allowed this vaccine to grow in cell culture and induced a potent antibody response in mice that was effective against infection with a lethal influenza virus. The mice showed no adverse reactions to the vaccine, and they were protected against an otherwise lethal influenza infection after only 14 days postvaccination and after as many as 140 days postvaccination. The ability to rapidly produce this safe and effective vaccine in cell culture is additionally advantageous.
新型流感病毒的出现会引发严重的人类疾病，这一威胁持续存在，也推动了新型流感疫苗研发方法的不断发展。传统上，流感疫苗的研发重点是产生体液免疫和/或细胞介导免疫，通常针对病毒表面糖蛋白血凝素（HA）和神经氨酸酶（NA）。在此，我们描述了一种新的候选疫苗，它利用了一种复制缺陷型水泡性口炎病毒（VSV）载体骨架，该骨架缺少天然的G表面糖蛋白基因（VSVΔG）。在VSVΔG载体中表达H5N1高致病性禽流感病毒（HPAIV）A/越南/1203/04（VN1203）的H5 HA以及小鼠适应株H1N1流感病毒A/波多黎各/8/34（PR8）的NA，恢复了重组病毒在细胞培养中的复制能力，且无需添加胰蛋白酶。我们在此表明，这种重组病毒候选疫苗通过肌肉注射或鼻内免疫途径接种给小鼠时无致病性，并且VSVΔG - H5N1在体内的复制显著减弱。这种重组病毒单剂量接种后也能提供针对致死性H5N1感染的保护。这种针对HPAIV的新型疫苗接种方法可能广泛适用于其他新兴的流感病毒株。
为可能发生的灾难性流感大流行做准备需要新型流感疫苗，这些疫苗要安全、能够快速生产和接种，并且在接种后不久以及长时间内都有效。我们研发了一种新的流感疫苗，它利用减毒的水泡性口炎病毒（VSV）载体来递送和表达流感病毒蛋白，接种疫苗的动物针对这些蛋白会产生强效抗体反应。在VSV颗粒表面表达的流感病毒血凝素和神经氨酸酶蛋白，使这种疫苗能够在细胞培养中生长，并在小鼠体内诱导出强效抗体反应，有效抵抗致死性流感病毒感染。小鼠对该疫苗无不良反应，接种疫苗仅14天后以及多达140天后，它们都受到保护，免受原本会致死的流感感染。能够在细胞培养中快速生产这种安全有效的疫苗还有额外的优势。
