Newcastle Disease Virus-Vectored Vaccines Expressing the Hemagglutinin or Neuraminidase Protein of H5N1 Highly Pathogenic Avian Influenza Virus Protect against Virus Challenge in Monkeys
Newcastle Disease Virus-Vectored Vaccines Expressing the Hemagglutinin or Neuraminidase Protein of H5N1 Highly Pathogenic Avian Influenza Virus Protect against Virus Challenge in Monkeys
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DOI：
10.1128/jvi.01946-09
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发表时间：
2010-02-01
影响因子：
5.4
通讯作者：
Bukreyev, Alexander
中科院分区：
文献类型：
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作者：
DiNapoli, Joshua M.;Nayak, Baibaswata;Bukreyev, Alexander
H5N1高致病性禽流感病毒(HPAIV)在人类中引起周期性暴发，导致严重感染，死亡率高达60%。流行毒株在人与人之间的传播率很低；然而，人们普遍担心，由于突变而导致的传播增强可能会导致全球大流行。我们以前设计了新城疫病毒(NDV)，一种禽副粘病毒，作为表达HPAIV血凝素(HA)蛋白的载体，我们发现这种疫苗(NDV/HA)通过呼吸道接种时，在灵长类动物中诱导了高水平的HPAIV特异性粘膜和血清抗体。在这里，我们开发了额外的新城疫病毒载体疫苗，表达HPAIV HA，其中多碱裂解位点被低致病性流感病毒株[HA(RV)]的多碱裂解位点取代，以解决载体复制或基因交换增强的问题，或者HPAIV神经氨酸酶(NA)。这三种疫苗病毒[新城疫病毒/HA、新城疫病毒/HA(RV)和新城疫病毒/NA]分别通过鼻腔/气管途径接种给非洲绿猴组。另一组动物通过雾化吸入接受新城疫病毒/血凝素。每一种疫苗结构都高度限制复制，在呼吸道分泌物中只检测到低水平的病毒脱落。所有组都产生了针对HPAIV同源和异种毒株的高水平中和抗体，并被同源HPAIV的2×10(7)pfu保护。因此，表达HPAIV HA、HA(RV)或NA的无针、高度减毒新城疫病毒载体疫苗已经被开发出来，并被证明在HPAIV感染的灵长类动物模型中具有单独的免疫原性和保护性。HA(RV)具有保护性的发现表明，将其纳入疫苗将是首选的。这项研究还确认NA是灵长类动物中一种独立的保护性HPAIV抗原。此外，我们还论证了新城疫病毒载体疫苗气雾剂输送的可行性。
H5N1 highly pathogenic avian influenza virus (HPAIV) causes periodic outbreaks in humans, resulting in severe infections with a high (60%) incidence of mortality. The circulating strains have low human-to-human transmissibility; however, widespread concerns exist that enhanced transmission due to mutations could lead to a global pandemic. We previously engineered Newcastle disease virus (NDV), an avian paramyxovirus, as a vector to express the HPAIV hemagglutinin (HA) protein, and we showed that this vaccine (NDV/HA) induced a high level of HPAIV-specific mucosal and serum antibodies in primates when administered through the respiratory tract. Here we developed additional NDV-vectored vaccines expressing either HPAIV HA in which the polybasic cleavage site was replaced with that from a low-pathogenicity strain of influenza virus [HA(RV)], in order to address concerns of enhanced vector replication or genetic exchange, or HPAIV neuraminidase (NA). The three vaccine viruses [NDV/HA, NDV/HA(RV), and NDV/NA] were administered separately to groups of African green monkeys by the intranasal/intratracheal route. An additional group of animals received NDV/HA by aerosol administration. Each of the vaccine constructs was highly restricted for replication, with only low levels of virus shedding detected in respiratory secretions. All groups developed high levels of neutralizing antibodies against homologous and heterologous strains of HPAIV and were protected against challenge with 2 x 10(7) PFU of homologous HPAIV. Thus, needle-free, highly attenuated NDV-vectored vaccines expressing either HPAIV HA, HA(RV), or NA have been developed and demonstrated to be individually immunogenic and protective in a primate model of HPAIV infection. The finding that HA(RV) was protective indicates that it would be preferred for inclusion in a vaccine. The study also identified NA as an independent protective HPAIV antigen in primates. Furthermore, we demonstrated the feasibility of aerosol delivery of NDV-vectored vaccines.