Department of Virology, Baxter Bioscience, Biomedical Research Center, Orth/Donau, Austria.
PLoS One. 2011 Jan 24;6(1):e16247. doi: 10.1371/journal.pone.0016247.
New highly pathogenic H5N1 influenza viruses are continuing to evolve with a potential threat for an influenza pandemic. So far, the H5N1 influenza viruses have not widely circulated in humans and therefore constitute a high risk for the non immune population. The aim of this study was to evaluate the cross-protective potential of the hemagglutinins of five H5N1 strains of divergent clades using a live attenuated modified vaccinia Ankara (MVA) vector vaccine.
METHODOLOGY/PRINCIPAL FINDINGS: The replication-deficient MVA virus was used to express influenza hemagglutinin (HA) proteins. Specifically, recombinant MVA viruses expressing the HA genes of the clade 1 virus A/Vietnam/1203/2004 (VN/1203), the clade 2.1.3 virus A/Indonesia/5/2005 (IN5/05), the clade 2.2 viruses A/turkey/Turkey/1/2005 (TT01/05) and A/chicken/Egypt/3/2006 (CE/06), and the clade 2.3.4 virus A/Anhui/1/2005 (AH1/05) were constructed. These experimental live vaccines were assessed in a lethal mouse model. Mice vaccinated with the VN/1203 hemagglutinin-expressing MVA induced excellent protection against all the above mentioned clades. Also mice vaccinated with the IN5/05 HA expressing MVA induced substantial protection against homologous and heterologous AH1/05 challenge. After vaccination with the CE/06 HA expressing MVA, mice were fully protected against clade 2.2 challenge and partially protected against challenge of other clades. Mice vaccinated with AH1/05 HA expressing MVA vectors were only partially protected against homologous and heterologous challenge. The live vaccines induced substantial amounts of neutralizing antibodies, mainly directed against the homologous challenge virus, and high levels of HA-specific IFN-γ secreting CD4 and CD8 T-cells against epitopes conserved among the H5 clades and subclades.
CONCLUSIONS/SIGNIFICANCE: The highest level of cross-protection was induced by the HA derived from the VN/1203 strain, suggesting that pandemic H5 vaccines utilizing MVA vector technology, should be based on the VN/1203 hemagglutinin. Furthermore, the recombinant MVA-HA-VN, as characterized in the present study, would be a promising candidate for such a vaccine.
新型高致病性 H5N1 流感病毒仍在持续进化，存在引发流感大流行的潜在威胁。迄今为止，H5N1 流感病毒尚未在人群中广泛传播，因此对非免疫人群构成了高度威胁。本研究旨在评估五种不同分支的 H5N1 流感病毒血凝素（HA）的交叉保护潜力，采用活减毒的改良安卡拉痘苗病毒（MVA）载体疫苗。
方法/主要发现：使用复制缺陷型 MVA 病毒表达流感血凝素（HA）蛋白。具体而言，构建了表达 1 分支病毒 A/Vietnam/1203/2004（VN/1203）、2.1.3 分支病毒 A/Indonesia/5/2005（IN5/05）、2.2 分支病毒 A/turkey/Turkey/1/2005（TT01/05）和 A/chicken/Egypt/3/2006（CE/06）血凝素基因的重组 MVA 病毒，以及 2.3.4 分支病毒 A/Anhui/1/2005（AH1/05）。在致死性小鼠模型中评估了这些实验性活疫苗。用 VN/1203 血凝素表达的 MVA 疫苗免疫的小鼠可获得针对上述所有分支的优异保护。同样，用 IN5/05 HA 表达的 MVA 疫苗免疫的小鼠可对同源和异源 AH1/05 挑战产生实质性保护。用 CE/06 HA 表达的 MVA 疫苗免疫后，小鼠可完全抵抗 2.2 分支的挑战，部分抵抗其他分支的挑战。用 AH1/05 HA 表达的 MVA 载体疫苗免疫的小鼠仅对同源和异源挑战产生部分保护。活疫苗诱导了大量中和抗体，主要针对同源性挑战病毒，以及针对 H5 分支和亚分支保守表位的 HA 特异性 IFN-γ 分泌的 CD4 和 CD8 T 细胞的高水平。
结论/意义：由 VN/1203 株衍生的 HA 诱导了最高水平的交叉保护，表明利用 MVA 载体技术的大流行性 H5 疫苗应基于 VN/1203 血凝素。此外，本研究中所描述的重组 MVA-HA-VN 将是此类疫苗的有前途的候选者。
