R&D Vaccines, Biomedical Research Center, Baxter BioScience, Orth/Donau, Austria.
PLoS One. 2010 Aug 16;5(8):e12217. doi: 10.1371/journal.pone.0012217.
The development of novel influenza vaccines inducing a broad immune response is an important objective. The aim of this study was to evaluate live vaccines which induce both strong humoral and cell-mediated immune responses against the novel human pandemic H1N1 influenza virus, and to show protection in a lethal animal challenge model.
METHODOLOGY/PRINCIPAL FINDINGS: For this purpose, the hemagglutinin (HA) and neuraminidase (NA) genes of the influenza A/California/07/2009 (H1N1) strain (CA/07) were inserted into the replication-deficient modified vaccinia Ankara (MVA) virus--a safe poxviral live vector--resulting in MVA-H1-Ca and MVA-N1-Ca vectors. These live vaccines, together with an inactivated whole virus vaccine, were assessed in a lung infection model using immune competent Balb/c mice, and in a lethal challenge model using severe combined immunodeficient (SCID) mice after passive serum transfer from immunized mice. Balb/c mice vaccinated with the MVA-H1-Ca virus or the inactivated vaccine were fully protected from lung infection after challenge with the influenza H1N1 wild-type strain, while the neuraminidase virus MVA-N1-Ca induced only partial protection. The live vaccines were already protective after a single dose and induced substantial amounts of neutralizing antibodies and of interferon-gamma-secreting (IFN-gamma) CD4- and CD8 T-cells in lungs and spleens. In the lungs, a rapid increase of HA-specific CD4- and CD8 T cells was observed in vaccinated mice shortly after challenge with influenza swine flu virus, which probably contributes to the strong inhibition of pulmonary viral replication observed. In addition, passive transfer of antisera raised in MVA-H1-Ca vaccinated immune-competent mice protected SCID mice from lethal challenge with the CA/07 wild-type virus.
CONCLUSIONS/SIGNIFICANCE: The non-replicating MVA-based H1N1 live vaccines induce a broad protective immune response and are promising vaccine candidates for pandemic influenza.
开发能诱导广泛免疫反应的新型流感疫苗是一个重要目标。本研究旨在评估既能诱导针对新型人源性大流行性 H1N1 流感病毒的体液和细胞免疫反应，又能在致死性动物攻毒模型中提供保护的活疫苗。
方法/主要发现：为此，将流感 A/加利福尼亚/07/2009（H1N1）株（CA/07）的血凝素（HA）和神经氨酸酶（NA）基因插入到复制缺陷型改良安卡拉痘苗病毒（MVA）——一种安全的痘病毒活载体——中，得到 MVA-H1-Ca 和 MVA-N1-Ca 载体。使用免疫功能正常的 Balb/c 小鼠进行肺部感染模型评估，使用免疫小鼠被动血清转移的严重联合免疫缺陷（SCID）小鼠进行致死性攻毒模型评估，对这些活疫苗和灭活全病毒疫苗进行了评估。用 MVA-H1-Ca 病毒或灭活疫苗免疫的 Balb/c 小鼠在受到流感 H1N1 野生型病毒攻击后完全免受肺部感染，而神经氨酸酶病毒 MVA-N1-Ca 仅诱导部分保护。单剂活疫苗即可提供保护，并在肺部和脾脏中诱导大量中和抗体和干扰素-γ分泌（IFN-γ）的 CD4+和 CD8+T 细胞。在肺部，接种疫苗的小鼠在受到猪流感病毒攻击后不久，即可观察到 HA 特异性 CD4+和 CD8+T 细胞的快速增加，这可能有助于观察到的肺部病毒复制的强烈抑制。此外，在 MVA-H1-Ca 免疫的免疫功能正常小鼠中产生的抗血清的被动转移可保护 SCID 小鼠免受 CA/07 野生型病毒的致死性攻击。
结论/意义：非复制型 MVA 为基础的 H1N1 活疫苗可诱导广泛的保护性免疫反应，是大流行性流感的有前途的疫苗候选物。
