Sequential Immunization with Universal Live Attenuated Influenza Vaccine Candidates Protects Ferrets against a High-Dose Heterologous Virus Challenge
Sequential Immunization with Universal Live Attenuated Influenza Vaccine Candidates Protects Ferrets against a High-Dose Heterologous Virus Challenge
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DOI：
10.3390/vaccines7030061
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发表时间：
2019-09-01
期刊：
影响因子：
7.8
通讯作者：
Rudenko, Larisa
中科院分区：
文献类型：
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作者：
Isakova-Sivak, Irina;Matyushenko, Victoria;Rudenko, Larisa
20多年来，开发通用流感疫苗一直是优先事项。我们在雪貂身上进行了两组表达嵌合血凝素(CHA)的减毒活流感疫苗(LAIV)的临床前研究。这些疫苗含有H1N1pdm09病毒的HA茎结构域，但具有抗原性无关的H5N1、H8N4和H9N2禽流感病毒的球形头部结构域。为了更好地匹配当前流行的甲型流感病毒的CD8 T细胞表位，两组通用LAIV候选病毒中的核蛋白(NP)来自不同的来源：一组LAIV包含来自A/Leningrad/17主供体病毒(MDV)的NP，另一组包含来自野生型(WT)H1N1pdm09病毒的NP，以更好地匹配目前流行的甲型流感病毒的CD8T细胞表位。为了避免不同的抗神经氨酸酶(NA)抗体的保护作用的差异，所有LAIV都被改造成含有LEN/17MDV的NA基因。用三种剂量(I)含MDV非嵌合HA和NP的经典LAIVs(NP-MDV)；(Ii)含MDV NP的CHA LAIVs(NP-MDV)；和(Iii)含H1N1pdm09病毒NP的CHA LAIVs(NP-WT)连续免疫幼年雪貂。与安慰剂组相比，所有疫苗接种方案都是安全的，没有显著提高体温或体重减轻。这两组基于CHA的疫苗诱导了一种广泛反应的HA茎定向抗体，而经典的LAIV没有。高剂量的H1N1pdm09病毒攻击在对照组和未免疫的雪貂中引起了显著的病理变化，包括呼吸道组织中的高病毒滴度、临床症状以及鼻甲和肺组织的组织病理学变化。三种接种方案都保护动物免受疾病的临床表现：免疫的雪貂没有体重下降或出现临床症状，其体温明显低于对照组。对病毒学和病理学数据的进一步分析显示，疫苗的交叉保护效力等级如下：CHA LAIVs(NP-WT)和GT；CHA LAIVs(NP-MDV)和GT；LAIVs(NP-MDV)。这项雪貂研究表明，原型通用的基于CHA的LAIV是进一步临床开发的非常有前途的候选者。
The development of universal influenza vaccines has been a priority for more than 20 years. We conducted a preclinical study in ferrets of two sets of live attenuated influenza vaccines (LAIVs) expressing chimeric hemagglutinin (cHA). These vaccines contained the HA stalk domain from H1N1pdm09 virus but had antigenically unrelated globular head domains from avian influenza viruses H5N1, H8N4 and H9N2. The viral nucleoproteins (NPs) in the two sets of universal LAIV candidates were from different sources: one LAIV set contained NP from A/Leningrad/17 master donor virus (MDV), while in the other set this gene was from wild-type (WT) H1N1pdm09 virus, in order to better match the CD8 T-cell epitopes of currently circulating influenza A viruses. To avoid any difference in protective effect of the various anti-neuraminidase (NA) antibodies, all LAIVs were engineered to contain the NA gene of Len/17 MDV. Naive ferrets were sequentially immunized with three doses of (i) classical LAIVs containing non-chimeric HA and NP from MDV (LAIVs (NP-MDV)); (ii) cHA-based LAIVs containing NP from MDV (cHA LAIVs (NP-MDV)); and (iii) cHA-based LAIVs containing NP from H1N1pdm09 virus (cHA LAIVs (NP-WT)). All vaccination regimens were safe, producing no significant increase in body temperature or weight loss, in comparison with the placebo group. The two groups of cHA-based vaccines induced a broadly reactive HA stalk-directed antibody, while classical LAIVs did not. A high-dose challenge with H1N1pdm09 virus induced significant pathology in the control, non-immunized ferrets, including high virus titers in respiratory tissues, clinical signs of disease and histopathological changes in nasal turbinates and lung tissues. All three vaccination regimens protected animals from clinical manifestations of disease: immunized ferrets did not lose weight or show clinical symptoms, and their fever was significantly lower than in the control group. Further analysis of virological and pathological data revealed the following hierarchy in the cross-protective efficacy of the vaccines: cHA LAIVs (NP-WT) > cHA LAIVs (NP-MDV) > LAIVs (NP-MDV). This ferret study showed that prototype universal cHA-based LAIVs are highly promising candidates for further clinical development.