流感2组血凝素茎段免疫原疫苗的保护效力

Protective efficacy of influenza group 2 hemagglutinin stem-fragment immunogen vaccines.

作者信息

Sutton Troy C, Chakraborty Saborni, Mallajosyula Vamsee V A, Lamirande Elaine W, Ganti Ketaki, Bock Kevin W, Moore Ian N, Varadarajan Raghavan, Subbarao Kanta

机构信息

Laboratory of Infectious Diseases, NIAID, NIH, Bethesda, MD USA.

Molecular Biophysics Unit, Indian Institute of Science, Bangalore, Karnataka India.

出版信息

NPJ Vaccines. 2017 Dec 15;2:35. doi: 10.1038/s41541-017-0036-2. eCollection 2017.

Abstract

The stem of the influenza A virus hemagglutinin (HA) is highly conserved and represents an attractive target for a universal influenza vaccine. The 18 HA subtypes of influenza A are phylogenetically divided into two groups, and while protection with group 1 HA stem vaccines has been demonstrated in animal models, studies on group 2 stem vaccines are limited. Thus, we engineered group 2 HA stem-immunogen (SI) vaccines targeting the epitope for the broadly neutralizing monoclonal antibody CR9114 and evaluated vaccine efficacy in mice and ferrets. Immunization induced antibodies that bound to recombinant HA protein and viral particles, and competed with CR9114 for binding to the HA stem. Mice vaccinated with H3 and H7-SI were protected from lethal homologous challenge with X-79 (H3N2) or A/Anhui/1/2013 (H7N9), and displayed moderate heterologous protection. In ferrets, H7-SI vaccination did not significantly reduce weight loss or nasal wash titers after robust 10 TCID H7N9 virus challenge. Epitope mapping revealed ferrets developed lower titers of antibodies that bound a narrow range of HA stem epitopes compared to mice, and this likely explains the lower efficacy in ferrets. Collectively, these findings indicate that while group 2 SI vaccines show promise, their immunogenicity and efficacy are reduced in larger outbred species, and will have to be enhanced for successful translation to a universal vaccine.

摘要

甲型流感病毒血凝素(HA)的茎部高度保守,是通用流感疫苗的一个有吸引力的靶点。甲型流感的18种HA亚型在系统发育上分为两组,虽然1组HA茎疫苗在动物模型中已证明有保护作用,但关于2组茎疫苗的研究有限。因此,我们构建了针对广泛中和单克隆抗体CR9114表位的2组HA茎免疫原(SI)疫苗,并在小鼠和雪貂中评估了疫苗效力。免疫诱导产生了与重组HA蛋白和病毒颗粒结合、并与CR9114竞争结合HA茎的抗体。用H3和H7-SI疫苗接种的小鼠对X-79(H3N2)或A/安徽/1/2013(H7N9)的致死性同源攻击具有保护作用,并表现出中等程度的异源保护。在雪貂中,用H7-SI疫苗接种后,在受到10个组织培养感染剂量(TCID)的H7N9病毒强力攻击后,体重减轻或鼻腔冲洗滴度没有显著降低。表位作图显示,与小鼠相比,雪貂产生的结合较窄范围HA茎表位的抗体滴度较低,这可能解释了雪貂中较低的效力。总的来说,这些发现表明,虽然2组SI疫苗有前景,但它们在较大的远交物种中的免疫原性和效力有所降低,必须加以提高才能成功转化为通用疫苗。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99dd/5732283/ce3acc4caf82/41541_2017_36_Fig1_HTML.jpg

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