Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection

被引：552

作者：

Yassine, Hadi M. ^{[1
]}

Boyington, Jeffrey C. ^{[1
]}

McTamney, Patrick M. ^{[1
]}

Wei, Chih-Jen ^{[1
]}

Kanekiyo, Masaru ^{[1
]}

Kong, Wing-Pui ^{[1
]}

Gallagher, John R. ^{[2
]}

Wang, Lingshu ^{[1
]}

Zhang, Yi ^{[1
]}

Joyce, M. Gordon ^{[1
]}

Lingwood, Daniel ^{[1
]}

Moin, Syed M. ^{[1
]}

Andersen, Hanne ^{[3
]}

Okuno, Yoshinobu ^{[4
]}

Rao, Srinivas S. ^{[1
]}

Harris, Audray K. ^{[2
]}

Kwong, Peter D. ^{[1
]}

Mascola, John R. ^{[1
]}

Nabel, Gary J. ^{[1
]}

Graham, Barney S. ^{[1
]}

机构：

[1] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA

[2] NIAID, Struct Informat Unit, Infect Dis Lab, NIH, Bethesda, MD 20892 USA

[3] BIOQUAL Inc, Rockville, MD USA

[4] Osaka Univ, Res Fdn Microbial Dis, Kanonji Inst, Kanonji, Japan

来源：

NATURE MEDICINE | 2015年 / 21卷 / 09期

基金：

美国国家卫生研究院;

关键词：

DEPENDENT CELLULAR CYTOTOXICITY; MONOCLONAL-ANTIBODIES; VIRUS; DESIGN; IMMUNOGEN; IMMUNITY; COMPLEX; DOMAIN; CELLS; MICE;

D O I：

10.1038/nm.3927

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The antibody response to influenza is primarily focused on the head region of the hemagglutinin (HA) glycoprotein, which in turn undergoes antigenic drift, thus necessitating annual updates of influenza vaccines. In contrast, the immunogenically subdominant stem region of HA is highly conserved and recognized by antibodies capable of binding multiple HA subtypes(1-6). Here we report the structure-based development of an H1 HA stem-only immunogen that confers heterosubtypic protection in mice and ferrets. Six iterative cycles of structure-based design (Gen1-Gen6) yielded successive H1 HA stabilized-stem (HA-SS) immunogens that lack the immunodominant head domain. Antigenic characterization, determination of two HA-SS crystal structures in complex with stem-specific monoclonal antibodies and cryo-electron microscopy analysis of HA-SS on ferritin nanoparticles (H1-SS-np) confirmed the preservation of key structural elements. Vaccination of mice and ferrets with H1-SS-np elicited broadly cross-reactive antibodies that completely protected mice and partially protected ferrets against lethal heterosubtypic H5N1 influenza virus challenge despite the absence of detectable H5N1 neutralizing activity in vitro. Passive transfer of immunoglobulin from H1-SS-np-immunized mice to naive mice conferred protection against H5N1 challenge, indicating that vaccine-elicited HA stem-specific antibodies can protect against diverse group 1 influenza strains.

引用

页码：1065 / +

页数：9

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