5C0R

Crystal Structure of a Generation 3 Influenza Hemagglutinin Stabilized Stem Complexed with the Broadly Neutralizing Antibody C179

Summary for 5C0R

• Entry DOI: 10.2210/pdb5c0r/pdb
• Related: 4HLZ 5C0S
• Descriptor: Hemagglutinin, Envelope glycoprotein, Fibritin fusion protein, C179 Fab light chain, C179 Fab heavy chain, ... (6 entities in total)
• Functional Keywords: hemagglutinin, immunogen, trimer, complex, viral protein-immune system complex, viral protein/immune system
• Biological source: Influenza A virus, Human immunodeficiency virus type 1 group M subtype B, Enterobacteria phage T4; More
• Total number of polymer chains: 3
• Total formula weight: 83575.86

Authors

Boyington, J.C.,kwong, P.D.,Nabel, G.J.,Mascola, J.R. (deposition date: 2015-06-12, release date: 2015-09-02, Last modification date: 2024-11-20)

Primary citation

Yassine, H.M.,Boyington, J.C.,McTamney, P.M.,Wei, C.J.,Kanekiyo, M.,Kong, W.P.,Gallagher, J.R.,Wang, L.,Zhang, Y.,Joyce, M.G.,Lingwood, D.,Moin, S.M.,Andersen, H.,Okuno, Y.,Rao, S.S.,Harris, A.K.,Kwong, P.D.,Mascola, J.R.,Nabel, G.J.,Graham, B.S.
Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection.
Nat. Med., 21:1065-1070, 2015

PubMed Abstract: 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. 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.

PubMed: 26301691
DOI: 10.1038/nm.3927

Experimental method

X-RAY DIFFRACTION (3.188 Å)