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TitleHemagglutinin-stem nanoparticles generate heterosubtypic influenza protection.
Journal, issue, pagesNat Med, Vol. 21, Issue 9, Page 1065-1070, Year 2015
Publish dateAug 24, 2015
AuthorsHadi M Yassine / Jeffrey C Boyington / Patrick M McTamney / Chih-Jen Wei / Masaru Kanekiyo / Wing-Pui Kong / John R Gallagher / Lingshu Wang / Yi Zhang / M Gordon Joyce / Daniel Lingwood / Syed M Moin / Hanne Andersen / Yoshinobu Okuno / Srinivas S Rao / Audray K Harris / Peter D Kwong / John R Mascola / Gary J Nabel / Barney S Graham /
PubMed AbstractThe 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 ...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.
External linksNat Med / PubMed:26301691
MethodsEM (single particle) / X-ray diffraction
Resolution3.188 - 16.0 Å
Structure data

EMDB-6332:
3D reconstruction of a ferritin-based nanoparticle displaying H1 Hemagglutinin stem epitopes
Method: EM (single particle) / Resolution: 16.0 Å

PDB-5c0r:
Crystal Structure of a Generation 3 Influenza Hemagglutinin Stabilized Stem Complexed with the Broadly Neutralizing Antibody C179
Method: X-RAY DIFFRACTION / Resolution: 3.188 Å

PDB-5c0s:
Crystal structure of a generation 4 influenza hemagglutinin stabilized stem in complex with the broadly neutralizing antibody CR6261
Method: X-RAY DIFFRACTION / Resolution: 4.3 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-HOH:
WATER / Water

Source
  • synthetic construct (others)
  • influenza a virus
  • human immunodeficiency virus type 1 group m subtype b
  • enterobacteria phage t4 (virus)
  • mus musculus (house mouse)
  • homo sapiens (human)
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / Hemagglutinin / immunogen / trimer / complex / VIRAL PROTEIN-IMMUNE SYSTEM complex

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