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Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM+ memory B cells.
- Source :
-
PloS one [PLoS One] 2008; Vol. 3 (12), pp. e3942. Date of Electronic Publication: 2008 Dec 16. - Publication Year :
- 2008
-
Abstract
- Background: The hemagglutinin (HA) glycoprotein is the principal target of protective humoral immune responses to influenza virus infections but such antibody responses only provide efficient protection against a narrow spectrum of HA antigenic variants within a given virus subtype. Avian influenza viruses such as H5N1 are currently panzootic and pose a pandemic threat. These viruses are antigenically diverse and protective strategies need to cross protect against diverse viral clades. Furthermore, there are 16 different HA subtypes and no certainty the next pandemic will be caused by an H5 subtype, thus it is important to develop prophylactic and therapeutic interventions that provide heterosubtypic protection.<br />Methods and Findings: Here we describe a panel of 13 monoclonal antibodies (mAbs) recovered from combinatorial display libraries that were constructed from human IgM(+) memory B cells of recent (seasonal) influenza vaccinees. The mAbs have broad heterosubtypic neutralizing activity against antigenically diverse H1, H2, H5, H6, H8 and H9 influenza subtypes. Restriction to variable heavy chain gene IGHV1-69 in the high affinity mAb panel was associated with binding to a conserved hydrophobic pocket in the stem domain of HA. The most potent antibody (CR6261) was protective in mice when given before and after lethal H5N1 or H1N1 challenge.<br />Conclusions: The human monoclonal CR6261 described in this study could be developed for use as a broad spectrum agent for prophylaxis or treatment of human or avian influenza infections without prior strain characterization. Moreover, the CR6261 epitope could be applied in targeted vaccine strategies or in the design of novel antivirals. Finally our approach of screening the IgM(+) memory repertoire could be applied to identify conserved and functionally relevant targets on other rapidly evolving pathogens.
- Subjects :
- Amino Acid Sequence
Animals
Antibodies, Monoclonal chemistry
Antibodies, Monoclonal isolation & purification
Antibodies, Viral chemistry
Antibodies, Viral immunology
Antibodies, Viral isolation & purification
Antibody Specificity immunology
B-Lymphocytes immunology
Binding Sites, Antibody
Cross Reactions
Dogs
Hemagglutinin Glycoproteins, Influenza Virus chemistry
Hemagglutinin Glycoproteins, Influenza Virus immunology
Humans
Hydrophobic and Hydrophilic Interactions
Influenza, Human immunology
Influenza, Human virology
Mice
Molecular Sequence Data
Neutralization Tests
Peptide Library
Protein Structure, Tertiary
Tissue Donors
Antibodies, Monoclonal immunology
B-Lymphocytes virology
Immunoglobulin M immunology
Immunologic Memory immunology
Influenza A Virus, H1N1 Subtype immunology
Influenza A Virus, H5N1 Subtype immunology
Influenza, Human prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 3
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 19079604
- Full Text :
- https://doi.org/10.1371/journal.pone.0003942