Heterosubtypic Neutralizing Monoclonal Antibodies Cross-Protective against H5N1 and H1N1 Recovered from Human IgM+ Memory B Cells

By M. Throsby, E. N. van den Brink, M. Jongeneelen, L. Poon, P. Alard, L. Cornelissen, A. Bakker, F. Cox, E. van Deventer, Yi Guan and 7 more. 2008

767 citations recorded by the source corpus.

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. 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. 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.

Subfields: Epidemiology, Immunology, Radiology, Nuclear Medicine and Imaging

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Epidemiology

1. Barney S. Graham
2. F. Krammer
3. A. García‐Sastre
4. P. Palese
5. M. Kanekiyo
6. J. Steel
7. Raymond Tellier
8. J. Tang

In Immunology

1. F. Krammer
2. A. García‐Sastre
3. P. Palese
4. L. Martínez-Sobrido
5. N. Baumgarth

In Radiology, Nuclear Medicine and Imaging

1. Barney S. Graham
2. M. Kanekiyo

Citations in the corpus

• Chimeric Hemagglutinin Influenza Virus Vaccine Constructs Elicit Broadly Protective Stalk-Specific Antibodies (2013, background): “Consistent with the protection seen following heterosubtypic challenges, IgG purified from vaccinated mice inhibited the entry of pseudoparticles in a dose-dependent manner, and with similar efficacy to that of CR6261 (3, 6).”
• Hemagglutinin-Pseudotyped Green Fluorescent Protein-Expressing Influenza Viruses for the Detection of Influenza Virus Neutralizing Antibodies (2009, background): “A few HA-specific MAbs with broad cross-neutralization activities have recently been described (5, 18, 20), and the use of HA-pseudotyped GFP-expressing influenza viruses should make possible rapid screenings for the identification of additional antibodies with such broad cross-neutralizing activiti”
• Next-Generation Influenza Vaccines. (2020, background): “…the Trp21HA2 residue, exhibit neutralizing breadth against multiple subtype viruses within influenza A group 1 subtypes (Okuno et al. 1993; Throsby et al. 2008; Ekiert et al. 2009; Sui et al. 2009), group 2 subtypes (Ekiert et al. 2011; Friesen et al. 2014), or across both group 1 and…”