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Recognition of influenza H3N2 variant virus by human neutralizing antibodies
Sandhya Bangaru, … , Andrew B. Ward, James E. Crowe Jr.
Sandhya Bangaru, … , Andrew B. Ward, James E. Crowe Jr.
Published July 7, 2016
Citation Information: JCI Insight. 2016;1(10):e86673. https://doi.org/10.1172/jci.insight.86673.
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Research Article Immunology Infectious disease

Recognition of influenza H3N2 variant virus by human neutralizing antibodies

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Abstract

Since 2011, over 300 human cases of infection, especially in exposed children, with the influenza A H3N2 variant (H3N2v) virus that circulates in swine in the US have been reported. The structural and genetic basis for the lack of protection against H3N2v induced by vaccines containing seasonal H3N2 antigens is poorly understood. We isolated 17 human monoclonal antibodies (mAbs) that neutralized H3N2v virus from subjects experimentally immunized with an H3N2v candidate vaccine. Six mAbs exhibited very potent neutralizing activity (IC50 < 200 ng/ml) against the H3N2v virus but not against current human H3N2 circulating strains. Fine epitope mapping and structural characterization of antigen-antibody complexes revealed that H3N2v specificity was attributable to amino acid polymorphisms in the 150-loop and the 190-helix antigenic sites on the hemagglutinin protein. H3N2v-specific antibodies also neutralized human H3N2 influenza strains naturally circulating between 1995 and 2005. These results reveal a high level of antigenic relatedness between the swine H3N2v virus and previously circulating human strains, consistent with the fact that early human H3 seasonal strains entered the porcine population in the 1990s and reentered the human population, where they had not been circulating, as H3N2v about a decade later. The data also explain the increased susceptibility to H3N2v viruses in young children, who lack prior exposure to human seasonal strains from the 1990s.

Authors

Sandhya Bangaru, Travis Nieusma, Nurgun Kose, Natalie J. Thornburg, Jessica A. Finn, Bryan S. Kaplan, Hannah G. King, Vidisha Singh, Rebecca M. Lampley, Gopal Sapparapu, Alberto Cisneros III, Kathryn M. Edwards, James C. Slaughter, Srilatha Edupuganti, Lilin Lai, Juergen A. Richt, Richard J. Webby, Andrew B. Ward, James E. Crowe Jr.

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Figure 5

Negative stain EM images of hemagglutinin-Fab complexes.

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Negative stain EM images of hemagglutinin-Fab complexes.
In each case th...
In each case the stem-binding antibody CR9114 was added to the complex in order to improve 3D reconstructions. (A) Reference-free 2D class averages of complex containing Fab 104 (left), single class average with Fab colored in red (middle), and 3D reconstruction (right). (B) Reference-free 2D class averages of complex containing Fab 126 (left), single class average with Fab colored in blue (middle), and 3D reconstruction (right). (C) Reference-free 2D class averages of complex containing Fab 71 (left), single class average with Fab colored in green (middle), and 3D reconstruction (right). (D) Side and top views of HA-Fab 126-CR9114 with Fab 126 removed and crystal structure of H3V (4FNK) fitted. Binding sites of the 3 antibodies described in A–C is highlighted using colors corresponding to Fabs.

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