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Address correspondence to: James E. Crowe Jr., Vanderbilt Vaccine Center, Vanderbilt University Medical Center, 11475 MRB IV, 2213 Garland Avenue, Nashville, Tennessee 37232-0417, USA. Phone: 615.343.8064; E-mail address: james.crowe@vanderbilt.edu.

SB, TN, JAF, NJT, BSK, AC, JAR, RJW, ABW, and JEC designed the research study and experiments.

SB, TN, JAF, NK, NJT, BSK, HGK, VS, RML, GS, AC, JAR, and ABW conducted laboratory experiments and acquired and analyzed data.

BSK and RJW conducted animal studies.

JCS gave statistical review. SE, LL, and KME conducted the parental vaccine study and acquired PBMCs.

SB and JEC wrote the manuscript.

All authors read and commented on the manuscript.

The authors thank F. Smith-House (Vanderbilt) and H. Liu (Kansas State) for technical support, Mark J. Mulligan (Emory) for clinical support during human sample acquisition, and Jill Janssen of the Vanderbilt Clinical Trials Center for regulatory support.

The original clinical trial of the H3N2v vaccine (DMID protocol 12-0011) was supported by NIAID, NIH and performed in the Emory Vaccine Center

SB was supported by the Vanderbilt International Scholar Program.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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Research Funding:

This work was supported by NIH grants R01 AI106002 and U19 AI117905; NIAID contracts HHSN272200900047C and HHSN272201400007C (to JEC), HHSN27220800007C (KME), and HHSN272200800005C and HHSN266200700006C (to BSK, RJW, and JAR); and the Vanderbilt NIH Clinical and Translational Science Award UL1 RR024975.

Recognition of influenza H3N2 variant virus by human neutralizing antibodies.

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JCI insight

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Volume 1, Number 10

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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.

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© 2016, American Society for Clinical Investigation

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