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Originally published in Science Express on 22 May 2009
Science 10 July 2009:
Vol. 325. no. 5937, pp. 197 - 201
DOI: 10.1126/science.1176225
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Reports

Antigenic and Genetic Characteristics of Swine-Origin 2009 A(H1N1) Influenza Viruses Circulating in Humans

Rebecca J. Garten1,*, C. Todd Davis1,*, Colin A. Russell2,3, Bo Shu1, Stephen Lindstrom1, Amanda Balish1, Wendy M. Sessions1, Xiyan Xu1, Eugene Skepner2, Varough Deyde1, Margaret Okomo-Adhiambo1, Larisa Gubareva1, John Barnes1, Catherine B. Smith1, Shannon L. Emery1, Michael J. Hillman1, Pierre Rivailler1, James Smagala1, Miranda de Graaf2,4, David F. Burke2, Ron A. M. Fouchier4, Claudia Pappas1, Celia M. Alpuche-Aranda5, Hugo López-Gatell5, Hiram Olivera5, Irma López5, Christopher A. Myers6, Dennis Faix6, Patrick J. Blair6, Cindy Yu7, Kimberly M. Keene8, P. David Dotson, Jr.9, David Boxrud10, Anthony R. Sambol11, Syed H. Abid12, Kirsten St. George13, Tammy Bannerman14, Amanda L. Moore15, David J. Stringer16, Patricia Blevins17, Gail J. Demmler-Harrison18, Michele Ginsberg19, Paula Kriner20, Steve Waterman21, Sandra Smole22, Hugo F. Guevara23, Edward A. Belongia24, Patricia A. Clark25, Sara T. Beatrice26, Ruben Donis1, Jacqueline Katz1, Lyn Finelli1, Carolyn B. Bridges1, Michael Shaw1, Daniel B. Jernigan1, Timothy M. Uyeki1, Derek J. Smith2,3,4,{dagger}, Alexander I. Klimov1 and Nancy J. Cox1,{dagger}

1 WHO Collaborating Center for Influenza, Centers for Disease Control and Prevention (CDC), Atlanta, GA 30333, USA.
2 Department of Zoology, University of Cambridge, Cambridge CB2 3EJ, UK.
3 Fogarty International Center, National Institutes of Health, Bethesda, MD 20892, USA.
4 Department of Virology, Erasmus Medical Center, 3000 CA Rotterdam, NL.
5 Instituto de Diagnóstico y Referencia Epidemiológicos (InDRE) Prolongación de Carpio, México, 11340 Mexico DF.
6 Naval Health Research Center, San Diego, CA 92152, USA.
7 Arizona State Public Health Laboratory, Phoeniz, AZ 85007, USA.
8 Colorado Department of Public Health and Environment, Denver, CO 80230, USA.
9 Indiana State Department of Health Laboratories, Indianapolis, IN 46202, USA.
10 Public Health Laboratory, Minnesota Department of Health, St. Paul, MN 55164, USA.
11 Nebraska Public Health Laboratory, Omaha, NE 68198, USA.
12 Westchester County Department of Laboratories & Research Public Health Laboratories, Valhalla, NY 10595,USA.
13 Wadsworth Center, New York State Department of Health, Slingerlands, NY 12159, USA.
14 Ohio Department of Health Laboratory, Reynoldsburg, OH 43068, Reynoldsburg, OH 43068, USA.
15 South Carolina Department of Health and Environmental Control, Columbia, SC 29223, USA.
16 Dallas County Health and Human Services, Dallas, TX 75207, USA.
17 San Antonio Metro Health District, Brooks City–Base, TX 78235, USA.
18 Diagnostic Virology Laboratory, Texas Children’s Hospital, Houston, TX 77030, USA.
19 San Diego Public Health Laboratory, San Diego, CA 92186, USA.
20 Imperial County Public Health Department, El Centro, CA 92243, USA.
21 CDC Border Infectious Disease Surveillance Project, Atlanta, GA 30333, USA.
22 William A. Hinton State Laboratory Institute, Massachusetts Department of Public Health, Jamaica Plain, MA 02130, USA.
23 California Department of Public Health, Viral and Rickettsial Disease Laboratory, Richmond, CA 94804, USA.
24 Marshfield Clinic Research Foundation, Marshfield, WI 54449, USA.
25 Michigan Department of Community Health, Lansing, MI 48906, USA.
26 Public Health Laboratory, NYC Department of Health and Mental Hygiene, New York, NY 10016, USA.


Figure 1
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  		Fig. 1. Host and lineage origins for the gene segments of the 2009 A(H1N1) virus: PB2, polymerase basic 2; PB1, polymerase basic 1; PA, polymerase acidic; HA, hemagglutinin; NP, nucleoprotein; NA, neuraminidase; M, matrix gene; NS, nonstructural gene. Color of gene segment in circle indicates host. Determination of lineage is explained in the main text.

 

Figure 2
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  		Fig. 2. A maximum likelihood phylogenetic tree for nucleotide sequences of the HA gene of selected influenza viruses. The selected viruses were chosen to be representative from among all available relevant sequences in GenBank: sequences that had both high and low divergence to avoid biasing the distribution of branch lengths; swine strains that had been isolated from humans and that had been isolated from swine; strains that were representative of the major gene lineages from different hosts; and the nearest BLAST relative to include the most closely related non-outbreak virus. Phylogenetic trees of a larger number of representative HA gene segments, and of all H1 HA swine gene segments, are shown in figs. S1D and S2D, respectively. Tree was inferred using PAUP* (version 4.0b10) (40), using GTR+I+{Gamma}4 (the general time-reversible model with the proportion of invariant sites and the gamma distribution of among-site rate variation with four categories estimated from the empirical data) as determined by ModelTest (41). Global optimization of the tree topology was performed by tree bisection-reconnection branch swapping. The robustness of individual nodes of the tree was assessed using a bootstrap resampling analysis (1000 replicates, with topologies inferred using the neighbor-joining method under the GTR+I+{Gamma}4 substitution model).

 

Figure 3
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  		Fig. 3. Antigenic map of 71 early swine-origin 2009 A(H1N1) influenza viruses and 11 antisera. An antigenic map is a geometric representation of binding assay data, in this case the HI assay data in tables S3 and S4. In such a map, the relative positions of strains (colored circles) and antisera (uncolored squares) are adjusted such that the distances between strains and antisera in the map represent the corresponding HI measurements with the least error. Distance in the map thus represents antigenic distance, and the closer antigens are to each other in the map, the more similar they are antigenically (38). The color of a circle in the map indicates whether the strain is a 2009 A(H1N1) influenza virus (blue) or an A(H1) swine influenza virus isolated between 1998 and 2007 from either a swine (purple) or a human (pink) infected with a swine influenza virus. The vertical and horizontal axes both represent antigenic distance, and because only the relative positions of antigens and antisera can be determined, the orientation of the map within these axes is free (thus an antigenic map can be rotated in the same way that a geographic map can be rotated). The spacing between grid lines is one unit of antigenic distance—corresponding to a twofold dilution of antiserum in the HI assay. Two units correspond to fourfold dilution, three units to eightfold dilution, etc. A difference higher than fourfold in HI titer is usually considered to be sufficient to necessitate an update of the human seasonal influenza virus vaccine. Antigenic clusters of human seasonal influenza viruses typically have a radius of two antigenic units (fourfold in HI) (38) (see fig. S3 for a zoomable PDF of this antigenic map that additionally includes the names of each strain and antiserum).

 

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