Human infections with novel reassortant influenza A(H3N2)v viruses, United States, 2011.
Systematic surveillance and characterization of novel viruses infecting humans and SIVs in swine are critical for early detection of viruses with pandemic potential. Since 2009, CDC has provided public health laboratories with a real-time reverse transcription PCR (rRT-PCR)-based Author affiliations: Centers for Disease Control and Prevention, Atlanta, Georgia, USA (S. Lindstrom, R. Garten, A. Balish, B. Shu, S. Emery, L. Berman, K. Sleeman, L. Gubareva, J. Villanueva, A. Klimov); and Battelle, Atlanta (N. Barnes) assay for diagnostic testing for influenza (10). This assay enables detection and discrimination of influenza A virus subtypes H1N1, H3N2, and H1N1pdm09 and preliminary identification of triple-reassortant viruses possessing the nucleoprotein gene originating from SIVs.
In 2011, public health laboratories in 5 states detected 12 cases of human infection with a novel variant of influenza virus, influenza A(H3N2)v virus, by using the CDC rRT-PCR protocol. Respiratory specimens from these patients were sent to CDC for virus confirmation. History of direct or indirect contact with swine was confirmed for 6 patients. However, swine contact could not be verified for the other 6, suggesting that these infections might have been contracted through limited person-to-person transmission (11-13) (Table 1). All 12 patients recovered fully from their illness (10-12).
Genetic sequence analysis of RNA isolated from clinical respiratory specimens (Table 1) revealed that these influenza A(H3N2)v viruses possessed a combination of gene segments not previously found in humans (Figure 1). Of the 8 gene segments, 7 (hemagglutinin, neuraminidase, polymerase basic proteins 1 and 2, polymerase acidic protein, nucleoprotein, and nonstructural protein) were similar to those of triple-reassortant SIV A(H3N2) currently circulating in North America and to those from human triple-reassortant influenza A(H3N2) viruses isolated in 2010 from Pennsylvania, Minnesota, and Wisconsin (4), including the proposed vaccine virus of swine origin, A/Minnesota/11/2010 (14) (Figure 2, panel A; online Technical Appendix Figure, www.nc.cdc.gov/EID/pdfs/11-1922-Techapp.pdf). However, the M genes of all 2011 influenza A(H3N2)v viruses were inherited from a pandemic (H1N1) 2009 virus (Figure 2, panel B). Although SIVs of subtypes A(H3N2) and A(H1N2) with the M gene of influenza A(H1N1)pdm09 virus have been detected in swine since 2009 (15), influenza A(H3N2)v virus possessing the M gene of influenza A(H1N1)pdm09 virus had not been detected in humans.
According to genetic analysis results, amino acid diversity among influenza A(H3N2)v hemagglutinins was low (0-3 aa) compared with that of influenza A/Minnesota/11/2010. In addition, there have been no conserved amino acid changes in the hemagglutinin when comparing 2011 influenza A(H3N2)v from humans with 2011 influenza A(H3N2) SIVs. In particular, the known receptor binding site of the hemagglutinin protein of influenza A(H3N2)v virus was typical of SIV A(H3N2) viruses recently isolated in North America.
Hemagglutinins of the influenza A(H3N2)v viruses differed substantially from the hemagglutinin of the 2011-12 human seasonal vaccine virus, A/Perth/16/2011 (58-60 aa), which resulted from divergent evolutionary paths for the H3 hemagglutinin in swine and human viruses. The effect of these substitutions on virus antigenicity was examined in the hemagglutination-inhibition assay by using a panel of reference ferret antiserum. Hemagglutination-inhibition analysis of 6 available influenza A(H3N2)v virus isolates revealed no measureable inhibition by antiserum against the current human seasonal influenza A(H3N2) vaccine virus, A/Perth/16/2009 (Table 2), indicating that influenza A(H3N2)v virus is antigenically distinct from influenza A(H3N2) viruses currently circulating among humans.
All influenza A(H3N2)v viruses tested were antigenically similar, demonstrating hemagglutination inhibition titers with only a 2-fold difference from antiserum against other influenza A(H3N2)v viruses. These viruses were also antigenically closely related to earlier human triple-reassortant virus isolates that contained the M gene from classical SIVs (A/Wisconsin/12/2010, A/ Pennsylvania/14/2010, and A/Minnesota/11/2010). All influenza A(H3N2)v viruses tested were also antigenically closely related to the proposed vaccine reassortant X-203 (13) between triple-reassortant A/Minnesota/11/2010 (H3N2) and A/PR/8/34 (H1N1) (Table 2).
The level of cross-protective immunity against influenza A(H3N2)v in humans previously vaccinated and/or exposed to previously circulated seasonal influenza A(H3N2) viruses is unknown. The antigenic characterization described here demonstrates that vaccination with the current trivalent influenza vaccine might not provide immune protection against influenza A(H3N2)v virus. A vaccine containing a contemporary influenza A(H3N2)v or an antigenically similar virus (such as A/Minnesota/11/2010) might be needed to elicit protective immunity.
Functional neuraminidase inhibition assays indicated that 6 influenza A(H3N2)v virus isolates were sensitive to the neuraminidase inhibitors oseltamivir and zanamivir. No genetic markers known to decrease sensitivity to neuraminidase inhibitors were found in the neuraminidase genes of all 12 influenza A(H3N2)v viruses. Similar to pandemic (H1N1) 2009 viruses, influenza A(H3N2)v viruses have genetic markers (V27A, S31N) in the M2 protein that confer resistance to the antiviral medications amantadine and rimantadine.
The detection of multiple cases of human infection with influenza A(H3N2)v virus within a 5-month period in 5 US states, coupled with possible human-to-human transmission, underscores the need for continued influenza surveillance at the swine-human interface. Coordinated surveillance of human and animal influenza viruses enables rapid detection of human infections with novel influenza viruses and timely identification of new virus variants in swine. As was evident during the 2009 influenza pandemic, this information is vital for development of resources that might be needed to effectively respond to the emergence and spread of a novel influenza virus in humans.
We thank our collaborators from the following institutions: Pennsylvania Department of Health, Pennsylvania Department of Agriculture, Indiana State Department of Health, Indiana Board of Animal Health, Webster County Health Department, Hamilton County Public Health, Iowa Department of Public Health, University of Iowa State Hygienic Laboratory, Maine Center for Disease Control, University of Southern Maine, New Hampshire Department of Agriculture, Massachusetts Department of Agriculture, Maine Department of Agriculture, US Department of Agriculture Swine Influenza Virus Team, Mineral County Health Department, and West Virginia Department of Public Health. We also thank Thomas Gomez, Douglas Jordan, Scott Epperson, Lynette Brammer, Lyn Finelli, Susan Trock, Michael Jhung, Joseph Bresee, Michael Shaw, Daniel Jernigan, and Nancy Cox for their contributions.
Proposed vaccine reassortant X-203 was prepared in the laboratory of Doris Bucher, New York Medical School, in cooperation with the CDC Influenza Division.
Dr Lindstrom is the team lead of the Diagnostics Development Team of the Virus Surveillance and Diagnosis Branch, Influenza Division, at the Centers for Disease Control and Prevention. His research interests are development and qualification of molecular diagnostic testing procedures for influenza viruses, confirmatory diagnostic testing and reporting of human cases of influenza, including infections potentially caused by novel influenza viruses.
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Author affiliations: Centers for Disease Control and Prevention, Atlanta, Georgia, USA (S. Lindstrom, R. Garten, A. Balish, B. Shu, S. Emery, L. Berman, K. Sleeman, L. Gubareva, J. Villanueva, A. Klimov); and Battelle, Atlanta (N. Barnes)
Address for correspondence: Alexander Klimov, Centers for Disease Control and Prevention, Mailstop G16, 1600 Clifton Road NE, Atlanta, GA 30333, USA: email: email@example.com
Table 1. Results of analysis of viral RNA isolated from original clinical samples from persons with influenza A(H3N2)v virus infection, United States, 2011 * Specimen Contact with collection Influenza virus strain swine (11-13) date A/Indiana/08/2011 No Jul 24 A/Pennsylvania/09/2011 Indirect Aug 20 A/Pennsylvania/10/2011 Direct Aug 26 A/Pennsylvania/11/2011 Indirect Aug 25 A/Maine/06/2011 Direct Oct 10 A/Indiana/10/2011 ([section]) Direct Oct 22 A/Maine/07/2011 Direct Oct 24 A/Iowa/07/2011 No Nov 14 A/Iowa/08/2011 No Nov 14 A/Iowa/09/2011 No Nov 14 A/West Virginia/06/2011 No Nov 21 A/West Virginia/07/2011 No Dec 07 Specimen rRT-PCR-positive Influenza virus strain type results ([dagger]) A/Indiana/08/2011 NPS InfA, H3, pdmInfA A/Pennsylvania/09/2011 NPS InfA, H3, pdmInfA A/Pennsylvania/10/2011 NPS InfA A/Pennsylvania/11/2011 NPS InfA, H3, pdmInfA A/Maine/06/2011 NPS InfA, H3, pdmInfA A/Indiana/10/2011 ([section]) Cell culture InfA, H3, pdmInfA A/Maine/07/2011 NPS InfA A/Iowa/07/2011 NPW InfA, H3, pdmInfA A/Iowa/08/2011 NS InfA, H3, pdmInfA A/Iowa/09/2011 NS InfA, H3, pdmInfA A/West Virginia/06/2011 NW InfA, H3, pdmInfA A/West Virginia/07/2011 NPS InfA Genes sequenced Influenza virus strain (double dagger) A/Indiana/08/2011 Full genome A/Pennsylvania/09/2011 Full PB2, PB1, HA, NP, NA, M, NS, partial PA A/Pennsylvania/10/2011 Full NS, partial HA, M, NA A/Pennsylvania/11/2011 Full PA, NP, NA, M NS, partial PB2, PB1, HA A/Maine/06/2011 Full genome A/Indiana/10/2011 ([section]) Full genome A/Maine/07/2011 Partial HA, M, NS A/Iowa/07/2011 Full PB2, PB1, PA, NP, NA, M, NS, partial HA A/Iowa/08/2011 Full genome A/Iowa/09/2011 Full genome A/West Virginia/06/2011 Full genome A/West Virginia/07/2011 Partial HA, NA, M * Influenza A(H3N2)v, influenza virus variant identified in humans; rRT-PCR, real-time reverse transcription PCR; NPS, nasopharyngeal swab; PB, polymerase basic protein; HA, hemagglutinin; NP nucleoprotein; NA, neuraminidase; M, matrix protein; NS, nonstructural protein; PA, polymerase acidic protein; NPW, nasopharyngeal wash; NS, nasal swab. ([dagger]) Results obtained by using the Centers for Disease Control and Prevention Human Influenza Virus Real-Time RT-PCR Diagnostic Panel. ([double dagger]) Sequences available from GenBank and the online Technical Appendix Table (wwwnc.cdc.gov/EID/pdfs/11-1922-Techapp.pdf). ([section]) This patient was >18 years of age; all others were <18. Table 2. Hemagglutinin-inhibition assay results, including the 6 available influenza A(H3N2)v viruses isolated in 2011, United States * Titers to reference ferret antiserum Influenza virus strain (culture method) PER/16 KS/13 WI/12 A/Perth/16/2009 (egg)f 1,280 <10 <10 A/Kansas/13/2009 (MDCK cells) <10 640 80 A/Wisconsin/12/2010 (MDCK cells) <10 40 1,280 A/Pennsylvania/14/2010 (egg) <10 160 320 A/Minnesota/11/2010 (egg) <10 <10 320 A/Minnesota/11/2010 X-203 (egg) (double dagger]) 10 <10 80 A/Indiana/08/2011 (MDCK cells) * <10 10 1,280 A/Indiana/10/2011 (MDCK cells) * <10 40 1,280 A/Indiana/10/2011 (egg) * <10 10 1,280 A/Iowa/07/2011 (MDCK cells) * <10 10 1,280 A/Iowa/08/2011 (MDCK cells) * <10 40 1,280 A/Iowa/09/2011 (MDCK cells) * <10 40 1,280 Titers to reference ferret antiserum Influenza virus strain (culture method) PA/14 MN/11 X203 A/Perth/16/2009 (egg)f <10 20 20 A/Kansas/13/2009 (MDCK cells) 160 40 40 A/Wisconsin/12/2010 (MDCK cells) 320 640 320 A/Pennsylvania/14/2010 (egg) 640 320 320 A/Minnesota/11/2010 (egg) 160 640 1,280 A/Minnesota/11/2010 X-203 (egg) (double dagger]) 40 320 640 A/Indiana/08/2011 (MDCK cells) * 640 640 320 A/Indiana/10/2011 (MDCK cells) * 320 1,280 640 A/Indiana/10/2011 (egg) * 320 640 320 A/Iowa/07/2011 (MDCK cells) * 640 1,280 640 A/Iowa/08/2011 (MDCK cells) * 640 640 640 A/Iowa/09/2011 (MDCK cells) * 640 1,280 640 Titers to reference ferret antiserum Influenza virus strain Specimen (culture method) IN/08 IN/10 collection date A/Perth/16/2009 (egg)f <10 <10 2009 Apr 7 A/Kansas/13/2009 (MDCK cells) 40 80 2009 Jul 29 A/Wisconsin/12/2010 (MDCK cells) 640 1,280 2010 Sep 10 A/Pennsylvania/14/2010 (egg) 640 640 2010 Oct 26 A/Minnesota/11/2010 (egg) 320 160 2010 Nov 26 A/Minnesota/11/2010 X-203 (egg) (double dagger]) 160 80 Not applicable A/Indiana/08/2011 (MDCK cells) * 1,280 1,280 2011 Jul 24 A/Indiana/10/2011 (MDCK cells) * 1,280 1,280 2011 Oct 22 A/Indiana/10/2011 (egg) * 1,280 1,280 2011 Oct 22 A/Iowa/07/2011 (MDCK cells) * 1,280 2,560 2011 Nov 14 A/Iowa/08/2011 (MDCK cells) * 1,280 2,560 2011 Nov 14 A/Iowa/09/2011 (MDCK cells) * 2,560 2,560 2011 Nov 14 * Influenza A(H3N2)v, virus variant identified in humans, United States, 2011. Gray shading indicates antigenically similar viruses. ([dagger]) Current seasonal influenza A(H3N2) vaccine virus. ([double dagger]) Reassortant virus possessing the hemagglutinin and neuraminidase genes of A/Minnesota/11/2010 and the remaining 6 genes of A/PR/8/34.
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|Author:||Lindstrom, Stephen; Garten, Rebecca; Balish, Amanda; Shu, Bo; Emery, Shannon; Berman, LaShondra; Bar|
|Publication:||Emerging Infectious Diseases|
|Date:||May 1, 2012|
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