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
) (). All 12 patients recovered fully from their illness (10–12
Results of analysis of viral RNA isolated from original clinical samples from persons with influenza A(H3N2)v virus infection, United States, 2011*
Genetic sequence analysis of RNA isolated from clinical respiratory specimens () revealed that these influenza A(H3N2)v viruses possessed a combination of gene segments not previously found in humans (). 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
) (, panel A; Technical Appendix
Figure). However, the M genes of all 2011 influenza A(H3N2)v viruses were inherited from a pandemic (H1N1) 2009 virus (, 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.
Derivation of genes segments of novel influenza A(H3N2) viruses isolated from humans, United States, 1990–2011. TR-SIV, triple reassortant swine influenza virus.
Figure 2 Phylogenetic analysis of the A) hemagglutinin and B) matrix genes of influenza A(H3N2)v viruses. Sequences obtained from human A(H3N2)v isolates in the United States during 2011 are shown in boldface; sequences of proposed vaccine virus are underlined (more ...)
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 (), indicating that influenza A(H3N2)v virus is antigenically distinct from influenza A(H3N2) viruses currently circulating among humans.
Hemagglutinin-inhibition assay results, including the 6 available influenza A(H3N2)v viruses isolated in 2011, United States*
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) ().
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.