Inefficient Transmission of H5N1 Influenza Viruses in a Ferret Contact Model▿
Identifieur interne : 000385 ( Pmc/Corpus ); précédent : 000384; suivant : 000386Inefficient Transmission of H5N1 Influenza Viruses in a Ferret Contact Model▿
Auteurs : Hui-Ling Yen ; Aleksandr S. Lipatov ; Natalia A. Ilyushina ; Elena A. Govorkova ; John Franks ; Neziha Yilmaz ; Alan Douglas ; Alan Hay ; Scott Krauss ; Jerold E. Rehg ; Erich Hoffmann ; Robert G. WebsterSource :
- Journal of Virology [ 0022-538X ] ; 2007.
Abstract
The abilities to infect and transmit efficiently among humans are essential for a novel influenza A virus to cause a pandemic. To evaluate the pandemic potential of widely disseminated H5N1 influenza viruses, a ferret contact model using experimental groups comprised of one inoculated ferret and two contact ferrets was used to study the transmissibility of four human H5N1 viruses isolated from 2003 to 2006. The effects of viral pathogenicity and receptor binding specificity (affinity to synthetic sialosaccharides with α2,3 or α2,6 linkages) on transmissibility were assessed. A/Vietnam/1203/04 and A/Vietnam/JP36-2/05 viruses, which possess “avian-like” α2,3-linked sialic acid (SA) receptor specificity, caused neurological symptoms and death in ferrets inoculated with 103 50% tissue culture infectious doses. A/Hong Kong/213/03 and A/Turkey/65-596/06 viruses, which show binding affinity for “human-like” α2,6-linked SA receptors in addition to their affinity for α2,3-linked SA receptors, caused mild clinical symptoms and were not lethal to the ferrets. No transmission of A/Vietnam/1203/04 or A/Turkey/65-596/06 virus was detected. One contact ferret developed neutralizing antibodies to A/Hong Kong/213/03 but did not exhibit any clinical signs or detectable virus shedding. In two groups, one of two naïve contact ferrets had detectable virus after 6 to 8 days when housed together with the A/Vietnam/JP36-2/05 virus-inoculated ferrets. Infected contact ferrets showed severe clinical signs, although little or no virus was detected in nasal washes. This limited virus shedding explained the absence of secondary transmission from the infected contact ferret to the other naïve ferret that were housed together. Our results suggest that despite their receptor binding affinity, circulating H5N1 viruses retain molecular determinants that restrict their spread among mammalian species.
Url:
DOI: 10.1128/JVI.00170-07
PubMed: 17459930
PubMed Central: 1933302
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PMC:1933302Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Inefficient Transmission of H5N1 Influenza Viruses in a Ferret Contact Model<xref ref-type="fn" rid="fn2">▿</xref>
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<author><name sortKey="Hoffmann, Erich" sort="Hoffmann, Erich" uniqKey="Hoffmann E" first="Erich" last="Hoffmann">Erich Hoffmann</name>
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<author><name sortKey="Webster, Robert G" sort="Webster, Robert G" uniqKey="Webster R" first="Robert G." last="Webster">Robert G. Webster</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Inefficient Transmission of H5N1 Influenza Viruses in a Ferret Contact Model<xref ref-type="fn" rid="fn2">▿</xref>
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<author><name sortKey="Yen, Hui Ling" sort="Yen, Hui Ling" uniqKey="Yen H" first="Hui-Ling" last="Yen">Hui-Ling Yen</name>
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</affiliation>
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<author><name sortKey="Lipatov, Aleksandr S" sort="Lipatov, Aleksandr S" uniqKey="Lipatov A" first="Aleksandr S." last="Lipatov">Aleksandr S. Lipatov</name>
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</affiliation>
</author>
<author><name sortKey="Ilyushina, Natalia A" sort="Ilyushina, Natalia A" uniqKey="Ilyushina N" first="Natalia A." last="Ilyushina">Natalia A. Ilyushina</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Govorkova, Elena A" sort="Govorkova, Elena A" uniqKey="Govorkova E" first="Elena A." last="Govorkova">Elena A. Govorkova</name>
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<author><name sortKey="Franks, John" sort="Franks, John" uniqKey="Franks J" first="John" last="Franks">John Franks</name>
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<author><name sortKey="Yilmaz, Neziha" sort="Yilmaz, Neziha" uniqKey="Yilmaz N" first="Neziha" last="Yilmaz">Neziha Yilmaz</name>
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<author><name sortKey="Douglas, Alan" sort="Douglas, Alan" uniqKey="Douglas A" first="Alan" last="Douglas">Alan Douglas</name>
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<author><name sortKey="Hay, Alan" sort="Hay, Alan" uniqKey="Hay A" first="Alan" last="Hay">Alan Hay</name>
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<author><name sortKey="Krauss, Scott" sort="Krauss, Scott" uniqKey="Krauss S" first="Scott" last="Krauss">Scott Krauss</name>
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<author><name sortKey="Rehg, Jerold E" sort="Rehg, Jerold E" uniqKey="Rehg J" first="Jerold E." last="Rehg">Jerold E. Rehg</name>
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<author><name sortKey="Hoffmann, Erich" sort="Hoffmann, Erich" uniqKey="Hoffmann E" first="Erich" last="Hoffmann">Erich Hoffmann</name>
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<author><name sortKey="Webster, Robert G" sort="Webster, Robert G" uniqKey="Webster R" first="Robert G." last="Webster">Robert G. Webster</name>
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<series><title level="j">Journal of Virology</title>
<idno type="ISSN">0022-538X</idno>
<idno type="eISSN">1098-5514</idno>
<imprint><date when="2007">2007</date>
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<front><div type="abstract" xml:lang="en"><p>The abilities to infect and transmit efficiently among humans are essential for a novel influenza A virus to cause a pandemic. To evaluate the pandemic potential of widely disseminated H5N1 influenza viruses, a ferret contact model using experimental groups comprised of one inoculated ferret and two contact ferrets was used to study the transmissibility of four human H5N1 viruses isolated from 2003 to 2006. The effects of viral pathogenicity and receptor binding specificity (affinity to synthetic sialosaccharides with α2,3 or α2,6 linkages) on transmissibility were assessed. A/Vietnam/1203/04 and A/Vietnam/JP36-2/05 viruses, which possess “avian-like” α2,3-linked sialic acid (SA) receptor specificity, caused neurological symptoms and death in ferrets inoculated with 10<sup>3</sup>
50% tissue culture infectious doses. A/Hong Kong/213/03 and A/Turkey/65-596/06 viruses, which show binding affinity for “human-like” α2,6-linked SA receptors in addition to their affinity for α2,3-linked SA receptors, caused mild clinical symptoms and were not lethal to the ferrets. No transmission of A/Vietnam/1203/04 or A/Turkey/65-596/06 virus was detected. One contact ferret developed neutralizing antibodies to A/Hong Kong/213/03 but did not exhibit any clinical signs or detectable virus shedding. In two groups, one of two naïve contact ferrets had detectable virus after 6 to 8 days when housed together with the A/Vietnam/JP36-2/05 virus-inoculated ferrets. Infected contact ferrets showed severe clinical signs, although little or no virus was detected in nasal washes. This limited virus shedding explained the absence of secondary transmission from the infected contact ferret to the other naïve ferret that were housed together. Our results suggest that despite their receptor binding affinity, circulating H5N1 viruses retain molecular determinants that restrict their spread among mammalian species.</p>
</div>
</front>
</TEI>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Virol</journal-id>
<journal-id journal-id-type="publisher-id">jvi</journal-id>
<journal-title>Journal of Virology</journal-title>
<issn pub-type="ppub">0022-538X</issn>
<issn pub-type="epub">1098-5514</issn>
<publisher><publisher-name>American Society for Microbiology</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">17459930</article-id>
<article-id pub-id-type="pmc">1933302</article-id>
<article-id pub-id-type="publisher-id">0170-07</article-id>
<article-id pub-id-type="doi">10.1128/JVI.00170-07</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Pathogenesis and Immunity</subject>
</subj-group>
</article-categories>
<title-group><article-title>Inefficient Transmission of H5N1 Influenza Viruses in a Ferret Contact Model<xref ref-type="fn" rid="fn2">▿</xref>
</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Yen</surname>
<given-names>Hui-Ling</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lipatov</surname>
<given-names>Aleksandr S.</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="fn" rid="fn1">¶</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ilyushina</surname>
<given-names>Natalia A.</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Govorkova</surname>
<given-names>Elena A.</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Franks</surname>
<given-names>John</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Yilmaz</surname>
<given-names>Neziha</given-names>
</name>
<xref ref-type="aff" rid="aff1">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Douglas</surname>
<given-names>Alan</given-names>
</name>
<xref ref-type="aff" rid="aff1">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hay</surname>
<given-names>Alan</given-names>
</name>
<xref ref-type="aff" rid="aff1">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Krauss</surname>
<given-names>Scott</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rehg</surname>
<given-names>Jerold E.</given-names>
</name>
<xref ref-type="aff" rid="aff1">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hoffmann</surname>
<given-names>Erich</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Webster</surname>
<given-names>Robert G.</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="corresp" rid="cor1">*</xref>
</contrib>
</contrib-group>
<aff id="aff1">Departments of Infectious Diseases (Division of Virology),<label>1</label>
Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee,<label>4</label>
Department of Virology, Refik Saydam Hygiene Institute, Sihhiye-Ankara, Turkey,<label>2</label>
Division of Virology, National Institute for Medical Research, London, United Kingdom<label>3</label>
</aff>
<author-notes><fn id="cor1"><label>*</label>
<p>Corresponding author. Mailing address: Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105. Phone: (901) 495-3400. E-mail: <email>robert.webster@stjude.org</email>
</p>
</fn>
<fn id="fn1"><label>¶</label>
<p>Present address: Southeast Poultry Research Laboratory, Agricultural Research Service, U.S. Department of Agriculture, 934 College Station Road, Athens, GA 30605.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><month>7</month>
<year>2007</year>
</pub-date>
<pub-date pub-type="epub"><day>25</day>
<month>4</month>
<year>2007</year>
</pub-date>
<volume>81</volume>
<issue>13</issue>
<fpage>6890</fpage>
<lpage>6898</lpage>
<history><date date-type="received"><day>25</day>
<month>1</month>
<year>2007</year>
</date>
<date date-type="accepted"><day>16</day>
<month>4</month>
<year>2007</year>
</date>
</history>
<copyright-statement>Copyright © 2007, American Society for Microbiology</copyright-statement>
<copyright-year>2007</copyright-year>
<self-uri xlink:title="pdf" xlink:href="zjv01307006890.pdf"></self-uri>
<abstract><p>The abilities to infect and transmit efficiently among humans are essential for a novel influenza A virus to cause a pandemic. To evaluate the pandemic potential of widely disseminated H5N1 influenza viruses, a ferret contact model using experimental groups comprised of one inoculated ferret and two contact ferrets was used to study the transmissibility of four human H5N1 viruses isolated from 2003 to 2006. The effects of viral pathogenicity and receptor binding specificity (affinity to synthetic sialosaccharides with α2,3 or α2,6 linkages) on transmissibility were assessed. A/Vietnam/1203/04 and A/Vietnam/JP36-2/05 viruses, which possess “avian-like” α2,3-linked sialic acid (SA) receptor specificity, caused neurological symptoms and death in ferrets inoculated with 10<sup>3</sup>
50% tissue culture infectious doses. A/Hong Kong/213/03 and A/Turkey/65-596/06 viruses, which show binding affinity for “human-like” α2,6-linked SA receptors in addition to their affinity for α2,3-linked SA receptors, caused mild clinical symptoms and were not lethal to the ferrets. No transmission of A/Vietnam/1203/04 or A/Turkey/65-596/06 virus was detected. One contact ferret developed neutralizing antibodies to A/Hong Kong/213/03 but did not exhibit any clinical signs or detectable virus shedding. In two groups, one of two naïve contact ferrets had detectable virus after 6 to 8 days when housed together with the A/Vietnam/JP36-2/05 virus-inoculated ferrets. Infected contact ferrets showed severe clinical signs, although little or no virus was detected in nasal washes. This limited virus shedding explained the absence of secondary transmission from the infected contact ferret to the other naïve ferret that were housed together. Our results suggest that despite their receptor binding affinity, circulating H5N1 viruses retain molecular determinants that restrict their spread among mammalian species.</p>
</abstract>
</article-meta>
</front>
<floats-wrap><fig position="float" id="f1"><label>FIG. 1.</label>
<caption><p>Phylogenetic tree based on the HA gene (nucleotides 77 to 1200, 1,124 bp) of H5N1 influenza A viruses. The nucleotide sequences were analyzed by Phylip3.65 software using the neighbor-joining method with 100 bootstraps. The tree was rooted to the A/Gs/Guandong/1/96 HA sequence. Viruses in colored bold type were included in this study. Abbreviations: Ck, chicken; Dk, duck; Gs, goose; Qa, quail; JWE, Japanese white eye; WS, whooper swan; BHG, bar-headed goose.</p>
</caption>
<graphic xlink:href="zjv0130793070001"></graphic>
</fig>
<fig position="float" id="f2"><label>FIG. 2.</label>
<caption><p>Temperature changes and virus titers of human H5N1 influenza viruses in a ferret contact model. Virus titers (log<sub>10</sub>
TCID<sub>50</sub>
/ml) are shown (<, below detection limit of 10<sup>1.5</sup>
TCID<sub>50</sub>
/ml). Shown are results for one donor ferret (inoculated) and two recipient (contact) ferrets in two independent tests of each virus. (A and B) HK/03 virus; (C and D) VN/04 virus; (E and F) VN/05 virus; (G) TK/06 virus. Overturned ferret figures indicate time of death (d, day), and the yellow stars indicate sites of virus isolation (virus was detected in the nasal turbinate, olfactory bulb, brain, trachea, lungs, and large intestine of an VN/04-inoculated ferret in panel D; virus was detected in the nasal turbinate, olfactory bulb, brain, and large intestine in panel F).</p>
</caption>
<graphic xlink:href="zjv0130793070002"></graphic>
</fig>
<fig position="float" id="f3"><label>FIG. 3.</label>
<caption><p>Ferret weight changes during H5N1 influenza virus transmission experiments. The changes in ferret weight are shown for one donor ferret (inoculated) and two recipient (contact) ferrets in two independent tests of each virus. (A and B) HK/03 virus; (C and D) VN/04 virus; (E and F) VN/05 virus; (G) TK/06 virus. Daily weight changes (as a percentage) of each ferret were compared to its own initial weight prior to the initiation of the experiments.</p>
</caption>
<graphic xlink:href="zjv0130793070003"></graphic>
</fig>
<fig position="float" id="f4"><label>FIG. 4.</label>
<caption><p>Virus titers detected in tissues of inoculated ferrets at 5 days postinoculation. Virus in brain, olfactory bulb, nasal turbinate, trachea, lungs, and large intestine was titrated in MDCK cells. Each data point represents the virus titer (log<sub>10</sub>
TCID<sub>50</sub>
/gram tissue) (mean ± SD) from two ferrets (data for the Wuhan/95 virus were obtained from one ferret).</p>
</caption>
<graphic xlink:href="zjv0130793070004"></graphic>
</fig>
<fig position="float" id="f5"><label>FIG. 5.</label>
<caption><p>Histopathologic findings in ferrets with H5N1 virus infection. (A) Views of hematoxylin-and-eosin-stained brain, lung, and liver samples of HK/03- and TK/06-inoculated ferrets and a VN/05-infected contact ferret. Uninfected ferret tissues were included as negative controls. Magnification, ×10. (B) Immunohistochemistry detected H5N1 viral antigen in the brain and liver of VN/04-inoculated or VN/05-infected contact ferrets. Magnification, ×20.</p>
</caption>
<graphic xlink:href="zjv0130793070005"></graphic>
</fig>
<table-wrap position="float" id="t1"><label>TABLE 1.</label>
<caption><p>Affinity of the H5N1 influenza viruses to sialyl substrates</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th colspan="1" rowspan="2" align="center" valign="middle">Virus<xref ref-type="table-fn" rid="t1fn1"><italic>a</italic>
</xref>
</th>
<th colspan="1" rowspan="2" align="center" valign="middle">Changes in HA receptor binding site<xref ref-type="table-fn" rid="t1fn2"><italic>b</italic>
</xref>
</th>
<th colspan="3" rowspan="1" align="center" valign="bottom">Affinity for sialyl substrate<xref ref-type="table-fn" rid="t1fn3"><italic>c</italic>
</xref>
<hr></hr>
</th>
</tr>
<tr><th colspan="1" rowspan="1" align="center" valign="bottom">Fetuin</th>
<th colspan="1" rowspan="1" align="center" valign="bottom">p6′SL</th>
<th colspan="1" rowspan="1" align="center" valign="bottom">p3′SL</th>
</tr>
</thead>
<tbody><tr><td colspan="1" rowspan="1" align="left" valign="top">HK/03 (E2/E1)</td>
<td colspan="1" rowspan="1" align="center" valign="top">S<sup>133</sup>
, N<sup>223</sup>
</td>
<td colspan="1" rowspan="1" align="center" valign="top">0.18 ± 0.03</td>
<td colspan="1" rowspan="1" align="center" valign="top">5.78 ± 0.82<xref ref-type="table-fn" rid="t1fn3"><italic>c</italic>
</xref>
</td>
<td colspan="1" rowspan="1" align="center" valign="top">1.05 ± 0.21</td>
</tr>
<tr><td colspan="1" rowspan="1" align="left" valign="top">VN/04 (E2/E1)</td>
<td colspan="1" rowspan="1" align="center" valign="top">S<sup>133</sup>
, S<sup>223</sup>
</td>
<td colspan="1" rowspan="1" align="center" valign="top">0.13 ± 0.03</td>
<td colspan="1" rowspan="1" align="center" valign="top">>100</td>
<td colspan="1" rowspan="1" align="center" valign="top">1.21 ± 0.05</td>
</tr>
<tr><td colspan="1" rowspan="1" align="left" valign="top">VN/05 (C1/E1)</td>
<td colspan="1" rowspan="1" align="center" valign="top">A<sup>133</sup>
, S<sup>223</sup>
</td>
<td colspan="1" rowspan="1" align="center" valign="top">0.15 ± 0.08</td>
<td colspan="1" rowspan="1" align="center" valign="top">>100</td>
<td colspan="1" rowspan="1" align="center" valign="top">0.12 ± 0.02<xref ref-type="table-fn" rid="t1fn4"><italic>d</italic>
</xref>
</td>
</tr>
<tr><td colspan="1" rowspan="1" align="left" valign="top">TK/06 (E2/E1)</td>
<td colspan="1" rowspan="1" align="center" valign="top">S<sup>133</sup>
, N<sup>223</sup>
</td>
<td colspan="1" rowspan="1" align="center" valign="top">0.15 ± 0.06</td>
<td colspan="1" rowspan="1" align="center" valign="top">10.34 ± 1.40<xref ref-type="table-fn" rid="t1fn3"><italic>c</italic>
</xref>
</td>
<td colspan="1" rowspan="1" align="center" valign="top">0.44 ± 0.05</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn id="t1fn1"><label>a</label>
<p>Virus abbreviations: HK/03, A/HK/213/03; VN/04, A/VN/1203/04; VN/05, A/VN/JP36-2/05; TK/06, A/Turkey/65-596/06. Virus passage history is indicated in parentheses after the virus as follows: C, passaged in MDCK cells; E, passaged in embryonated chicken eggs (e.g., E2/E1, virus was passaged twice in embryonated chicken eggs prior to arrival at St. Jude's Children's Research Hospital; it was subsequently passaged once in eggs prior to the experiments).</p>
</fn>
<fn id="t1fn2"><label>b</label>
<p>Changes in conserved residues. H5 numbering was used.</p>
</fn>
<fn id="t1fn3"><label>c</label>
<p>The dissociation constant <italic>K</italic>
<sub>diss</sub>
= mean ± standard error × <italic>t</italic>
<sub>α</sub>
,<sub><italic>n</italic>
</sub>
<sub>−1</sub>
(μM sialic acid), where <italic>t<sub>α</sub>
</italic>
is Student's coefficient with probability α = 0.95, from four independent experiments. Fetuin possesses both α2,3- and α2,6-linked SA, while p3′SL and p6′SL are synthetic sialosaccharides with α2,3 and α2,6 linkages, respectively.</p>
</fn>
<fn id="t1fn4"><label>d</label>
<p>Significantly different from the value for other viruses (<italic>P</italic>
< 0.05 by analysis of variance).</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap position="float" id="t2"><label>TABLE 2.</label>
<caption><p>Growth of the H5N1 influenza viruses</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th colspan="1" rowspan="2" align="center" valign="middle">Virus</th>
<th colspan="3" rowspan="1" align="center" valign="bottom">Virus growth<xref ref-type="table-fn" rid="t2fn1"><italic>a</italic>
</xref>
<hr></hr>
</th>
</tr>
<tr><th colspan="1" rowspan="1" align="center" valign="bottom">Log<sub>10</sub>
TCID<sub>50</sub>
/ml</th>
<th colspan="1" rowspan="1" align="center" valign="bottom">Log<sub>10</sub>
PFU/ml</th>
<th colspan="1" rowspan="1" align="center" valign="bottom">Log<sub>10</sub>
EID<sub>50</sub>
/ml</th>
</tr>
</thead>
<tbody><tr><td colspan="1" rowspan="1" align="left" valign="top">HK/03</td>
<td colspan="1" rowspan="1" align="center" valign="top">8.5 ± 0.0</td>
<td colspan="1" rowspan="1" align="center" valign="top">8.1 ± 0.03</td>
<td colspan="1" rowspan="1" align="center" valign="top">8.5 ± 0.4</td>
</tr>
<tr><td colspan="1" rowspan="1" align="left" valign="top">VN/04</td>
<td colspan="1" rowspan="1" align="center" valign="top">9.0 ± 0.0</td>
<td colspan="1" rowspan="1" align="center" valign="top">9.1 ± 0.01</td>
<td colspan="1" rowspan="1" align="center" valign="top">9.5 ± 0.3</td>
</tr>
<tr><td colspan="1" rowspan="1" align="left" valign="top">VN/05</td>
<td colspan="1" rowspan="1" align="center" valign="top">8.4 ± 0.2</td>
<td colspan="1" rowspan="1" align="center" valign="top">8.4 ± 0.1</td>
<td colspan="1" rowspan="1" align="center" valign="top">9.3 ± 0.4</td>
</tr>
<tr><td colspan="1" rowspan="1" align="left" valign="top">TK/06</td>
<td colspan="1" rowspan="1" align="center" valign="top">8.5 ± 0.0</td>
<td colspan="1" rowspan="1" align="center" valign="top">8.3 ± 0.3</td>
<td colspan="1" rowspan="1" align="center" valign="top">8.8 ± 0.4</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn id="t2fn1"><label>a</label>
<p>All data are the mean ± SDs from three independent experiments.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap position="float" id="t3"><label>TABLE 3.</label>
<caption><p>Ferret postexposure neutralizing antibody titers and virus shedding after rechallenge</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th colspan="1" rowspan="2" align="center" valign="middle">Virus</th>
<th colspan="1" rowspan="2" align="center" valign="middle">Study group</th>
<th colspan="3" rowspan="1" align="center" valign="bottom">Neutralizing antibody titer in ferret<xref ref-type="table-fn" rid="t3fn1"><italic>a</italic>
</xref>
<hr></hr>
</th>
<th colspan="3" rowspan="1" align="center" valign="bottom">Virus shedding after rechallenge in ferret<xref ref-type="table-fn" rid="t3fn2"><italic>b</italic>
</xref>
<hr></hr>
</th>
</tr>
<tr><th colspan="1" rowspan="1" align="center" valign="bottom">Inoculated</th>
<th colspan="1" rowspan="1" align="center" valign="bottom">Contact 1</th>
<th colspan="1" rowspan="1" align="center" valign="bottom">Contact 2</th>
<th colspan="1" rowspan="1" align="center" valign="bottom">Inoculated</th>
<th colspan="1" rowspan="1" align="center" valign="bottom">Contact 1</th>
<th colspan="1" rowspan="1" align="center" valign="bottom">Contact 2</th>
</tr>
</thead>
<tbody><tr><td colspan="1" rowspan="1" align="left" valign="top">HK/03</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">1</td>
<td colspan="1" rowspan="1" align="left" valign="top">1:5,120</td>
<td colspan="1" rowspan="1" align="left" valign="top"><</td>
<td colspan="1" rowspan="1" align="left" valign="top"><</td>
<td colspan="1" rowspan="1" align="center" valign="top">ND</td>
<td colspan="1" rowspan="1" align="center" valign="top">ND</td>
<td colspan="1" rowspan="1" align="center" valign="top">ND</td>
</tr>
<tr><td colspan="1" rowspan="1" align="left" valign="top"></td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">2</td>
<td colspan="1" rowspan="1" align="left" valign="top">1:5,120<xref ref-type="table-fn" rid="t3fn3"><italic>c</italic>
</xref>
</td>
<td colspan="1" rowspan="1" align="left" valign="top"><<xref ref-type="table-fn" rid="t3fn3"><italic>c</italic>
</xref>
</td>
<td colspan="1" rowspan="1" align="left" valign="top">1:80<xref ref-type="table-fn" rid="t3fn3"><italic>c</italic>
</xref>
</td>
<td colspan="1" rowspan="1" align="center" valign="top">−</td>
<td colspan="1" rowspan="1" align="center" valign="top">+</td>
<td colspan="1" rowspan="1" align="center" valign="top">−</td>
</tr>
<tr><td colspan="1" rowspan="1" align="left" valign="top">VN/04</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">1</td>
<td colspan="1" rowspan="1" align="left" valign="top">1:1,280<xref ref-type="table-fn" rid="t3fn3"><italic>c</italic>
</xref>
</td>
<td colspan="1" rowspan="1" align="left" valign="top"><<xref ref-type="table-fn" rid="t3fn3"><italic>c</italic>
</xref>
</td>
<td colspan="1" rowspan="1" align="left" valign="top"><<xref ref-type="table-fn" rid="t3fn3"><italic>c</italic>
</xref>
</td>
<td colspan="1" rowspan="1" align="center" valign="top">ND</td>
<td colspan="1" rowspan="1" align="center" valign="top">ND</td>
<td colspan="1" rowspan="1" align="center" valign="top">ND</td>
</tr>
<tr><td colspan="1" rowspan="1" align="left" valign="top"></td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">2</td>
<td colspan="1" rowspan="1" align="left" valign="top">NAV<xref ref-type="table-fn" rid="t3fn3"><italic>c</italic>
</xref>
</td>
<td colspan="1" rowspan="1" align="left" valign="top"><<xref ref-type="table-fn" rid="t3fn3"><italic>c</italic>
</xref>
</td>
<td colspan="1" rowspan="1" align="left" valign="top"><<xref ref-type="table-fn" rid="t3fn3"><italic>c</italic>
</xref>
</td>
<td colspan="1" rowspan="1" align="center" valign="top">NAV</td>
<td colspan="1" rowspan="1" align="center" valign="top">+</td>
<td colspan="1" rowspan="1" align="center" valign="top">+</td>
</tr>
<tr><td colspan="1" rowspan="1" align="left" valign="top">VN/05</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">1</td>
<td colspan="1" rowspan="1" align="left" valign="top">1:1,280<xref ref-type="table-fn" rid="t3fn3"><italic>c</italic>
</xref>
</td>
<td colspan="1" rowspan="1" align="left" valign="top"><<xref ref-type="table-fn" rid="t3fn3"><italic>c</italic>
</xref>
</td>
<td colspan="1" rowspan="1" align="left" valign="top">1:1,280<xref ref-type="table-fn" rid="t3fn3"><italic>c</italic>
</xref>
</td>
<td colspan="1" rowspan="1" align="center" valign="top">ND</td>
<td colspan="1" rowspan="1" align="center" valign="top">ND</td>
<td colspan="1" rowspan="1" align="center" valign="top">ND</td>
</tr>
<tr><td colspan="1" rowspan="1" align="left" valign="top"></td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">2</td>
<td colspan="1" rowspan="1" align="left" valign="top">NAV<xref ref-type="table-fn" rid="t3fn3"><italic>c</italic>
</xref>
</td>
<td colspan="1" rowspan="1" align="left" valign="top">NAV<xref ref-type="table-fn" rid="t3fn3"><italic>c</italic>
</xref>
</td>
<td colspan="1" rowspan="1" align="left" valign="top"><<xref ref-type="table-fn" rid="t3fn3"><italic>c</italic>
</xref>
</td>
<td colspan="1" rowspan="1" align="center" valign="top">NAV</td>
<td colspan="1" rowspan="1" align="center" valign="top">NAV</td>
<td colspan="1" rowspan="1" align="center" valign="top">+</td>
</tr>
<tr><td colspan="1" rowspan="1" align="left" valign="top">TK/06</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">1</td>
<td colspan="1" rowspan="1" align="left" valign="top">1:2,560<xref ref-type="table-fn" rid="t3fn3"><italic>c</italic>
</xref>
</td>
<td colspan="1" rowspan="1" align="left" valign="top"><<xref ref-type="table-fn" rid="t3fn3"><italic>c</italic>
</xref>
</td>
<td colspan="1" rowspan="1" align="left" valign="top"><<xref ref-type="table-fn" rid="t3fn3"><italic>c</italic>
</xref>
</td>
<td colspan="1" rowspan="1" align="center" valign="top">−</td>
<td colspan="1" rowspan="1" align="center" valign="top">+</td>
<td colspan="1" rowspan="1" align="center" valign="top">+</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn id="t3fn1"><label>a</label>
<p>Sera were collected from the one inoculated ferret and the two contact ferrets in each experimental group after they had been housed together for 21 days. Neutralizing antibodies to homologous virus (100 TCID<sub>50</sub>
) were titrated in MDCK cells. NAV, not available (animal died due to severe symptoms during the transmission experiment); <, titer of <1:20.</p>
</fn>
<fn id="t3fn2"><label>b</label>
<p>Ferrets that survived the transmission experiments were rechallenged intranasally with 10<sup>3</sup>
TCID<sub>50</sub>
of homologous virus. Nasal washes and rectal swabs were collected every other day to detect virus shedding. +, virus shedding detected; −, virus shedding was not detected; ND, rechallenge of the homologous virus was not done in these ferrets.</p>
</fn>
<fn id="t3fn3"><label>c</label>
<p>This ferret exhibited an antibody titer of 1:20 to 1:80 against A/New York/55/04 (H3N2) virus by hemagglutination inhibition assay prior to the experiment.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap position="float" id="t4"><label>TABLE 4.</label>
<caption><p>Molecular changes during transmission of VN/05 influenza virus</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th colspan="1" rowspan="2" align="center" valign="middle">Gene segment</th>
<th colspan="1" rowspan="2" align="center" valign="middle">Position</th>
<th colspan="1" rowspan="2" align="center" valign="middle">Residue in stock virus</th>
<th colspan="2" rowspan="1" align="center" valign="bottom">Amino acid change
<hr></hr>
</th>
</tr>
<tr><th colspan="1" rowspan="1" align="center" valign="bottom">Group 1, contact ferret 2</th>
<th colspan="1" rowspan="1" align="center" valign="bottom">Group 2, contact ferret 1</th>
</tr>
</thead>
<tbody><tr><td colspan="1" rowspan="1" align="left" valign="top">PB1</td>
<td colspan="1" rowspan="1" align="left" valign="top">123</td>
<td colspan="1" rowspan="1" align="left" valign="top">T</td>
<td colspan="1" rowspan="1" align="left" valign="top">A/T</td>
<td colspan="1" rowspan="1" align="left" valign="top">A</td>
</tr>
<tr><td colspan="1" rowspan="1" align="left" valign="top">PA</td>
<td colspan="1" rowspan="1" align="left" valign="top">52</td>
<td colspan="1" rowspan="1" align="left" valign="top">H</td>
<td colspan="1" rowspan="1" align="left" valign="top">H/R</td>
<td colspan="1" rowspan="1" align="left" valign="top">H/R</td>
</tr>
<tr><td colspan="1" rowspan="1" align="left" valign="top"></td>
<td colspan="1" rowspan="1" align="left" valign="top">341</td>
<td colspan="1" rowspan="1" align="left" valign="top">V</td>
<td colspan="1" rowspan="1" align="left" valign="top">L</td>
<td colspan="1" rowspan="1" align="left" valign="top">L</td>
</tr>
<tr><td colspan="1" rowspan="1" align="left" valign="top"></td>
<td colspan="1" rowspan="1" align="left" valign="top">388</td>
<td colspan="1" rowspan="1" align="left" valign="top">G/S</td>
<td colspan="1" rowspan="1" align="left" valign="top">S</td>
<td colspan="1" rowspan="1" align="left" valign="top">S</td>
</tr>
<tr><td colspan="1" rowspan="1" align="left" valign="top">NA</td>
<td colspan="1" rowspan="1" align="left" valign="top">274<xref ref-type="table-fn" rid="t4fn1"><italic>a</italic>
</xref>
</td>
<td colspan="1" rowspan="1" align="left" valign="top">H</td>
<td colspan="1" rowspan="1" align="left" valign="top">Y</td>
<td colspan="1" rowspan="1" align="left" valign="top">H</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn id="t4fn1"><label>a</label>
<p>N2 numbering was used.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</floats-wrap>
</pmc>
</record>
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