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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Neutralizing antibodies derived from the B cells of 1918 influenza pandemic survivors</title>
<author><name sortKey="Yu, Xiaocong" sort="Yu, Xiaocong" uniqKey="Yu X" first="Xiaocong" last="Yu">Xiaocong Yu</name>
<affiliation><nlm:aff id="A1">Departments of Pediatrics and of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tsibane, Tshidi" sort="Tsibane, Tshidi" uniqKey="Tsibane T" first="Tshidi" last="Tsibane">Tshidi Tsibane</name>
<affiliation><nlm:aff id="A2">Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mcgraw, Patricia A" sort="Mcgraw, Patricia A" uniqKey="Mcgraw P" first="Patricia A." last="Mcgraw">Patricia A. Mcgraw</name>
<affiliation><nlm:aff id="A1">Departments of Pediatrics and of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="House, Frances S" sort="House, Frances S" uniqKey="House F" first="Frances S." last="House">Frances S. House</name>
<affiliation><nlm:aff id="A1">Departments of Pediatrics and of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Keefer, Christopher J" sort="Keefer, Christopher J" uniqKey="Keefer C" first="Christopher J." last="Keefer">Christopher J. Keefer</name>
<affiliation><nlm:aff id="A1">Departments of Pediatrics and of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hicar, Mark D" sort="Hicar, Mark D" uniqKey="Hicar M" first="Mark D." last="Hicar">Mark D. Hicar</name>
<affiliation><nlm:aff id="A1">Departments of Pediatrics and of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tumpey, Terrence M" sort="Tumpey, Terrence M" uniqKey="Tumpey T" first="Terrence M." last="Tumpey">Terrence M. Tumpey</name>
<affiliation><nlm:aff id="A3">Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pappas, Claudia" sort="Pappas, Claudia" uniqKey="Pappas C" first="Claudia" last="Pappas">Claudia Pappas</name>
<affiliation><nlm:aff id="A2">Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A3">Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Perrone, Lucy A" sort="Perrone, Lucy A" uniqKey="Perrone L" first="Lucy A." last="Perrone">Lucy A. Perrone</name>
<affiliation><nlm:aff id="A3">Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Martinez, Osvaldo" sort="Martinez, Osvaldo" uniqKey="Martinez O" first="Osvaldo" last="Martinez">Osvaldo Martinez</name>
<affiliation><nlm:aff id="A2">Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Stevens, James" sort="Stevens, James" uniqKey="Stevens J" first="James" last="Stevens">James Stevens</name>
<affiliation><nlm:aff id="A3">Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A4">Department of Molecular Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Wilson, Ian A" sort="Wilson, Ian A" uniqKey="Wilson I" first="Ian A." last="Wilson">Ian A. Wilson</name>
<affiliation><nlm:aff id="A4">Department of Molecular Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Aguilar, Patricia V" sort="Aguilar, Patricia V" uniqKey="Aguilar P" first="Patricia V." last="Aguilar">Patricia V. Aguilar</name>
<affiliation><nlm:aff id="A2">Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Altschuler, Eric L" sort="Altschuler, Eric L" uniqKey="Altschuler E" first="Eric L." last="Altschuler">Eric L. Altschuler</name>
<affiliation><nlm:aff id="A5">Department of Physical Medicine and Rehabilitation, University of Medicine & Dentistry of New Jersey, Newark, NJ 07103, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Basler, Christopher F" sort="Basler, Christopher F" uniqKey="Basler C" first="Christopher F." last="Basler">Christopher F. Basler</name>
<affiliation><nlm:aff id="A2">Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Crowe, James E" sort="Crowe, James E" uniqKey="Crowe J" first="James E." last="Crowe">James E. Crowe</name>
<affiliation><nlm:aff id="A1">Departments of Pediatrics and of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA</nlm:aff>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">18716625</idno>
<idno type="pmc">2848880</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2848880</idno>
<idno type="RBID">PMC:2848880</idno>
<idno type="doi">10.1038/nature07231</idno>
<date when="2008">2008</date>
<idno type="wicri:Area/Pmc/Corpus">000532</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000532</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Neutralizing antibodies derived from the B cells of 1918 influenza pandemic survivors</title>
<author><name sortKey="Yu, Xiaocong" sort="Yu, Xiaocong" uniqKey="Yu X" first="Xiaocong" last="Yu">Xiaocong Yu</name>
<affiliation><nlm:aff id="A1">Departments of Pediatrics and of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tsibane, Tshidi" sort="Tsibane, Tshidi" uniqKey="Tsibane T" first="Tshidi" last="Tsibane">Tshidi Tsibane</name>
<affiliation><nlm:aff id="A2">Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mcgraw, Patricia A" sort="Mcgraw, Patricia A" uniqKey="Mcgraw P" first="Patricia A." last="Mcgraw">Patricia A. Mcgraw</name>
<affiliation><nlm:aff id="A1">Departments of Pediatrics and of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="House, Frances S" sort="House, Frances S" uniqKey="House F" first="Frances S." last="House">Frances S. House</name>
<affiliation><nlm:aff id="A1">Departments of Pediatrics and of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Keefer, Christopher J" sort="Keefer, Christopher J" uniqKey="Keefer C" first="Christopher J." last="Keefer">Christopher J. Keefer</name>
<affiliation><nlm:aff id="A1">Departments of Pediatrics and of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hicar, Mark D" sort="Hicar, Mark D" uniqKey="Hicar M" first="Mark D." last="Hicar">Mark D. Hicar</name>
<affiliation><nlm:aff id="A1">Departments of Pediatrics and of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tumpey, Terrence M" sort="Tumpey, Terrence M" uniqKey="Tumpey T" first="Terrence M." last="Tumpey">Terrence M. Tumpey</name>
<affiliation><nlm:aff id="A3">Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pappas, Claudia" sort="Pappas, Claudia" uniqKey="Pappas C" first="Claudia" last="Pappas">Claudia Pappas</name>
<affiliation><nlm:aff id="A2">Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A3">Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Perrone, Lucy A" sort="Perrone, Lucy A" uniqKey="Perrone L" first="Lucy A." last="Perrone">Lucy A. Perrone</name>
<affiliation><nlm:aff id="A3">Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Martinez, Osvaldo" sort="Martinez, Osvaldo" uniqKey="Martinez O" first="Osvaldo" last="Martinez">Osvaldo Martinez</name>
<affiliation><nlm:aff id="A2">Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Stevens, James" sort="Stevens, James" uniqKey="Stevens J" first="James" last="Stevens">James Stevens</name>
<affiliation><nlm:aff id="A3">Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A4">Department of Molecular Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Wilson, Ian A" sort="Wilson, Ian A" uniqKey="Wilson I" first="Ian A." last="Wilson">Ian A. Wilson</name>
<affiliation><nlm:aff id="A4">Department of Molecular Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Aguilar, Patricia V" sort="Aguilar, Patricia V" uniqKey="Aguilar P" first="Patricia V." last="Aguilar">Patricia V. Aguilar</name>
<affiliation><nlm:aff id="A2">Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Altschuler, Eric L" sort="Altschuler, Eric L" uniqKey="Altschuler E" first="Eric L." last="Altschuler">Eric L. Altschuler</name>
<affiliation><nlm:aff id="A5">Department of Physical Medicine and Rehabilitation, University of Medicine & Dentistry of New Jersey, Newark, NJ 07103, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Basler, Christopher F" sort="Basler, Christopher F" uniqKey="Basler C" first="Christopher F." last="Basler">Christopher F. Basler</name>
<affiliation><nlm:aff id="A2">Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Crowe, James E" sort="Crowe, James E" uniqKey="Crowe J" first="James E." last="Crowe">James E. Crowe</name>
<affiliation><nlm:aff id="A1">Departments of Pediatrics and of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">Nature</title>
<idno type="ISSN">0028-0836</idno>
<idno type="eISSN">1476-4687</idno>
<imprint><date when="2008">2008</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p id="P1">Investigation of the human antibody response to influenza virus infection has been largely limited to serology, with relatively little analysis at the molecular level. The 1918 H1N1 influenza virus pandemic was the most severe of the modern era<xref ref-type="bibr" rid="R1">1</xref>
. Recent work has recovered the gene sequences of this unusual strain<xref ref-type="bibr" rid="R2">2</xref>
, so that the 1918 pandemic virus could be reconstituted to display its unique virulence phenotypes<xref ref-type="bibr" rid="R3">3</xref>
,<xref ref-type="bibr" rid="R4">4</xref>
. However, little is known about adaptive immunity to this virus. We took advantage of the 1918 virus sequencing and the resultant production of recombinant 1918 hemagglutinin (HA) protein antigen to characterize at the clonal level neutralizing antibodies induced by natural exposure of survivors to the 1918 pandemic virus. In our study, each of 32 individuals tested that were born in or before 1915 exhibited seroreactivity with 1918 virus, nearly 90 years after the pandemic. Seven of 8 donor samples tested had circulating B cells that secreted antibodies that bound 1918 HA. We isolated B cells from subjects and generated five monoclonal antibodies that exhibited potent neutralizing activity against 1918 virus from three separate donors. These antibodies also cross-reacted with the genetically similar HA of a 1930 swine H1N1 influenza strain, but not with HAs of more contemporary human influenza viruses. The antibody genes exhibited an unusually high degree of somatic mutation. The antibodies bound to the 1918 HA protein with high affinity, exhibited exceptional virus neutralizing potency, and protected mice from lethal infection. Isolation of viruses that escaped inhibition suggested that the antibodies recognize classical antigenic sites on the HA surface. Thus, these studies reveal that survivors of the 1918 influenza pandemic possess highly functional, virus-neutralizing antibodies to this uniquely virulent virus, and that humans can sustain circulating B memory cells to viruses for many decades after exposure - well into the tenth decade of life.</p>
</div>
</front>
</TEI>
<pmc article-type="research-article" xml:lang="EN"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">0410462</journal-id>
<journal-id journal-id-type="pubmed-jr-id">6011</journal-id>
<journal-id journal-id-type="nlm-ta">Nature</journal-id>
<journal-title>Nature</journal-title>
<issn pub-type="ppub">0028-0836</issn>
<issn pub-type="epub">1476-4687</issn>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">18716625</article-id>
<article-id pub-id-type="pmc">2848880</article-id>
<article-id pub-id-type="doi">10.1038/nature07231</article-id>
<article-id pub-id-type="manuscript">NIHMS154734</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Neutralizing antibodies derived from the B cells of 1918 influenza pandemic survivors</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Yu</surname>
<given-names>Xiaocong</given-names>
</name>
<xref rid="A1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tsibane</surname>
<given-names>Tshidi</given-names>
</name>
<xref rid="A2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>McGraw</surname>
<given-names>Patricia A.</given-names>
</name>
<xref rid="A1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>House</surname>
<given-names>Frances S.</given-names>
</name>
<xref rid="A1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Keefer</surname>
<given-names>Christopher J.</given-names>
</name>
<xref rid="A1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hicar</surname>
<given-names>Mark D.</given-names>
</name>
<xref rid="A1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tumpey</surname>
<given-names>Terrence M.</given-names>
</name>
<xref rid="A3" ref-type="aff">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Pappas</surname>
<given-names>Claudia</given-names>
</name>
<xref rid="A2" ref-type="aff">2</xref>
<xref rid="A3" ref-type="aff">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Perrone</surname>
<given-names>Lucy A.</given-names>
</name>
<xref rid="A3" ref-type="aff">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Martinez</surname>
<given-names>Osvaldo</given-names>
</name>
<xref rid="A2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Stevens</surname>
<given-names>James</given-names>
</name>
<xref rid="A3" ref-type="aff">3</xref>
<xref rid="A4" ref-type="aff">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wilson</surname>
<given-names>Ian A.</given-names>
</name>
<xref rid="A4" ref-type="aff">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Aguilar</surname>
<given-names>Patricia V.</given-names>
</name>
<xref rid="A2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Altschuler</surname>
<given-names>Eric L.</given-names>
</name>
<xref rid="A5" ref-type="aff">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Basler</surname>
<given-names>Christopher F.</given-names>
</name>
<xref rid="A2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Crowe</surname>
<given-names>James E.</given-names>
<suffix>Jr.</suffix>
</name>
<xref rid="A1" ref-type="aff">1</xref>
</contrib>
</contrib-group>
<aff id="A1"><label>1</label>
Departments of Pediatrics and of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA</aff>
<aff id="A2"><label>2</label>
Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA</aff>
<aff id="A3"><label>3</label>
Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA</aff>
<aff id="A4"><label>4</label>
Department of Molecular Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA</aff>
<aff id="A5"><label>5</label>
Department of Physical Medicine and Rehabilitation, University of Medicine & Dentistry of New Jersey, Newark, NJ 07103, USA</aff>
<author-notes><corresp id="FN1">Correspondence should be addressed to JEC (<email>James.Crowe@vanderbilt.edu</email>
), CFB (<email>Chris.Basler@mssm.edu</email>
) or ELA (<email>Eric.Altschuler@umdnj.edu</email>
)</corresp>
<fn id="FN6" fn-type="conflict"><p>The authors declare no competing financial interests.</p>
</fn>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>15</day>
<month>3</month>
<year>2010</year>
</pub-date>
<pub-date pub-type="epub"><day>17</day>
<month>8</month>
<year>2008</year>
</pub-date>
<pub-date pub-type="ppub"><day>25</day>
<month>9</month>
<year>2008</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>3</day>
<month>4</month>
<year>2010</year>
</pub-date>
<volume>455</volume>
<issue>7212</issue>
<fpage>532</fpage>
<lpage>536</lpage>
<abstract><p id="P1">Investigation of the human antibody response to influenza virus infection has been largely limited to serology, with relatively little analysis at the molecular level. The 1918 H1N1 influenza virus pandemic was the most severe of the modern era<xref ref-type="bibr" rid="R1">1</xref>
. Recent work has recovered the gene sequences of this unusual strain<xref ref-type="bibr" rid="R2">2</xref>
, so that the 1918 pandemic virus could be reconstituted to display its unique virulence phenotypes<xref ref-type="bibr" rid="R3">3</xref>
,<xref ref-type="bibr" rid="R4">4</xref>
. However, little is known about adaptive immunity to this virus. We took advantage of the 1918 virus sequencing and the resultant production of recombinant 1918 hemagglutinin (HA) protein antigen to characterize at the clonal level neutralizing antibodies induced by natural exposure of survivors to the 1918 pandemic virus. In our study, each of 32 individuals tested that were born in or before 1915 exhibited seroreactivity with 1918 virus, nearly 90 years after the pandemic. Seven of 8 donor samples tested had circulating B cells that secreted antibodies that bound 1918 HA. We isolated B cells from subjects and generated five monoclonal antibodies that exhibited potent neutralizing activity against 1918 virus from three separate donors. These antibodies also cross-reacted with the genetically similar HA of a 1930 swine H1N1 influenza strain, but not with HAs of more contemporary human influenza viruses. The antibody genes exhibited an unusually high degree of somatic mutation. The antibodies bound to the 1918 HA protein with high affinity, exhibited exceptional virus neutralizing potency, and protected mice from lethal infection. Isolation of viruses that escaped inhibition suggested that the antibodies recognize classical antigenic sites on the HA surface. Thus, these studies reveal that survivors of the 1918 influenza pandemic possess highly functional, virus-neutralizing antibodies to this uniquely virulent virus, and that humans can sustain circulating B memory cells to viruses for many decades after exposure - well into the tenth decade of life.</p>
</abstract>
<contract-num rid="AI1">U54 AI057157-019002
||AI</contract-num>
<contract-num rid="AI1">R01 AI048677-04
||AI</contract-num>
<contract-sponsor id="AI1">National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID</contract-sponsor>
</article-meta>
</front>
</pmc>
</record>
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