Antigenic Change in Human Influenza A(H2N2) Viruses Detected by Using Human Plasma from Aged and Younger Adult Individuals
Identifieur interne : 000C49 ( Pmc/Corpus ); précédent : 000C48; suivant : 000C50Antigenic Change in Human Influenza A(H2N2) Viruses Detected by Using Human Plasma from Aged and Younger Adult Individuals
Auteurs : Yukimasa Matsuzawa ; Kiyoko Iwatsuki-Horimoto ; Yoshinori Nishimoto ; Yukiko Abe ; Satoshi Fukuyama ; Taiki Hamabata ; Moe Okuda ; Yui Go ; Tokiko Watanabe ; Masaki Imai ; Yasumichi Arai ; Ron A. M. Fouchier ; Seiya Yamayoshi ; Yoshihiro KawaokaSource :
- Viruses [ 1999-4915 ] ; 2019.
Abstract
Human influenza A(H2N2) viruses emerged in 1957 and were replaced by A(H3N2) viruses in 1968. The antigenicity of human H2N2 viruses has been tested by using ferret antisera or mouse and human monoclonal antibodies. Here, we examined the antigenicity of human H2N2 viruses by using human plasma samples obtained from 50 aged individuals who were born between 1928 and 1933 and from 33 younger adult individuals who were born after 1962. The aged individuals possessed higher neutralization titers against H2N2 viruses isolated in 1957 and 1963 than those against H2N2 viruses isolated in 1968, whereas the younger adults who were born between 1962 and 1968 possessed higher neutralization titers against H2N2 viruses isolated in 1963 than those against other H2N2 viruses. Antigenic cartography revealed the antigenic changes that occurred in human H2N2 viruses during circulation in humans for 11 years, as detected by ferret antisera. These results show that even though aged individuals were likely exposed to more recent H2N2 viruses that are antigenically distinct from the earlier H2N2 viruses, they did not possess high neutralizing antibody titers to the more recent viruses, suggesting immunological imprinting of these individuals with the first H2N2 viruses they encountered and that this immunological imprinting lasts for over 50 years.
Url:
DOI: 10.3390/v11110978
PubMed: 31652870
PubMed Central: 6893718
Links to Exploration step
PMC:6893718Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Antigenic Change in Human Influenza A(H2N2) Viruses Detected by Using Human Plasma from Aged and Younger Adult Individuals</title><author><name sortKey="Matsuzawa, Yukimasa" sort="Matsuzawa, Yukimasa" uniqKey="Matsuzawa Y" first="Yukimasa" last="Matsuzawa">Yukimasa Matsuzawa</name><affiliation><nlm:aff id="af1-viruses-11-00978">Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;<email>ymatsuza@ims.u-tokyo.ac.jp</email> (Y.M.);<email>fukuyamarry@gmail.com</email> (S.F.);<email>kk176356@stu-cbms.k.u-tokyo.ac.jp</email> (M.O.);<email>yuigo555@gmail.com</email> (Y.G.);<email>tokiko.watanabe@wisc.edu</email> (T.W.);<email>mimai@ims.u-tokyo.ac.jp</email> (M.I.);<email>yamayo@ims.u-tokyo.ac.jp</email> (S.Y.)</nlm:aff></affiliation></author><author><name sortKey="Iwatsuki Horimoto, Kiyoko" sort="Iwatsuki Horimoto, Kiyoko" uniqKey="Iwatsuki Horimoto K" first="Kiyoko" last="Iwatsuki-Horimoto">Kiyoko Iwatsuki-Horimoto</name><affiliation><nlm:aff id="af1-viruses-11-00978">Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;<email>ymatsuza@ims.u-tokyo.ac.jp</email> (Y.M.);<email>fukuyamarry@gmail.com</email> (S.F.);<email>kk176356@stu-cbms.k.u-tokyo.ac.jp</email> (M.O.);<email>yuigo555@gmail.com</email> (Y.G.);<email>tokiko.watanabe@wisc.edu</email> (T.W.);<email>mimai@ims.u-tokyo.ac.jp</email> (M.I.);<email>yamayo@ims.u-tokyo.ac.jp</email> (S.Y.)</nlm:aff></affiliation></author><author><name sortKey="Nishimoto, Yoshinori" sort="Nishimoto, Yoshinori" uniqKey="Nishimoto Y" first="Yoshinori" last="Nishimoto">Yoshinori Nishimoto</name><affiliation><nlm:aff id="af2-viruses-11-00978">Center for Supercentenarian Medical Research, Shinjuku-ku, Tokyo 160-8582, Japan;<email>ynishimo@z3.keio.jp</email> (Y.N.);<email>yukiko_abe@keio.jp</email> (Y.A.);<email>yasumich@keio.jp</email> (Y.A.)</nlm:aff></affiliation></author><author><name sortKey="Abe, Yukiko" sort="Abe, Yukiko" uniqKey="Abe Y" first="Yukiko" last="Abe">Yukiko Abe</name><affiliation><nlm:aff id="af2-viruses-11-00978">Center for Supercentenarian Medical Research, Shinjuku-ku, Tokyo 160-8582, Japan;<email>ynishimo@z3.keio.jp</email> (Y.N.);<email>yukiko_abe@keio.jp</email> (Y.A.);<email>yasumich@keio.jp</email> (Y.A.)</nlm:aff></affiliation></author><author><name sortKey="Fukuyama, Satoshi" sort="Fukuyama, Satoshi" uniqKey="Fukuyama S" first="Satoshi" last="Fukuyama">Satoshi Fukuyama</name><affiliation><nlm:aff id="af1-viruses-11-00978">Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;<email>ymatsuza@ims.u-tokyo.ac.jp</email> (Y.M.);<email>fukuyamarry@gmail.com</email> (S.F.);<email>kk176356@stu-cbms.k.u-tokyo.ac.jp</email> (M.O.);<email>yuigo555@gmail.com</email> (Y.G.);<email>tokiko.watanabe@wisc.edu</email> (T.W.);<email>mimai@ims.u-tokyo.ac.jp</email> (M.I.);<email>yamayo@ims.u-tokyo.ac.jp</email> (S.Y.)</nlm:aff></affiliation></author><author><name sortKey="Hamabata, Taiki" sort="Hamabata, Taiki" uniqKey="Hamabata T" first="Taiki" last="Hamabata">Taiki Hamabata</name><affiliation><nlm:aff id="af1-viruses-11-00978">Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;<email>ymatsuza@ims.u-tokyo.ac.jp</email> (Y.M.);<email>fukuyamarry@gmail.com</email> (S.F.);<email>kk176356@stu-cbms.k.u-tokyo.ac.jp</email> (M.O.);<email>yuigo555@gmail.com</email> (Y.G.);<email>tokiko.watanabe@wisc.edu</email> (T.W.);<email>mimai@ims.u-tokyo.ac.jp</email> (M.I.);<email>yamayo@ims.u-tokyo.ac.jp</email> (S.Y.)</nlm:aff></affiliation></author><author><name sortKey="Okuda, Moe" sort="Okuda, Moe" uniqKey="Okuda M" first="Moe" last="Okuda">Moe Okuda</name><affiliation><nlm:aff id="af1-viruses-11-00978">Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;<email>ymatsuza@ims.u-tokyo.ac.jp</email> (Y.M.);<email>fukuyamarry@gmail.com</email> (S.F.);<email>kk176356@stu-cbms.k.u-tokyo.ac.jp</email> (M.O.);<email>yuigo555@gmail.com</email> (Y.G.);<email>tokiko.watanabe@wisc.edu</email> (T.W.);<email>mimai@ims.u-tokyo.ac.jp</email> (M.I.);<email>yamayo@ims.u-tokyo.ac.jp</email> (S.Y.)</nlm:aff></affiliation></author><author><name sortKey="Go, Yui" sort="Go, Yui" uniqKey="Go Y" first="Yui" last="Go">Yui Go</name><affiliation><nlm:aff id="af1-viruses-11-00978">Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;<email>ymatsuza@ims.u-tokyo.ac.jp</email> (Y.M.);<email>fukuyamarry@gmail.com</email> (S.F.);<email>kk176356@stu-cbms.k.u-tokyo.ac.jp</email> (M.O.);<email>yuigo555@gmail.com</email> (Y.G.);<email>tokiko.watanabe@wisc.edu</email> (T.W.);<email>mimai@ims.u-tokyo.ac.jp</email> (M.I.);<email>yamayo@ims.u-tokyo.ac.jp</email> (S.Y.)</nlm:aff></affiliation></author><author><name sortKey="Watanabe, Tokiko" sort="Watanabe, Tokiko" uniqKey="Watanabe T" first="Tokiko" last="Watanabe">Tokiko Watanabe</name><affiliation><nlm:aff id="af1-viruses-11-00978">Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;<email>ymatsuza@ims.u-tokyo.ac.jp</email> (Y.M.);<email>fukuyamarry@gmail.com</email> (S.F.);<email>kk176356@stu-cbms.k.u-tokyo.ac.jp</email> (M.O.);<email>yuigo555@gmail.com</email> (Y.G.);<email>tokiko.watanabe@wisc.edu</email> (T.W.);<email>mimai@ims.u-tokyo.ac.jp</email> (M.I.);<email>yamayo@ims.u-tokyo.ac.jp</email> (S.Y.)</nlm:aff></affiliation></author><author><name sortKey="Imai, Masaki" sort="Imai, Masaki" uniqKey="Imai M" first="Masaki" last="Imai">Masaki Imai</name><affiliation><nlm:aff id="af1-viruses-11-00978">Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;<email>ymatsuza@ims.u-tokyo.ac.jp</email> (Y.M.);<email>fukuyamarry@gmail.com</email> (S.F.);<email>kk176356@stu-cbms.k.u-tokyo.ac.jp</email> (M.O.);<email>yuigo555@gmail.com</email> (Y.G.);<email>tokiko.watanabe@wisc.edu</email> (T.W.);<email>mimai@ims.u-tokyo.ac.jp</email> (M.I.);<email>yamayo@ims.u-tokyo.ac.jp</email> (S.Y.)</nlm:aff></affiliation></author><author><name sortKey="Arai, Yasumichi" sort="Arai, Yasumichi" uniqKey="Arai Y" first="Yasumichi" last="Arai">Yasumichi Arai</name><affiliation><nlm:aff id="af2-viruses-11-00978">Center for Supercentenarian Medical Research, Shinjuku-ku, Tokyo 160-8582, Japan;<email>ynishimo@z3.keio.jp</email> (Y.N.);<email>yukiko_abe@keio.jp</email> (Y.A.);<email>yasumich@keio.jp</email> (Y.A.)</nlm:aff></affiliation></author><author><name sortKey="Fouchier, Ron A M" sort="Fouchier, Ron A M" uniqKey="Fouchier R" first="Ron A. M." last="Fouchier">Ron A. M. Fouchier</name><affiliation><nlm:aff id="af3-viruses-11-00978">Department of Viroscience, Erasmus Medical Center, Doctor Molewaterplein 40, 3015 GD Rotterdam, The Netherlands;<email>r.fouchier@erasmusmc.nl</email></nlm:aff></affiliation></author><author><name sortKey="Yamayoshi, Seiya" sort="Yamayoshi, Seiya" uniqKey="Yamayoshi S" first="Seiya" last="Yamayoshi">Seiya Yamayoshi</name><affiliation><nlm:aff id="af1-viruses-11-00978">Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;<email>ymatsuza@ims.u-tokyo.ac.jp</email> (Y.M.);<email>fukuyamarry@gmail.com</email> (S.F.);<email>kk176356@stu-cbms.k.u-tokyo.ac.jp</email> (M.O.);<email>yuigo555@gmail.com</email> (Y.G.);<email>tokiko.watanabe@wisc.edu</email> (T.W.);<email>mimai@ims.u-tokyo.ac.jp</email> (M.I.);<email>yamayo@ims.u-tokyo.ac.jp</email> (S.Y.)</nlm:aff></affiliation></author><author><name sortKey="Kawaoka, Yoshihiro" sort="Kawaoka, Yoshihiro" uniqKey="Kawaoka Y" first="Yoshihiro" last="Kawaoka">Yoshihiro Kawaoka</name><affiliation><nlm:aff id="af1-viruses-11-00978">Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;<email>ymatsuza@ims.u-tokyo.ac.jp</email> (Y.M.);<email>fukuyamarry@gmail.com</email> (S.F.);<email>kk176356@stu-cbms.k.u-tokyo.ac.jp</email> (M.O.);<email>yuigo555@gmail.com</email> (Y.G.);<email>tokiko.watanabe@wisc.edu</email> (T.W.);<email>mimai@ims.u-tokyo.ac.jp</email> (M.I.);<email>yamayo@ims.u-tokyo.ac.jp</email> (S.Y.)</nlm:aff></affiliation><affiliation><nlm:aff id="af4-viruses-11-00978">Department of Special Pathogens, International Research Center for Infectious Diseases, Institute Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan</nlm:aff></affiliation><affiliation><nlm:aff id="af5-viruses-11-00978">Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31652870</idno><idno type="pmc">6893718</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893718</idno><idno type="RBID">PMC:6893718</idno><idno type="doi">10.3390/v11110978</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000C49</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000C49</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Antigenic Change in Human Influenza A(H2N2) Viruses Detected by Using Human Plasma from Aged and Younger Adult Individuals</title><author><name sortKey="Matsuzawa, Yukimasa" sort="Matsuzawa, Yukimasa" uniqKey="Matsuzawa Y" first="Yukimasa" last="Matsuzawa">Yukimasa Matsuzawa</name><affiliation><nlm:aff id="af1-viruses-11-00978">Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;<email>ymatsuza@ims.u-tokyo.ac.jp</email> (Y.M.);<email>fukuyamarry@gmail.com</email> (S.F.);<email>kk176356@stu-cbms.k.u-tokyo.ac.jp</email> (M.O.);<email>yuigo555@gmail.com</email> (Y.G.);<email>tokiko.watanabe@wisc.edu</email> (T.W.);<email>mimai@ims.u-tokyo.ac.jp</email> (M.I.);<email>yamayo@ims.u-tokyo.ac.jp</email> (S.Y.)</nlm:aff></affiliation></author><author><name sortKey="Iwatsuki Horimoto, Kiyoko" sort="Iwatsuki Horimoto, Kiyoko" uniqKey="Iwatsuki Horimoto K" first="Kiyoko" last="Iwatsuki-Horimoto">Kiyoko Iwatsuki-Horimoto</name><affiliation><nlm:aff id="af1-viruses-11-00978">Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;<email>ymatsuza@ims.u-tokyo.ac.jp</email> (Y.M.);<email>fukuyamarry@gmail.com</email> (S.F.);<email>kk176356@stu-cbms.k.u-tokyo.ac.jp</email> (M.O.);<email>yuigo555@gmail.com</email> (Y.G.);<email>tokiko.watanabe@wisc.edu</email> (T.W.);<email>mimai@ims.u-tokyo.ac.jp</email> (M.I.);<email>yamayo@ims.u-tokyo.ac.jp</email> (S.Y.)</nlm:aff></affiliation></author><author><name sortKey="Nishimoto, Yoshinori" sort="Nishimoto, Yoshinori" uniqKey="Nishimoto Y" first="Yoshinori" last="Nishimoto">Yoshinori Nishimoto</name><affiliation><nlm:aff id="af2-viruses-11-00978">Center for Supercentenarian Medical Research, Shinjuku-ku, Tokyo 160-8582, Japan;<email>ynishimo@z3.keio.jp</email> (Y.N.);<email>yukiko_abe@keio.jp</email> (Y.A.);<email>yasumich@keio.jp</email> (Y.A.)</nlm:aff></affiliation></author><author><name sortKey="Abe, Yukiko" sort="Abe, Yukiko" uniqKey="Abe Y" first="Yukiko" last="Abe">Yukiko Abe</name><affiliation><nlm:aff id="af2-viruses-11-00978">Center for Supercentenarian Medical Research, Shinjuku-ku, Tokyo 160-8582, Japan;<email>ynishimo@z3.keio.jp</email> (Y.N.);<email>yukiko_abe@keio.jp</email> (Y.A.);<email>yasumich@keio.jp</email> (Y.A.)</nlm:aff></affiliation></author><author><name sortKey="Fukuyama, Satoshi" sort="Fukuyama, Satoshi" uniqKey="Fukuyama S" first="Satoshi" last="Fukuyama">Satoshi Fukuyama</name><affiliation><nlm:aff id="af1-viruses-11-00978">Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;<email>ymatsuza@ims.u-tokyo.ac.jp</email> (Y.M.);<email>fukuyamarry@gmail.com</email> (S.F.);<email>kk176356@stu-cbms.k.u-tokyo.ac.jp</email> (M.O.);<email>yuigo555@gmail.com</email> (Y.G.);<email>tokiko.watanabe@wisc.edu</email> (T.W.);<email>mimai@ims.u-tokyo.ac.jp</email> (M.I.);<email>yamayo@ims.u-tokyo.ac.jp</email> (S.Y.)</nlm:aff></affiliation></author><author><name sortKey="Hamabata, Taiki" sort="Hamabata, Taiki" uniqKey="Hamabata T" first="Taiki" last="Hamabata">Taiki Hamabata</name><affiliation><nlm:aff id="af1-viruses-11-00978">Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;<email>ymatsuza@ims.u-tokyo.ac.jp</email> (Y.M.);<email>fukuyamarry@gmail.com</email> (S.F.);<email>kk176356@stu-cbms.k.u-tokyo.ac.jp</email> (M.O.);<email>yuigo555@gmail.com</email> (Y.G.);<email>tokiko.watanabe@wisc.edu</email> (T.W.);<email>mimai@ims.u-tokyo.ac.jp</email> (M.I.);<email>yamayo@ims.u-tokyo.ac.jp</email> (S.Y.)</nlm:aff></affiliation></author><author><name sortKey="Okuda, Moe" sort="Okuda, Moe" uniqKey="Okuda M" first="Moe" last="Okuda">Moe Okuda</name><affiliation><nlm:aff id="af1-viruses-11-00978">Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;<email>ymatsuza@ims.u-tokyo.ac.jp</email> (Y.M.);<email>fukuyamarry@gmail.com</email> (S.F.);<email>kk176356@stu-cbms.k.u-tokyo.ac.jp</email> (M.O.);<email>yuigo555@gmail.com</email> (Y.G.);<email>tokiko.watanabe@wisc.edu</email> (T.W.);<email>mimai@ims.u-tokyo.ac.jp</email> (M.I.);<email>yamayo@ims.u-tokyo.ac.jp</email> (S.Y.)</nlm:aff></affiliation></author><author><name sortKey="Go, Yui" sort="Go, Yui" uniqKey="Go Y" first="Yui" last="Go">Yui Go</name><affiliation><nlm:aff id="af1-viruses-11-00978">Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;<email>ymatsuza@ims.u-tokyo.ac.jp</email> (Y.M.);<email>fukuyamarry@gmail.com</email> (S.F.);<email>kk176356@stu-cbms.k.u-tokyo.ac.jp</email> (M.O.);<email>yuigo555@gmail.com</email> (Y.G.);<email>tokiko.watanabe@wisc.edu</email> (T.W.);<email>mimai@ims.u-tokyo.ac.jp</email> (M.I.);<email>yamayo@ims.u-tokyo.ac.jp</email> (S.Y.)</nlm:aff></affiliation></author><author><name sortKey="Watanabe, Tokiko" sort="Watanabe, Tokiko" uniqKey="Watanabe T" first="Tokiko" last="Watanabe">Tokiko Watanabe</name><affiliation><nlm:aff id="af1-viruses-11-00978">Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;<email>ymatsuza@ims.u-tokyo.ac.jp</email> (Y.M.);<email>fukuyamarry@gmail.com</email> (S.F.);<email>kk176356@stu-cbms.k.u-tokyo.ac.jp</email> (M.O.);<email>yuigo555@gmail.com</email> (Y.G.);<email>tokiko.watanabe@wisc.edu</email> (T.W.);<email>mimai@ims.u-tokyo.ac.jp</email> (M.I.);<email>yamayo@ims.u-tokyo.ac.jp</email> (S.Y.)</nlm:aff></affiliation></author><author><name sortKey="Imai, Masaki" sort="Imai, Masaki" uniqKey="Imai M" first="Masaki" last="Imai">Masaki Imai</name><affiliation><nlm:aff id="af1-viruses-11-00978">Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;<email>ymatsuza@ims.u-tokyo.ac.jp</email> (Y.M.);<email>fukuyamarry@gmail.com</email> (S.F.);<email>kk176356@stu-cbms.k.u-tokyo.ac.jp</email> (M.O.);<email>yuigo555@gmail.com</email> (Y.G.);<email>tokiko.watanabe@wisc.edu</email> (T.W.);<email>mimai@ims.u-tokyo.ac.jp</email> (M.I.);<email>yamayo@ims.u-tokyo.ac.jp</email> (S.Y.)</nlm:aff></affiliation></author><author><name sortKey="Arai, Yasumichi" sort="Arai, Yasumichi" uniqKey="Arai Y" first="Yasumichi" last="Arai">Yasumichi Arai</name><affiliation><nlm:aff id="af2-viruses-11-00978">Center for Supercentenarian Medical Research, Shinjuku-ku, Tokyo 160-8582, Japan;<email>ynishimo@z3.keio.jp</email> (Y.N.);<email>yukiko_abe@keio.jp</email> (Y.A.);<email>yasumich@keio.jp</email> (Y.A.)</nlm:aff></affiliation></author><author><name sortKey="Fouchier, Ron A M" sort="Fouchier, Ron A M" uniqKey="Fouchier R" first="Ron A. M." last="Fouchier">Ron A. M. Fouchier</name><affiliation><nlm:aff id="af3-viruses-11-00978">Department of Viroscience, Erasmus Medical Center, Doctor Molewaterplein 40, 3015 GD Rotterdam, The Netherlands;<email>r.fouchier@erasmusmc.nl</email></nlm:aff></affiliation></author><author><name sortKey="Yamayoshi, Seiya" sort="Yamayoshi, Seiya" uniqKey="Yamayoshi S" first="Seiya" last="Yamayoshi">Seiya Yamayoshi</name><affiliation><nlm:aff id="af1-viruses-11-00978">Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;<email>ymatsuza@ims.u-tokyo.ac.jp</email> (Y.M.);<email>fukuyamarry@gmail.com</email> (S.F.);<email>kk176356@stu-cbms.k.u-tokyo.ac.jp</email> (M.O.);<email>yuigo555@gmail.com</email> (Y.G.);<email>tokiko.watanabe@wisc.edu</email> (T.W.);<email>mimai@ims.u-tokyo.ac.jp</email> (M.I.);<email>yamayo@ims.u-tokyo.ac.jp</email> (S.Y.)</nlm:aff></affiliation></author><author><name sortKey="Kawaoka, Yoshihiro" sort="Kawaoka, Yoshihiro" uniqKey="Kawaoka Y" first="Yoshihiro" last="Kawaoka">Yoshihiro Kawaoka</name><affiliation><nlm:aff id="af1-viruses-11-00978">Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;<email>ymatsuza@ims.u-tokyo.ac.jp</email> (Y.M.);<email>fukuyamarry@gmail.com</email> (S.F.);<email>kk176356@stu-cbms.k.u-tokyo.ac.jp</email> (M.O.);<email>yuigo555@gmail.com</email> (Y.G.);<email>tokiko.watanabe@wisc.edu</email> (T.W.);<email>mimai@ims.u-tokyo.ac.jp</email> (M.I.);<email>yamayo@ims.u-tokyo.ac.jp</email> (S.Y.)</nlm:aff></affiliation><affiliation><nlm:aff id="af4-viruses-11-00978">Department of Special Pathogens, International Research Center for Infectious Diseases, Institute Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan</nlm:aff></affiliation><affiliation><nlm:aff id="af5-viruses-11-00978">Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA</nlm:aff></affiliation></author></analytic><series><title level="j">Viruses</title><idno type="eISSN">1999-4915</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Human influenza A(H2N2) viruses emerged in 1957 and were replaced by A(H3N2) viruses in 1968. The antigenicity of human H2N2 viruses has been tested by using ferret antisera or mouse and human monoclonal antibodies. Here, we examined the antigenicity of human H2N2 viruses by using human plasma samples obtained from 50 aged individuals who were born between 1928 and 1933 and from 33 younger adult individuals who were born after 1962. The aged individuals possessed higher neutralization titers against H2N2 viruses isolated in 1957 and 1963 than those against H2N2 viruses isolated in 1968, whereas the younger adults who were born between 1962 and 1968 possessed higher neutralization titers against H2N2 viruses isolated in 1963 than those against other H2N2 viruses. Antigenic cartography revealed the antigenic changes that occurred in human H2N2 viruses during circulation in humans for 11 years, as detected by ferret antisera. These results show that even though aged individuals were likely exposed to more recent H2N2 viruses that are antigenically distinct from the earlier H2N2 viruses, they did not possess high neutralizing antibody titers to the more recent viruses, suggesting immunological imprinting of these individuals with the first H2N2 viruses they encountered and that this immunological imprinting lasts for over 50 years.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Neumann, G" uniqKey="Neumann G">G. Neumann</name></author><author><name sortKey="Noda, T" uniqKey="Noda T">T. Noda</name></author><author><name sortKey="Kawaoka, Y" uniqKey="Kawaoka Y">Y. Kawaoka</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nabel, G J" uniqKey="Nabel G">G.J. Nabel</name></author><author><name sortKey="Wei, C J" uniqKey="Wei C">C.J. Wei</name></author><author><name sortKey="Ledgerwood, J E" uniqKey="Ledgerwood J">J.E. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Viruses</journal-id><journal-id journal-id-type="iso-abbrev">Viruses</journal-id><journal-id journal-id-type="publisher-id">viruses</journal-id><journal-title-group><journal-title>Viruses</journal-title></journal-title-group><issn pub-type="epub">1999-4915</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31652870</article-id><article-id pub-id-type="pmc">6893718</article-id><article-id pub-id-type="doi">10.3390/v11110978</article-id><article-id pub-id-type="publisher-id">viruses-11-00978</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Antigenic Change in Human Influenza A(H2N2) Viruses Detected by Using Human Plasma from Aged and Younger Adult Individuals</article-title></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-8470-7796</contrib-id><name><surname>Matsuzawa</surname><given-names>Yukimasa</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00978">1</xref></contrib><contrib contrib-type="author"><name><surname>Iwatsuki-Horimoto</surname><given-names>Kiyoko</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00978">1</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-7062-3057</contrib-id><name><surname>Nishimoto</surname><given-names>Yoshinori</given-names></name><xref ref-type="aff" rid="af2-viruses-11-00978">2</xref></contrib><contrib contrib-type="author"><name><surname>Abe</surname><given-names>Yukiko</given-names></name><xref ref-type="aff" rid="af2-viruses-11-00978">2</xref></contrib><contrib contrib-type="author"><name><surname>Fukuyama</surname><given-names>Satoshi</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00978">1</xref></contrib><contrib contrib-type="author"><name><surname>Hamabata</surname><given-names>Taiki</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00978">1</xref></contrib><contrib contrib-type="author"><name><surname>Okuda</surname><given-names>Moe</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00978">1</xref></contrib><contrib contrib-type="author"><name><surname>Go</surname><given-names>Yui</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00978">1</xref></contrib><contrib contrib-type="author"><name><surname>Watanabe</surname><given-names>Tokiko</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00978">1</xref></contrib><contrib contrib-type="author"><name><surname>Imai</surname><given-names>Masaki</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00978">1</xref></contrib><contrib contrib-type="author"><name><surname>Arai</surname><given-names>Yasumichi</given-names></name><xref ref-type="aff" rid="af2-viruses-11-00978">2</xref></contrib><contrib contrib-type="author"><name><surname>Fouchier</surname><given-names>Ron A.M.</given-names></name><xref ref-type="aff" rid="af3-viruses-11-00978">3</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-7768-5157</contrib-id><name><surname>Yamayoshi</surname><given-names>Seiya</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00978">1</xref></contrib><contrib contrib-type="author"><name><surname>Kawaoka</surname><given-names>Yoshihiro</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00978">1</xref><xref ref-type="aff" rid="af4-viruses-11-00978">4</xref><xref ref-type="aff" rid="af5-viruses-11-00978">5</xref><xref rid="c1-viruses-11-00978" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-viruses-11-00978"><label>1</label>Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;<email>ymatsuza@ims.u-tokyo.ac.jp</email> (Y.M.);<email>fukuyamarry@gmail.com</email> (S.F.);<email>kk176356@stu-cbms.k.u-tokyo.ac.jp</email> (M.O.);<email>yuigo555@gmail.com</email> (Y.G.);<email>tokiko.watanabe@wisc.edu</email> (T.W.);<email>mimai@ims.u-tokyo.ac.jp</email> (M.I.);<email>yamayo@ims.u-tokyo.ac.jp</email> (S.Y.)</aff><aff id="af2-viruses-11-00978"><label>2</label>Center for Supercentenarian Medical Research, Shinjuku-ku, Tokyo 160-8582, Japan;<email>ynishimo@z3.keio.jp</email> (Y.N.);<email>yukiko_abe@keio.jp</email> (Y.A.);<email>yasumich@keio.jp</email> (Y.A.)</aff><aff id="af3-viruses-11-00978"><label>3</label>Department of Viroscience, Erasmus Medical Center, Doctor Molewaterplein 40, 3015 GD Rotterdam, The Netherlands;<email>r.fouchier@erasmusmc.nl</email></aff><aff id="af4-viruses-11-00978"><label>4</label>Department of Special Pathogens, International Research Center for Infectious Diseases, Institute Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan</aff><aff id="af5-viruses-11-00978"><label>5</label>Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA</aff><author-notes><corresp id="c1-viruses-11-00978"><label>*</label>Correspondence: <email>yoshihiro.kawaoka@wisc.edu</email></corresp></author-notes><pub-date pub-type="epub"><day>23</day><month>10</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>11</month><year>2019</year></pub-date><volume>11</volume><issue>11</issue><elocation-id>978</elocation-id><history><date date-type="received"><day>30</day><month>9</month><year>2019</year></date><date date-type="accepted"><day>21</day><month>10</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 by the authors.</copyright-statement><copyright-year>2019</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p>Human influenza A(H2N2) viruses emerged in 1957 and were replaced by A(H3N2) viruses in 1968. The antigenicity of human H2N2 viruses has been tested by using ferret antisera or mouse and human monoclonal antibodies. Here, we examined the antigenicity of human H2N2 viruses by using human plasma samples obtained from 50 aged individuals who were born between 1928 and 1933 and from 33 younger adult individuals who were born after 1962. The aged individuals possessed higher neutralization titers against H2N2 viruses isolated in 1957 and 1963 than those against H2N2 viruses isolated in 1968, whereas the younger adults who were born between 1962 and 1968 possessed higher neutralization titers against H2N2 viruses isolated in 1963 than those against other H2N2 viruses. Antigenic cartography revealed the antigenic changes that occurred in human H2N2 viruses during circulation in humans for 11 years, as detected by ferret antisera. These results show that even though aged individuals were likely exposed to more recent H2N2 viruses that are antigenically distinct from the earlier H2N2 viruses, they did not possess high neutralizing antibody titers to the more recent viruses, suggesting immunological imprinting of these individuals with the first H2N2 viruses they encountered and that this immunological imprinting lasts for over 50 years.</p></abstract><kwd-group><kwd>influenza A virus</kwd><kwd>aged individuals</kwd><kwd>H2N2</kwd><kwd>antigenic drift</kwd><kwd>antigenic change</kwd></kwd-group></article-meta></front><body><sec sec-type="intro" id="sec1-viruses-11-00978"><title>1. Introduction</title><p>In 1957, an influenza A(H2N2) virus caused the so-called Asian flu. The pandemic H2N2 virus became a seasonal influenza virus and continued to circulate until 1968, when the H3N2 pandemic virus replaced the H2N2 virus [<xref rid="B1-viruses-11-00978" ref-type="bibr">1</xref>]. The H2N2 viruses have not circulated in the human population since then. Therefore, most humans who were born after 1968 lack immunity, including neutralizing antibodies, to the H2N2 viruses [<xref rid="B2-viruses-11-00978" ref-type="bibr">2</xref>,<xref rid="B3-viruses-11-00978" ref-type="bibr">3</xref>].</p><p>Between 1957 and 1968, the human H2N2 viruses accumulated amino acid mutations in their HAs to escape from neutralizing antibodies [<xref rid="B4-viruses-11-00978" ref-type="bibr">4</xref>] and adapt to humans [<xref rid="B5-viruses-11-00978" ref-type="bibr">5</xref>], which may have altered their antigenicity. In fact, ferret antisera against several H2N2 isolates were used to reveal differences in antigenicity among the human H2N2 isolates [<xref rid="B6-viruses-11-00978" ref-type="bibr">6</xref>,<xref rid="B7-viruses-11-00978" ref-type="bibr">7</xref>,<xref rid="B8-viruses-11-00978" ref-type="bibr">8</xref>]. Mouse or human monoclonal antibodies were also used to characterize antigenic changes in the HA [<xref rid="B9-viruses-11-00978" ref-type="bibr">9</xref>,<xref rid="B10-viruses-11-00978" ref-type="bibr">10</xref>]; however, these experiments used H2N2 isolates that were propagated in embryonated chicken eggs with egg-adapted amino acid mutations in the HA that affect the HA antigenicity. To solve this problem, Linster et al. [<xref rid="B11-viruses-11-00978" ref-type="bibr">11</xref>] collected H2N2 isolates that were obtained by culture in tertiary monkey kidney cells and/or MDCK cells for a maximum of five passages, without prior inoculation into embryonated chicken eggs. Using such isolates and ferret antisera against these isolates, they found antigenic changes among H2N2 viruses isolated between 1957 and 1968 [<xref rid="B11-viruses-11-00978" ref-type="bibr">11</xref>]. The T128D and N139K substitutions together with the E126T, S154P, A184T, and A188T substitutions around the receptor-binding site of HA were important for the antigenic changes in the H2N2 viruses [<xref rid="B11-viruses-11-00978" ref-type="bibr">11</xref>].</p><p>In this study, we performed a serological examination of human plasma samples obtained from 50 aged individuals who were born between 1928 and 1933 and 33 younger adult individuals who were born after 1962 to examine how the human immune system sees antigenic changes in human H2N2 viruses.</p></sec><sec id="sec2-viruses-11-00978"><title>2. Materials and Methods</title><sec id="sec2dot1-viruses-11-00978"><title>2.1. Ethical Issues</title><p>All protocols and experiments in this study were approved by the ethics committees of the Institute of Medical Science at the University of Tokyo (ID: 26-65-1119; date: 7 April 2018) and the Keio University School of Medicine (ID: 20160297; date: 2 April 2018. Written informed consent was obtained from all participants in this study. The Kawasaki Wellbeing Project is registered in the University Hospital Medical Information Network Clinical Trial Registry (ID: UMIN000026053).</p></sec><sec id="sec2dot2-viruses-11-00978"><title>2.2. Sample Collection</title><p>Plasma samples were collected from 50 aged individuals who were born between 1928 and 1933 (85–89 years old) (<xref rid="viruses-11-00978-t001" ref-type="table">Table 1</xref>). These individuals had participated in the Kawasaki Wellbeing Project, which recruits healthy individuals aged 85–89 years-old, from May to July 2018. Plasma samples from 33 younger adult volunteers born after 1962 (23–55 years old), who participated in a seasonal influenza vaccine surveillance project, were collected before these individuals received the seasonal influenza vaccine from January to November 2018 (<xref rid="viruses-11-00978-t001" ref-type="table">Table 1</xref>). Information on the vaccination history of most of the individuals was limited. Each blood sample was collected in a 5-mL vacuum tube containing EDTA-2Na (Terumo, Tokyo, Japan). Plasma was separated from whole blood by using a Leucosep (Greiner Bio-One, Kremsmünster, Austria) and was stored at −20 °C until use.</p></sec><sec id="sec2dot3-viruses-11-00978"><title>2.3. Biosafety Consideration</title><p>All experiments with human H2N2 viruses were conducted in a biosafety level (BSL) 3 laboratory at the University of Tokyo, which is approved for such use by the Ministry of Agriculture, Forestry, and Fisheries, Japan.</p></sec><sec id="sec2dot4-viruses-11-00978"><title>2.4. Cells and Viruses</title><p>Madin–Darby canine kidney (MDCK) cells were maintained in Eagle’s minimal essential medium (MEM) containing 5% newborn calf serum at 37 °C in 5% CO<sub>2</sub>. Influenza A(H2N2) viruses, A/Netherlands/M1/57 (M1/57), A/Netherlands/K1/63 (K1/63), A/Netherlands/B1/68 (B1/68), and A/Netherlands/B2/68 (B2/68), were kindly provided by Ron Fouchier (Eramus Medical Center, Rotterdam, Netherlands) [<xref rid="B11-viruses-11-00978" ref-type="bibr">11</xref>]. The isolates were obtained by culture in tertiary monkey kidney cells and/or MDCK cells for a maximum of five passages, without prior inoculation into embryonated chicken eggs [<xref rid="B11-viruses-11-00978" ref-type="bibr">11</xref>]. The 50% tissue culture infectious dose (TCID<sub>50</sub>) was determined with MDCK cells and the Reed and Muench formula.</p></sec><sec id="sec2dot5-viruses-11-00978"><title>2.5. Virus Neutralization Assay</title><p>Virus neutralization assays were conducted by using the methodology described in the WHO manual on Animal Influenza Diagnosis and Surveillance (<uri xlink:href="http://www.wpro.who.int/emerging_diseases/documents/docs/manualonanimalaidiagnosisandsurveillance.pdf">http://www.wpro.who.int/emerging_diseases/documents/docs/manualonanimalaidiagnosisandsurveillance.pdf</uri>) with some modifications. Briefly, plasma samples were initially treated with a receptor-destroying enzyme (RDE II, DENKA SEIKEN Co., LTD, Tokyo, Japan) to remove non-specific inhibitors. Two-fold serially diluted plasma samples were mixed with 100 TCID<sub>50</sub> of each isolate. The mixtures were incubated for 30 min at 37 °C and were then inoculated into an MDCK monolayer in a 96-well microplate. Cytopathic effect was observed to detect the presence of viral propagation 3 days after inoculation. The reciprocal number of the minimum dilution of plasma needed to suppress the appearance of CPE was used as the neutralization titer.</p></sec><sec id="sec2dot6-viruses-11-00978"><title>2.6. Phylogenetic Analysis</title><p>The HA sequences of 17 viruses described previously [<xref rid="B11-viruses-11-00978" ref-type="bibr">11</xref>] were aligned using the software of ClustalW. The phylogenetic tree was inferred by using the Maximum Likelihood method and Jones-Taylor-Thornton (JTT) matrix-based model [<xref rid="B12-viruses-11-00978" ref-type="bibr">12</xref>]. The tree with the highest log likelihood (−1787.57) is shown. The percentage of trees in which the associated taxa clustered together is shown next to the branches. Initial tree(s) for the heuristic search were obtained automatically by applying Neighbor-Join and BioNJ algorithms to a matrix of pairwise distances estimated using a JTT model, and then selecting the topology with the superior log likelihood value. The tree is drawn to scale, with branch lengths measured in the number of substitutions per site. There were 329 positions in the final dataset. Evolutionary analyses were conducted by using the software MEGA X [<xref rid="B4-viruses-11-00978" ref-type="bibr">4</xref>]. A/mallard/Netherlands/31/2006 virus is defined as an outgroup.</p></sec><sec id="sec2dot7-viruses-11-00978"><title>2.7. Statistical Analysis</title><p>A non-parametric, repeated measures, one-way ANOVA Friedman’s test followed by a two-stage linear step-up procedure of Benjamini, Krieger, and Yekutieli was performed by using GraphPad Prism 7.04 software. <italic>p</italic> values <0.05 were considered significantly different. No samples were excluded from the analysis.</p></sec><sec id="sec2dot8-viruses-11-00978"><title>2.8. Antigenic Cartography</title><p>The neutralization data were analyzed by using antigenic cartography (<uri xlink:href="https://acmacs-web.antigenic-cartography.org/">https://acmacs-web.antigenic-cartography.org/</uri>), which is a method to visualize and increase the resolution of neutralization results, as detailed previously [<xref rid="B13-viruses-11-00978" ref-type="bibr">13</xref>]. Plasma samples with no or only one numerical antibody titer were not included because they cannot be placed properly in an antigenic map.</p></sec></sec><sec sec-type="results" id="sec3-viruses-11-00978"><title>3. Results and Discussions</title><p>To examine the antigenicity of the H2N2 viruses that circulated in humans, we used 50 plasma samples that were obtained from aged individuals (<xref rid="viruses-11-00978-t002" ref-type="table">Table 2</xref>) because individuals who were born between 1928 and 1933 were likely exposed to human H2N2 viruses between 1957 and 1968. We also used 33 plasma samples from younger adults who were born after 1962 (<xref rid="viruses-11-00978-t002" ref-type="table">Table 2</xref>). We chose 4 human H2N2 isolates—A/Netherlands/M1/57 (H2N2; M1/57), A/Netherlands/K1/63 (H2N2; K1/63), A/Netherlands/B1/68 (H2N2; B1/68), and A/Netherlands/B2/68 (H2N2; B2/68)—based on phylogenic analysis (<xref ref-type="fig" rid="viruses-11-00978-f001">Figure 1</xref>) and a previous report [<xref rid="B11-viruses-11-00978" ref-type="bibr">11</xref>]. These isolates were obtained by culture in tertiary monkey kidney cells and MDCK cells for a maximum of five passages, without prior inoculation into embryonated chicken eggs [<xref rid="B11-viruses-11-00978" ref-type="bibr">11</xref>].</p><p>Using these 83 plasma samples and four human H2N2 isolates, we performed a virus neutralization assay to compare the antigenicity of the human H2N2 isolates (<xref rid="viruses-11-00978-t002" ref-type="table">Table 2</xref>). The aged individuals (ID #1–50) possessed higher neutralization titers against M1/57 and K1/63 than those against B1/68 and B2/68 (<xref ref-type="fig" rid="viruses-11-00978-f002">Figure 2</xref>A,C). The neutralizing titers against B1/68 of the aged individuals were lower than those against B2/68, whereas those against M1/57 were similar to those against K1/63 (<xref ref-type="fig" rid="viruses-11-00978-f002">Figure 2</xref>A,C). The neutralizing titers against K1/63 and B2/68 of the younger adult individuals were higher than those against M1/57 and B1/68 (<xref ref-type="fig" rid="viruses-11-00978-f002">Figure 2</xref>B,C). Younger adults who were born after 1972 (ID #75–83) had minimal neutralization titers against the human H2N2 viruses tested (<xref ref-type="fig" rid="viruses-11-00978-f002">Figure 2</xref>C). To visualize the antigenicity of the human H2N2 viruses, we constructed an antigenic map using the neutralizing titers of <xref rid="viruses-11-00978-t002" ref-type="table">Table 2</xref>. This map revealed the antigenic differences among the H2N2 viruses tested and the gradual drift in their antigenicity during circulation in humans (<xref ref-type="fig" rid="viruses-11-00978-f003">Figure 3</xref>). The results obtained with these human sera were similar to those previously obtained using ferret antisera [<xref rid="B11-viruses-11-00978" ref-type="bibr">11</xref>].</p><p>Human H2N2 viruses circulated in the human population between 1957 and 1968. Mouse and human monoclonal antibodies [<xref rid="B9-viruses-11-00978" ref-type="bibr">9</xref>,<xref rid="B10-viruses-11-00978" ref-type="bibr">10</xref>] and ferret antisera [<xref rid="B6-viruses-11-00978" ref-type="bibr">6</xref>,<xref rid="B7-viruses-11-00978" ref-type="bibr">7</xref>,<xref rid="B8-viruses-11-00978" ref-type="bibr">8</xref>,<xref rid="B11-viruses-11-00978" ref-type="bibr">11</xref>] revealed the antigenic change in H2N2 viruses. Here, we elucidated the antigenic change in H2N2 viruses by using 83 human plasma samples that were obtained from the aged and younger adult individuals. Overall, the antigenicity of H2N2 viruses revealed by human plasma was similar to that revealed by ferret antisera. Ferret antisera showed that the antigenic change between M1/57 and B1/68 was caused by the T128D and R139K substitutions together with other five other changes (<xref rid="viruses-11-00978-t003" ref-type="table">Table 3</xref>). These substitutions may play a central role in the antigenic change revealed by human plasma since some human neutralizing monoclonal antibodies against H2-HA recognize the region surrounding these seven amino acids [<xref rid="B10-viruses-11-00978" ref-type="bibr">10</xref>]. Furthermore, human plasma showed that the antigenicity of B1/68 differed from that of B2/68. At the seven amino acid positions that were important for the antigenic change between M1/57 and B1/68, E126K, P154Q, and A184E substitutions are present between B1/68 and B2/68 (<xref rid="viruses-11-00978-t003" ref-type="table">Table 3</xref>). These 3 amino acid substitutions may, therefore, contribute to the antigenic difference between the viruses.</p><p>Although some of the aged individuals likely have been infected with or exposed to later H2N2 viruses, almost of all of the aged individuals maintained high neutralization titers against the H2N2 viruses that caused the pandemic or its antigenically closely related viruses, but possessed low neutralization titers against later H2N2 viruses. These data suggest that immunological imprinting toward the pandemic H2N2 virus occurred. This would also mean that the immunological imprinting was maintained for 50 years.</p><p>Antigenic cartography is usually performed by using antisera obtained from ferrets infected with an influenza virus [<xref rid="B13-viruses-11-00978" ref-type="bibr">13</xref>]. In this study, we used human plasma samples obtained from aged and younger adults for the antigenic cartography of human H2N2 viruses. Previous studies showed that human infant sera and ferret antisera see the antigenicity of H1N1 and H3N2 viruses differently [<xref rid="B14-viruses-11-00978" ref-type="bibr">14</xref>,<xref rid="B15-viruses-11-00978" ref-type="bibr">15</xref>]. However, the positions of four H2N2 viruses in the antigenic map we made with the human plasma samples were similar to those obtained with ferret antisera (<xref ref-type="fig" rid="viruses-11-00978-f003">Figure 3</xref> and ref [<xref rid="B11-viruses-11-00978" ref-type="bibr">11</xref>]). This variation in findings with respect to the antigenic differences recognized by human sera/plasma and ferret antisera between H2N2 and H1N1 or H3N2 is interesting and deserves further study.</p><p>Human H2N2 viruses were replaced by human H3N2 viruses in 1968. Therefore, we had thought that people who were born after 1968 were unlikely to possess neutralizing antibodies against human H2N2 viruses. However, they did possess some neutralization titers against the H2N2 viruses. This finding could be explained by antibodies against the HA stem and/or NA because anti-HA stem antibodies are usually cross-reactive with members of group 1 HA [<xref rid="B16-viruses-11-00978" ref-type="bibr">16</xref>,<xref rid="B17-viruses-11-00978" ref-type="bibr">17</xref>,<xref rid="B18-viruses-11-00978" ref-type="bibr">18</xref>] and antibodies against the NA of the seasonal H3N2 virus could suppress H2N2 virus replication, given that the NA of H3N2 virus was inherited from human H2N2 virus [<xref rid="B1-viruses-11-00978" ref-type="bibr">1</xref>].</p><p>In conclusion, the plasma of individuals who were born between 1928 and 1933 revealed the antigenic change in human H2N2 viruses and the possibility of immunological imprinting of infected individuals against pandemic H2N2 virus, which lasts for half a century.</p></sec></body><back><ack><title>Acknowledgments</title><p>We thank Susan Watson for scientific editing, and Hiroshi Ueki and Daisuke Jubishi for blood sample collection.</p></ack><notes><title>Author Contributions</title><p>Y.M., K.I.-H., T.W., M.I., and Y.K. designed this study. Y.M. and K.I-H. performed experiments. S.Y. and Y.K. analyzed the data and wrote the manuscript. Y.N., Y.A. (Yukiko Abe), and Y.A. (Yasumichi Arai) collected blood samples from volunteers. S.F. coordinated blood sample collection. T.H., M.O., and Y.G. contributed to the preparation of the plasma samples. R.A.M.F. provided human H2N2 isolates. All of the authors reviewed the manuscript and approved the final version.</p></notes><notes><title>Funding</title><p>This research was supported by Leading Advanced Projects for medical innovation (LEAP) from the Japan Agency for Medical Research and Development (AMED) (JP18am001007), by Grants-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Science, Sports, and Technology (MEXT) of Japan (Nos. 16H06429, 16K21723, and 16H06434), by Grant-in-Aid for Scientific Research (B) from Japan Society for the Promotion of Science (JSPS) (18H03055), by the Japan Initiative for Global Research Network on Infectious Diseases (J-GRID) from AMED (JP19fm0108006), by a Research Program on Emerging and Re-emerging Infectious Diseases from AMED (JP19fk0108031, JP19fk0108056 and JP19fk0108066), and by JST Research Complex Program (JP15667051). R.F. is supported by National Institute of Allergy and Infectious Diseases/NIH contract no. HHSN272201400008C.</p></notes><notes notes-type="COI-statement"><title>Conflicts of Interest</title><p>Y.K. has received speaker’s honoraria from Toyama Chemical and Astellas Inc.; has received grant support from Chugai Pharmaceuticals, Daiichi Sankyo Pharmaceutical, Toyama Chemical, Tauns Laboratories, Inc., Otsuka Pharmaceutical Co., Ltd., and Denka Seiken Co., Ltd.; and is a co-founder of FluGen. Y.Arai. has received a research grant from Daiichi Sankyo Co, Ltd. and Novartis Pharma K K. 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The neutralization titers against the viruses indicated in <xref rid="viruses-11-00978-t002" ref-type="table">Table 2</xref> were plotted. A non-parametric Friedman’s test followed by a two-stage linear step-up procedure of Benjamini, Krieger, and Yekutieli was performed. * and *** mean <italic>p</italic> < 0.05 and <italic>p</italic> < 0.0001, respectively. (<bold>C</bold>) Bubble chart of the neutralization titers of all of the individuals. The bigger the circle, the higher the neutralization titer.</p></caption><graphic xlink:href="viruses-11-00978-g002"></graphic></fig><fig id="viruses-11-00978-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>An antigenic map of human H2N2 viruses. An antigenic map was generated from the neutralization data shown in <xref rid="viruses-11-00978-t002" ref-type="table">Table 2</xref>. Viruses are represented as circles and plasma samples obtained from aged or younger adults are represented as black or grey squares, respectively. Sera with no or only 1 numerical antibody titer are not shown as they cannot be placed properly in an antigenic map. The grid indicates one unit of antigenic distance, a two-fold dilution in neutralization titer.</p></caption><graphic xlink:href="viruses-11-00978-g003"></graphic></fig><table-wrap id="viruses-11-00978-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">viruses-11-00978-t001_Table 1</object-id><label>Table 1</label><caption><p>Characteristics of the participants in this study.</p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="4" colspan="2" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin"></th><th colspan="10" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1">No. of Individuals</th></tr><tr><th colspan="10" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">Birth Year</th></tr><tr><th colspan="6" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">Aged Individuals</th><th colspan="4" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">Younger Adult Individuals</th></tr><tr><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1928</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1929</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1930</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1931</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1932</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1933</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1960s</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1970s</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1980s</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1990s</th></tr></thead><tbody><tr><td colspan="2" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">Males</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">10</td><td align="center" valign="middle" rowspan="1" colspan="1">5</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td><td align="center" valign="middle" rowspan="1" colspan="1">2</td></tr><tr><td colspan="2" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">Females</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">9</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1</td></tr><tr><td colspan="2" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">Total</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">9</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">9</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">8</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">8</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">8</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">8</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">19</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">8</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3</td></tr><tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Medical history <sup>b</sup></td><td align="center" valign="middle" rowspan="1" colspan="1">Heart disease</td><td align="center" valign="middle" rowspan="1" colspan="1">3/9</td><td align="center" valign="middle" rowspan="1" colspan="1">1/9</td><td align="center" valign="middle" rowspan="1" colspan="1">3/8</td><td align="center" valign="middle" rowspan="1" colspan="1">1/8</td><td align="center" valign="middle" rowspan="1" colspan="1">1/8</td><td align="center" valign="middle" rowspan="1" colspan="1">1/8</td><td align="center" valign="middle" rowspan="1" colspan="1">NA <sup>a</sup></td><td align="center" valign="middle" rowspan="1" colspan="1">NA</td><td align="center" valign="middle" rowspan="1" colspan="1">NA</td><td align="center" valign="middle" rowspan="1" colspan="1">NA</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Diabetes</td><td align="center" valign="middle" rowspan="1" colspan="1">0/9</td><td align="center" valign="middle" rowspan="1" colspan="1">0/9</td><td align="center" valign="middle" rowspan="1" colspan="1">1/8</td><td align="center" valign="middle" rowspan="1" colspan="1">2/8</td><td align="center" valign="middle" rowspan="1" colspan="1">1/8</td><td align="center" valign="middle" rowspan="1" colspan="1">1/8</td><td align="center" valign="middle" rowspan="1" colspan="1">NA</td><td align="center" valign="middle" rowspan="1" colspan="1">NA</td><td align="center" valign="middle" rowspan="1" colspan="1">NA</td><td align="center" valign="middle" rowspan="1" colspan="1">NA</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cancer</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3/9</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2/9</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2/8</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4/8</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2/8</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2/8</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NA</td></tr></tbody></table><table-wrap-foot><fn><p><sup>a</sup> Not available. <sup>b</sup> Summary of available medical history of each individual.</p></fn></table-wrap-foot></table-wrap><table-wrap id="viruses-11-00978-t002" orientation="portrait" position="float"><object-id pub-id-type="pii">viruses-11-00978-t002_Table 2</object-id><label>Table 2</label><caption><p>Neutralization titers of aged and younger adult individuals.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">ID</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Birth Year (age)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">M1/57 <sup>a</sup></th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">K1/63 <sup>b</sup></th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">B1/68 <sup>c</sup></th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">B2/68 <sup>d</sup></th></tr></thead><tbody><tr><td align="center" valign="middle" rowspan="1" colspan="1">1</td><td align="center" valign="middle" rowspan="1" colspan="1">1928 (89)</td><td align="center" valign="middle" rowspan="1" colspan="1">128</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">2</td><td align="center" valign="middle" rowspan="1" colspan="1">1928 (89)</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">3</td><td align="center" valign="middle" rowspan="1" colspan="1">1928 (89)</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">1928 (89)</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">5</td><td align="center" valign="middle" rowspan="1" colspan="1">1928 (89)</td><td align="center" valign="middle" rowspan="1" colspan="1">256</td><td align="center" valign="middle" rowspan="1" colspan="1">128</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">6</td><td align="center" valign="middle" rowspan="1" colspan="1">1928 (89)</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">7</td><td align="center" valign="middle" rowspan="1" colspan="1">1928 (89)</td><td align="center" valign="middle" rowspan="1" colspan="1">256</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">1928 (89)</td><td align="center" valign="middle" rowspan="1" colspan="1">128</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">9</td><td align="center" valign="middle" rowspan="1" colspan="1">1928 (89)</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">10</td><td align="center" valign="middle" rowspan="1" colspan="1">1929 (89)</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">11</td><td align="center" valign="middle" rowspan="1" colspan="1">1929 (89)</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">12</td><td align="center" valign="middle" rowspan="1" colspan="1">1929 (89)</td><td align="center" valign="middle" rowspan="1" colspan="1">128</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">13</td><td align="center" valign="middle" rowspan="1" colspan="1">1929 (89)</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">14</td><td align="center" valign="middle" rowspan="1" colspan="1">1929 (89)</td><td align="center" valign="middle" rowspan="1" colspan="1">256</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">15</td><td align="center" valign="middle" rowspan="1" colspan="1">1929 (89)</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1">1929 (89)</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">17</td><td align="center" valign="middle" rowspan="1" colspan="1">1929 (88)</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">18</td><td align="center" valign="middle" rowspan="1" colspan="1">1929 (88)</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">128</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">19</td><td align="center" valign="middle" rowspan="1" colspan="1">1930 (88)</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">20</td><td align="center" valign="middle" rowspan="1" colspan="1">1930 (88)</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">21</td><td align="center" valign="middle" rowspan="1" colspan="1">1930 (88)</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">22</td><td align="center" valign="middle" rowspan="1" colspan="1">1930 (88)</td><td align="center" valign="middle" rowspan="1" colspan="1">256</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">23</td><td align="center" valign="middle" rowspan="1" colspan="1">1930 (87)</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">24</td><td align="center" valign="middle" rowspan="1" colspan="1">1930 (87)</td><td align="center" valign="middle" rowspan="1" colspan="1">128</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">25</td><td align="center" valign="middle" rowspan="1" colspan="1">1930 (87)</td><td align="center" valign="middle" rowspan="1" colspan="1">256</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">26</td><td align="center" valign="middle" rowspan="1" colspan="1">1930 (87)</td><td align="center" valign="middle" rowspan="1" colspan="1">256</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">27</td><td align="center" valign="middle" rowspan="1" colspan="1">1931 (87)</td><td align="center" valign="middle" rowspan="1" colspan="1">128</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">28</td><td align="center" valign="middle" rowspan="1" colspan="1">1931 (87)</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">29</td><td align="center" valign="middle" rowspan="1" colspan="1">1931 (87)</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">30</td><td align="center" valign="middle" rowspan="1" colspan="1">1931 (87)</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">31</td><td align="center" valign="middle" rowspan="1" colspan="1">1931 (86)</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">1931 (86)</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">33</td><td align="center" valign="middle" rowspan="1" colspan="1">1931 (86)</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">34</td><td align="center" valign="middle" rowspan="1" colspan="1">1931 (86)</td><td align="center" valign="middle" rowspan="1" colspan="1">128</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">35</td><td align="center" valign="middle" rowspan="1" colspan="1">1932 (86)</td><td align="center" valign="middle" rowspan="1" colspan="1">256</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">36</td><td align="center" valign="middle" rowspan="1" colspan="1">1932 (86)</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">37</td><td align="center" valign="middle" rowspan="1" colspan="1">1932 (86)</td><td align="center" valign="middle" rowspan="1" colspan="1">256</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">38</td><td align="center" valign="middle" rowspan="1" colspan="1">1932 (86)</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">39</td><td align="center" valign="middle" rowspan="1" colspan="1">1932 (86)</td><td align="center" valign="middle" rowspan="1" colspan="1">256</td><td align="center" valign="middle" rowspan="1" colspan="1">128</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">40</td><td align="center" valign="middle" rowspan="1" colspan="1">1932 (85)</td><td align="center" valign="middle" rowspan="1" colspan="1">256</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">41</td><td align="center" valign="middle" rowspan="1" colspan="1">1932 (85)</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">42</td><td align="center" valign="middle" rowspan="1" colspan="1">1932 (85)</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">43</td><td align="center" valign="middle" rowspan="1" colspan="1">1933 (85)</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">44</td><td align="center" valign="middle" rowspan="1" colspan="1">1933 (85)</td><td align="center" valign="middle" rowspan="1" colspan="1">256</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">45</td><td align="center" valign="middle" rowspan="1" colspan="1">1933 (85)</td><td align="center" valign="middle" rowspan="1" colspan="1">256</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">46</td><td align="center" valign="middle" rowspan="1" colspan="1">1933 (85)</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">47</td><td align="center" valign="middle" rowspan="1" colspan="1">1933 (85)</td><td align="center" valign="middle" rowspan="1" colspan="1">128</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">48</td><td align="center" valign="middle" rowspan="1" colspan="1">1933 (85)</td><td align="center" valign="middle" rowspan="1" colspan="1">>512</td><td align="center" valign="middle" rowspan="1" colspan="1">128</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">49</td><td align="center" valign="middle" rowspan="1" colspan="1">1933 (85)</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">50</td><td align="center" valign="middle" rowspan="1" colspan="1">1933 (85)</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">128</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">51</td><td align="center" valign="middle" rowspan="1" colspan="1">1962 (56)</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">128</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">52</td><td align="center" valign="middle" rowspan="1" colspan="1">1962 (55)</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">53</td><td align="center" valign="middle" rowspan="1" colspan="1">1962 (55)</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">54</td><td align="center" valign="middle" rowspan="1" colspan="1">1962 (55)</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">55</td><td align="center" valign="middle" rowspan="1" colspan="1">1963 (55)</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">>512</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">56</td><td align="center" valign="middle" rowspan="1" colspan="1">1963 (55)</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">>512</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1">256</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">57</td><td align="center" valign="middle" rowspan="1" colspan="1">1963 (55)</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">128</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">58</td><td align="center" valign="middle" rowspan="1" colspan="1">1963 (55)</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1">256</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">59</td><td align="center" valign="middle" rowspan="1" colspan="1">1964 (54)</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">128</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">60</td><td align="center" valign="middle" rowspan="1" colspan="1">1965 (53)</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">61</td><td align="center" valign="middle" rowspan="1" colspan="1">1966 (52)</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">62</td><td align="center" valign="middle" rowspan="1" colspan="1">1966 (51)</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">128</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">63</td><td align="center" valign="middle" rowspan="1" colspan="1">1967 (51)</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">64</td><td align="center" valign="middle" rowspan="1" colspan="1">1967 (50)</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">65</td><td align="center" valign="middle" rowspan="1" colspan="1">1968 (50)</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">66</td><td align="center" valign="middle" rowspan="1" colspan="1">1968 (49)</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">67</td><td align="center" valign="middle" rowspan="1" colspan="1">1969 (49)</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">68</td><td align="center" valign="middle" rowspan="1" colspan="1">1969 (49)</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">69</td><td align="center" valign="middle" rowspan="1" colspan="1">1969 (48)</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">70</td><td align="center" valign="middle" rowspan="1" colspan="1">1970 (48)</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">71</td><td align="center" valign="middle" rowspan="1" colspan="1">1970 (47)</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1">32</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">72</td><td align="center" valign="middle" rowspan="1" colspan="1">1970 (47)</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">73</td><td align="center" valign="middle" rowspan="1" colspan="1">1970 (47)</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1">16</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">74</td><td align="center" valign="middle" rowspan="1" colspan="1">1970 (47)</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1">8</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">75</td><td align="center" valign="middle" rowspan="1" colspan="1">1972 (45)</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">76</td><td align="center" valign="middle" rowspan="1" colspan="1">1974 (44)</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">77</td><td align="center" valign="middle" rowspan="1" colspan="1">1978 (39)</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">78</td><td align="center" valign="middle" rowspan="1" colspan="1">1980 (37)</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">79</td><td align="center" valign="middle" rowspan="1" colspan="1">1982 (36)</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">80</td><td align="center" valign="middle" rowspan="1" colspan="1">1985 (33)</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">81</td><td align="center" valign="middle" rowspan="1" colspan="1">1990 (27)</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">82</td><td align="center" valign="middle" rowspan="1" colspan="1">1992 (26)</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" rowspan="1" colspan="1">4</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">83</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1994 (23)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><4</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4</td></tr></tbody></table><table-wrap-foot><fn><p>Neutralization titers of plasma samples of aged individuals (ID 1–50) and younger adult individuals (ID 51–83) against A/Netherland/M1/57 <sup>a</sup>, A/Netherland/K1/63 <sup>b</sup>, A/Netherland/B1/68 <sup>c</sup>, or A/Netherland/B2/68 <sup>d</sup> were measured.</p></fn></table-wrap-foot></table-wrap><table-wrap id="viruses-11-00978-t003" orientation="portrait" position="float"><object-id pub-id-type="pii">viruses-11-00978-t003_Table 3</object-id><label>Table 3</label><caption><p>Comparison of amino acids that are important for HA antigenicity <sup>a.</sup></p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="2" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" colspan="1">Isolate</th><th colspan="7" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1">Amino Acid Position at</th></tr><tr><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">126</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">128</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">132</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">139</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">154</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">184</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">188</th></tr></thead><tbody><tr><td align="center" valign="middle" rowspan="1" colspan="1">A/Netherland/M1/57</td><td align="center" valign="middle" rowspan="1" colspan="1">T</td><td align="center" valign="middle" rowspan="1" colspan="1">T</td><td align="center" valign="middle" rowspan="1" colspan="1">R</td><td align="center" valign="middle" rowspan="1" colspan="1">N</td><td align="center" valign="middle" rowspan="1" colspan="1">S</td><td align="center" valign="middle" rowspan="1" colspan="1">T</td><td align="center" valign="middle" rowspan="1" colspan="1">T</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">A/Netherland/K1/63</td><td align="center" valign="middle" rowspan="1" colspan="1">T</td><td align="center" valign="middle" rowspan="1" colspan="1">T</td><td align="center" valign="middle" rowspan="1" colspan="1">R</td><td align="center" valign="middle" rowspan="1" colspan="1">N</td><td align="center" valign="middle" rowspan="1" colspan="1">P</td><td align="center" valign="middle" rowspan="1" colspan="1">A</td><td align="center" valign="middle" rowspan="1" colspan="1">A</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">A/Netherland/B1/68</td><td align="center" valign="middle" rowspan="1" colspan="1">E</td><td align="center" valign="middle" rowspan="1" colspan="1">D</td><td align="center" valign="middle" rowspan="1" colspan="1">K</td><td align="center" valign="middle" rowspan="1" colspan="1">K</td><td align="center" valign="middle" rowspan="1" colspan="1">P</td><td align="center" valign="middle" rowspan="1" colspan="1">A</td><td align="center" valign="middle" rowspan="1" colspan="1">A</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">A/Netherland/B2/68</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">K</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">D</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">K</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">K</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Q</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">E</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">A</td></tr></tbody></table><table-wrap-foot><fn><p><sup>a</sup> Amino acids that are different among the HAs of the four isolates at previously identified antigenic determinants [<xref rid="B11-viruses-11-00978" ref-type="bibr">11</xref>] are listed.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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