Multinational Impact of the 1968 Hong Kong Influenza Pandemic: Evidence for a Smoldering Pandemic
Identifieur interne : 000075 ( Istex/Corpus ); précédent : 000074; suivant : 000076Multinational Impact of the 1968 Hong Kong Influenza Pandemic: Evidence for a Smoldering Pandemic
Auteurs : Cécile Viboud ; Rebecca F. Grais ; Bernard A. P. Lafont ; Mark A. Miller ; Lone SimonsenSource :
- The Journal of Infectious Diseases [ 0022-1899 ] ; 2005.
Abstract
BackgroundThe first pandemic season of A/H3N2 influenza virus (1968/1969) resulted in significant mortality in the United States, but it was the second pandemic season of A/H3N2 influenza virus (1969/1970) that caused the majority of deaths in England. We further explored the global pattern of mortality caused by the pandemic during this period MethodsWe estimated the influenza-related excess mortality in 6 countries (United States, Canada, England and Wales, France, Japan, and Australia) using national vital statistics by age for 1967–1978. Geographical and temporal pandemic patterns in mortality were compared with the genetic drift of the influenza viruses by analyzing hemagglutinin and neuraminidase sequences from GenBank ResultsIn North America, the majority of influenza-related deaths in 1968/1969 and 1969/1970 occurred during the first pandemic season (United States, 70%; Canada, 54%). Conversely, in Europe and Asia, the pattern was reversed: 70% of deaths occurred during the second pandemic season. The second pandemic season coincided with a drift in the neuraminidase antigen ConclusionWe found a consistent pattern of mortality being delayed until the second pandemic season of A/H3N2 circulation in Europe and Asia. We hypothesize that this phenomenon may be explained by higher preexisting neuraminidase immunity (from the A/H2N2 era) in Europe and Asia than in North America, combined with a subsequent drift in the neuraminidase antigen during 1969/1970
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DOI: 10.1086/431150
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Grais</name><affiliation><mods:affiliation>Fogarty International Center and</mods:affiliation></affiliation></author><author><name sortKey="Lafont, Bernard A P" sort="Lafont, Bernard A P" uniqKey="Lafont B" first="Bernard A. P." last="Lafont">Bernard A. P. Lafont</name><affiliation><mods:affiliation>National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland</mods:affiliation></affiliation></author><author><name sortKey="Miller, Mark A" sort="Miller, Mark A" uniqKey="Miller M" first="Mark A." last="Miller">Mark A. Miller</name><affiliation><mods:affiliation>Fogarty International Center and</mods:affiliation></affiliation></author><author><name sortKey="Simonsen, Lone" sort="Simonsen, Lone" uniqKey="Simonsen L" first="Lone" last="Simonsen">Lone Simonsen</name><affiliation><mods:affiliation>National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">The Journal of Infectious Diseases</title><title level="j" type="abbrev">The Journal of Infectious Diseases</title><idno type="ISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><imprint><publisher>The University of Chicago Press</publisher><date when="2005-07-15">2005</date><biblScope unit="vol">192</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="233">233</biblScope><biblScope unit="page" to="248">248</biblScope></imprint><idno type="ISSN">0022-1899</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-1899</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">BackgroundThe first pandemic season of A/H3N2 influenza virus (1968/1969) resulted in significant mortality in the United States, but it was the second pandemic season of A/H3N2 influenza virus (1969/1970) that caused the majority of deaths in England. We further explored the global pattern of mortality caused by the pandemic during this period MethodsWe estimated the influenza-related excess mortality in 6 countries (United States, Canada, England and Wales, France, Japan, and Australia) using national vital statistics by age for 1967–1978. Geographical and temporal pandemic patterns in mortality were compared with the genetic drift of the influenza viruses by analyzing hemagglutinin and neuraminidase sequences from GenBank ResultsIn North America, the majority of influenza-related deaths in 1968/1969 and 1969/1970 occurred during the first pandemic season (United States, 70%; Canada, 54%). Conversely, in Europe and Asia, the pattern was reversed: 70% of deaths occurred during the second pandemic season. The second pandemic season coincided with a drift in the neuraminidase antigen ConclusionWe found a consistent pattern of mortality being delayed until the second pandemic season of A/H3N2 circulation in Europe and Asia. 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Miller</name><affiliations><json:string>Fogarty International Center and</json:string></affiliations></json:item><json:item><name>Lone Simonsen</name><affiliations><json:string>National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland</json:string></affiliations></json:item></author><arkIstex>ark:/67375/HXZ-MGDWGJB8-C</arkIstex><language><json:string>unknown</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>BackgroundThe first pandemic season of A/H3N2 influenza virus (1968/1969) resulted in significant mortality in the United States, but it was the second pandemic season of A/H3N2 influenza virus (1969/1970) that caused the majority of deaths in England. We further explored the global pattern of mortality caused by the pandemic during this period MethodsWe estimated the influenza-related excess mortality in 6 countries (United States, Canada, England and Wales, France, Japan, and Australia) using national vital statistics by age for 1967–1978. Geographical and temporal pandemic patterns in mortality were compared with the genetic drift of the influenza viruses by analyzing hemagglutinin and neuraminidase sequences from GenBank ResultsIn North America, the majority of influenza-related deaths in 1968/1969 and 1969/1970 occurred during the first pandemic season (United States, 70%; Canada, 54%). Conversely, in Europe and Asia, the pattern was reversed: 70% of deaths occurred during the second pandemic season. The second pandemic season coincided with a drift in the neuraminidase antigen ConclusionWe found a consistent pattern of mortality being delayed until the second pandemic season of A/H3N2 circulation in Europe and Asia. 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Tam</json:string></persName><placeName><json:string>Paris</json:string><json:string>Singapore</json:string><json:string>United States</json:string><json:string>Australia</json:string><json:string>UK</json:string><json:string>Hong Kong</json:string><json:string>Canada</json:string><json:string>Melbourne</json:string><json:string>Cardiff</json:string><json:string>London</json:string><json:string>American</json:string><json:string>Seattle</json:string><json:string>Europe</json:string><json:string>Japan</json:string><json:string>America</json:string><json:string>Wales</json:string><json:string>France</json:string><json:string>England</json:string></placeName><ref_url></ref_url><ref_bibl><json:string>[9, 31, 35]</json:string><json:string>[50]</json:string><json:string>[27, 28, 31, 49]</json:string><json:string>[27, 28, 31]</json:string><json:string>[29]</json:string><json:string>[22]</json:string><json:string>[8]</json:string><json:string>[14, 16, 42]</json:string><json:string>Smith et al.</json:string><json:string>[1]</json:string><json:string>[32]</json:string><json:string>[38]</json:string><json:string>[53]</json:string><json:string>[7, 8]</json:string><json:string>[48]</json:string><json:string>[9, 10]</json:string><json:string>[4, 11]</json:string><json:string>[9, 17, 51]</json:string><json:string>[3, 11]</json:string><json:string>[52]</json:string><json:string>[7]</json:string><json:string>[18, 19]</json:string><json:string>[42, 43]</json:string><json:string>[9]</json:string><json:string>[51]</json:string><json:string>August 1968</json:string><json:string>[27, 28]</json:string><json:string>[2]</json:string><json:string>[24]</json:string><json:string>Lindstrom et al.</json:string><json:string>Viboud et al.</json:string><json:string>[9, 12]</json:string></ref_bibl><bibl></bibl></unitex></namedEntities><ark><json:string>ark:/67375/HXZ-MGDWGJB8-C</json:string></ark><categories><wos><json:string>1 - science</json:string><json:string>2 - microbiology</json:string><json:string>2 - infectious diseases</json:string><json:string>2 - immunology</json:string></wos><scienceMetrix><json:string>1 - health sciences</json:string><json:string>2 - biomedical research</json:string><json:string>3 - microbiology</json:string></scienceMetrix><scopus><json:string>1 - Health Sciences</json:string><json:string>2 - Medicine</json:string><json:string>3 - Infectious Diseases</json:string><json:string>1 - Health Sciences</json:string><json:string>2 - Medicine</json:string><json:string>3 - Immunology and Allergy</json:string></scopus><inist><json:string>1 - sciences appliquees, technologies et medecines</json:string><json:string>2 - sciences biologiques et medicales</json:string><json:string>3 - sciences medicales</json:string></inist></categories><publicationDate>2005</publicationDate><copyrightDate>2005</copyrightDate><doi><json:string>10.1086/431150</json:string></doi><id>605E9544CC0719D70FAFC4ED721CBA613F72E7ED</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/ark:/67375/HXZ-MGDWGJB8-C/fulltext.pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/ark:/67375/HXZ-MGDWGJB8-C/bundle.zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/ark:/67375/HXZ-MGDWGJB8-C/fulltext.tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main">Multinational Impact of the 1968 Hong Kong Influenza Pandemic: Evidence for a Smoldering Pandemic
</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>The University of Chicago Press</publisher><date when="2005-07-15">2005</date></publicationStmt><notesStmt><note type="content-type" source="research-article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</note><note type="publication-type" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note></notesStmt><sourceDesc><biblStruct type="article"><analytic><title level="a" type="main" xml:lang="en">Multinational Impact of the 1968 Hong Kong Influenza Pandemic: Evidence for a Smoldering Pandemic<ref type="fn" target="#fn1"></ref></title><author xml:id="author-0000"><persName><surname>Viboud</surname><forename type="first">Cécile</forename></persName><affiliation><orgName type="institution">Fogarty International Center and</orgName></affiliation></author><author xml:id="author-0001"><persName><surname>Grais</surname><forename type="first">Rebecca F.</forename></persName><affiliation><orgName type="institution">Fogarty International Center and</orgName></affiliation></author><author xml:id="author-0002"><persName><surname>Lafont</surname><forename type="first">Bernard A. P.</forename></persName><affiliation><orgName type="institution">National Institute of Allergy and Infectious Diseases</orgName><address><addrLine>National Institutes of Health, Bethesda, Maryland</addrLine></address></affiliation></author><author xml:id="author-0003"><persName><surname>Miller</surname><forename type="first">Mark A.</forename></persName><affiliation><orgName type="institution">Fogarty International Center and</orgName></affiliation></author><author xml:id="author-0004"><persName><surname>Simonsen</surname><forename type="first">Lone</forename></persName><affiliation><orgName type="institution">National Institute of Allergy and Infectious Diseases</orgName><address><addrLine>National Institutes of Health, Bethesda, Maryland</addrLine></address></affiliation></author><idno type="istex">605E9544CC0719D70FAFC4ED721CBA613F72E7ED</idno><idno type="ark">ark:/67375/HXZ-MGDWGJB8-C</idno><idno type="DOI">10.1086/431150</idno></analytic><monogr><title level="j" type="main">The Journal of Infectious Diseases</title><title level="j" type="abbrev">The Journal of Infectious Diseases</title><idno type="hwp">jinfdis</idno><idno type="publisher-id">jid</idno><idno type="pISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><imprint><publisher>The University of Chicago Press</publisher><date when="2005-07-15">2005</date><biblScope unit="vol">192</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="233">233</biblScope><biblScope unit="page" to="248">248</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><encodingDesc><schemaRef type="ODD" url="https://xml-schema.delivery.istex.fr/tei-istex.odd"></schemaRef><appInfo><application ident="pub2tei" version="1.0.10" when="2019-12-09"><label>pub2TEI-ISTEX</label><desc>A set of style sheets for converting XML documents encoded in various scientific publisher formats into a common TEI format.
<ref target="http://www.tei-c.org/">We use TEI</ref></desc></application></appInfo></encodingDesc><profileDesc><abstract><p><hi rend="bold">Background</hi>The first pandemic season of A/H3N2 influenza virus (1968/1969) resulted in significant mortality in the United States, but it was the second pandemic season of A/H3N2 influenza virus (1969/1970) that caused the majority of deaths in England. We further explored the global pattern of mortality caused by the pandemic during this period</p><p><hi rend="bold">Methods</hi>We estimated the influenza-related excess mortality in 6 countries (United States, Canada, England and Wales, France, Japan, and Australia) using national vital statistics by age for 1967–1978. Geographical and temporal pandemic patterns in mortality were compared with the genetic drift of the influenza viruses by analyzing hemagglutinin and neuraminidase sequences from <ref type="uri" target="http://www.ncbi.nih.gov/GenBank/GenBankOverview.html">GenBank</ref></p><p><hi rend="bold">Results</hi>In North America, the majority of influenza-related deaths in 1968/1969 and 1969/1970 occurred during the first pandemic season (United States, 70%; Canada, 54%). Conversely, in Europe and Asia, the pattern was reversed: 70% of deaths occurred during the second pandemic season. The second pandemic season coincided with a drift in the neuraminidase antigen</p><p><hi rend="bold">Conclusion</hi>We found a consistent pattern of mortality being delayed until the second pandemic season of A/H3N2 circulation in Europe and Asia. We hypothesize that this phenomenon may be explained by higher preexisting neuraminidase immunity (from the A/H2N2 era) in Europe and Asia than in North America, combined with a subsequent drift in the neuraminidase antigen during 1969/1970</p></abstract><textClass ana="subject"><keywords scheme="heading"><term>Major Articles and Brief Reports</term></keywords></textClass><langUsage><language ident="EN"></language></langUsage></profileDesc><revisionDesc><change when="2019-12-09" who="#istex" xml:id="pub2tei">formatting</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/HXZ-MGDWGJB8-C/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup, element #text not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article">
<front>
<journal-meta>
<journal-id journal-id-type="hwp">jinfdis</journal-id>
<journal-id journal-id-type="publisher-id">jid</journal-id>
<journal-title>The Journal of Infectious Diseases</journal-title>
<abbrev-journal-title>The Journal of Infectious Diseases</abbrev-journal-title>
<issn pub-type="ppub">0022-1899</issn>
<issn pub-type="epub">1537-6613</issn>
<publisher>
<publisher-name>The University of Chicago Press</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.1086/431150</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Major Articles and Brief Reports</subject>
<subj-group subj-group-type="heading">
<subject>Viruses</subject>
<subj-group subj-group-type="heading">
<subject>Major Articles</subject>
</subj-group>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Multinational Impact of the 1968 Hong Kong Influenza Pandemic: Evidence for a Smoldering Pandemic<xref ref-type="fn" rid="fn1"></xref>
</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Viboud</surname>
<given-names>Cécile</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Grais</surname>
<given-names>Rebecca F.</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="fn" rid="fn2">a</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Lafont</surname>
<given-names>Bernard A. P.</given-names>
</name>
<xref ref-type="aff" rid="aff2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Miller</surname>
<given-names>Mark A.</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Simonsen</surname>
<given-names>Lone</given-names>
</name>
<xref ref-type="aff" rid="aff2">2</xref>
<author-comment><p>for the Multinational Influenza Seasonal Mortality Study Group</p></author-comment>
<xref ref-type="fn" rid="fn3">b</xref>
</contrib>
<aff id="aff1">
<label>1</label>Fogarty International Center and</aff>
<aff id="aff2">
<label>2</label>National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland</aff>
</contrib-group>
<author-notes>
<corresp id="cor1">Reprints or correspondence: Dr. Cécile Viboud, Fogarty International Center, National Institutes of Health, 16 Center Dr., Bethesda, MD 20892 (<email>viboudc@mail.nih.gov</email>)</corresp>
</author-notes>
<pub-date pub-type="ppub">
<day>15</day>
<month>7</month>
<year>2005</year>
</pub-date>
<volume>192</volume>
<issue>2</issue>
<fpage>233</fpage>
<lpage>248</lpage>
<history>
<date date-type="received">
<day>19</day>
<month>10</month>
<year>2004</year>
</date>
<date date-type="accepted">
<day>31</day>
<month>1</month>
<year>2005</year>
</date>
</history>
<copyright-year>2005</copyright-year>
<abstract>
<p>
<bold>Background</bold>The first pandemic season of A/H3N2 influenza virus (1968/1969) resulted in significant mortality in the United States, but it was the second pandemic season of A/H3N2 influenza virus (1969/1970) that caused the majority of deaths in England. We further explored the global pattern of mortality caused by the pandemic during this period</p>
<p>
<bold>Methods</bold>We estimated the influenza-related excess mortality in 6 countries (United States, Canada, England and Wales, France, Japan, and Australia) using national vital statistics by age for 1967–1978. Geographical and temporal pandemic patterns in mortality were compared with the genetic drift of the influenza viruses by analyzing hemagglutinin and neuraminidase sequences from <ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nih.gov/GenBank/GenBankOverview.html">GenBank</ext-link>
</p>
<p>
<bold>Results</bold>In North America, the majority of influenza-related deaths in 1968/1969 and 1969/1970 occurred during the first pandemic season (United States, 70%; Canada, 54%). Conversely, in Europe and Asia, the pattern was reversed: 70% of deaths occurred during the second pandemic season. The second pandemic season coincided with a drift in the neuraminidase antigen</p>
<p>
<bold>Conclusion</bold>We found a consistent pattern of mortality being delayed until the second pandemic season of A/H3N2 circulation in Europe and Asia. We hypothesize that this phenomenon may be explained by higher preexisting neuraminidase immunity (from the A/H2N2 era) in Europe and Asia than in North America, combined with a subsequent drift in the neuraminidase antigen during 1969/1970</p>
</abstract>
</article-meta>
</front>
<body>
<p>Annual influenza epidemics are sustained in the human population through gradual mutations in hemagglutinin and neuraminidase, the surface antigens of the virus. The genetic makeup of the influenza virus allows frequent minor drifts every 2–5 years in response to selection pressure to evade human immunity [<xref ref-type="bibr" rid="ref1">1</xref>]. Rarely, reassortment between human and nonhuman viruses results in larger shifts, in which a new virus subtype emerges and replaces the previously circulating one [<xref ref-type="bibr" rid="ref2">2</xref>]. A new pandemic virus rapidly invades the human population with partial or no immunity and may cause severe illness worldwide [<xref ref-type="bibr" rid="ref3">3</xref>, <xref ref-type="bibr" rid="ref4">4</xref>]. Although the impact of influenza is not always higher during pandemics than during interpandemic periods, a shift in the age distribution of mortality toward younger age groups distinguishes pandemic from epidemic impact [<xref ref-type="bibr" rid="ref5">5</xref>, <xref ref-type="bibr" rid="ref6">6</xref>]</p>
<p>The influenza virus responsible for the last pandemic, A/Hong Kong/68 (A/H3N2), was first isolated in Hong Kong in July 1968 [<xref ref-type="bibr" rid="ref7">7</xref>]. The new A/H3N2 virus exhibited a shift in hemagglutinin but not in neuraminidase; it replaced A/H2N2 viruses that had been circulating in all countries since 1957. Despite rapid and extensive spread by international air travel [<xref ref-type="bibr" rid="ref7">7</xref>, <xref ref-type="bibr" rid="ref8">8</xref>], the impact of the new virus was not the same in all geographical regions. A marked increase in mortality occurred in the United States during the first pandemic season (1968/1969), especially in persons <65 years old, but was not seen elsewhere [<xref ref-type="bibr" rid="ref7">7</xref>]. Conversely, in England, the second pandemic season (1969/1970) of A/H3N2 virus proved to be more severe than the first [<xref ref-type="bibr" rid="ref9">9</xref>, <xref ref-type="bibr" rid="ref10">10</xref>]</p>
<p>The reasons for the delayed severe impact in England are still not understood [<xref ref-type="bibr" rid="ref4">4</xref>, <xref ref-type="bibr" rid="ref11">11</xref>]. Such a delay is counterintuitive, since a novel virus introduced in a susceptible population should demonstrate decreasing impact over time as immunity increases [<xref ref-type="bibr" rid="ref9">9</xref>, <xref ref-type="bibr" rid="ref12">12</xref>]. Here, we analyze monthly mortality data on 6 countries (on 4 continents) and review published morbidity and virological studies to extend the current understanding of the Hong Kong A/H3N2 pandemic. To explain the epidemiological patterns, we investigate the genetic sequences of influenza surface antigens. Finally, we discuss the implications of these patterns for pandemic preparedness</p>
<sec id="S1">
<title>Methods</title>
<p>A detailed description of the data sources and analytic approach is given in the Appendix</p>
<sec id="SS1.1">
<title>Data Sources</title>
<p>
<bold>
<italic>Mortality and population data</italic>
</bold>Monthly age-specific data on pneumonia and influenza (P&I) and all-cause mortality were compiled from vital statistics on the United States, Canada, England and Wales (referred to as “England” for simplicity), France, Japan, and Australia for 1967–1979, which includes the 2 pandemic seasons, 1968/1969 and 1969/1970. No details on age were available for Japan. Before analysis, we calculated the monthly incidence per 100,000 persons for both mortality outcomes</p>
<p>
<bold>
<italic>Review of the literature for virological surveillance and morbidity data</italic>
</bold>We compiled literature reports, mostly from World Health Organization sources, to compare the date of the first isolation of the pandemic strain and the timing of the 2 pandemic seasons in each country [<xref ref-type="bibr" rid="ref13">13</xref>
<xref ref-type="bibr" rid="ref14"></xref>
<xref ref-type="bibr" rid="ref15"></xref>
<xref ref-type="bibr" rid="ref16"></xref>
<xref ref-type="bibr" rid="ref17"></xref>
<xref ref-type="bibr" rid="ref18"></xref>–<xref ref-type="bibr" rid="ref19">19</xref>] (<xref ref-type="fig" rid="Fig1">figure 1</xref>). To compare influenza morbidity patterns, we analyzed published weekly time series of influenza virological isolates and summary estimates of morbidity. We restricted the analysis to follow-up studies that covered both pandemic seasons [<xref ref-type="bibr" rid="ref9">9</xref>, <xref ref-type="bibr" rid="ref17">17</xref>, <xref ref-type="bibr" rid="ref20">20</xref>
<xref ref-type="bibr" rid="ref21"></xref>
<xref ref-type="bibr" rid="ref22"></xref>–<xref ref-type="bibr" rid="ref23">23</xref>]. We also searched the available published literature for general-population influenza seroepidemiological surveys that reported the prevalence of new influenza infections [<xref ref-type="bibr" rid="ref9">9</xref>, <xref ref-type="bibr" rid="ref20">20</xref>
<xref ref-type="bibr" rid="ref21"></xref>
<xref ref-type="bibr" rid="ref22"></xref>
<xref ref-type="bibr" rid="ref23"></xref>–<xref ref-type="bibr" rid="ref24">24</xref>]</p>
<p>
<bold>
<italic>Influenza genetic sequences</italic>
</bold>Temporal and/or geographical differences in the antigens of circulating viruses may explain intercountry differences in patterns of mortality. For viruses collected during 1966–1975, we analyzed all hemagglutinin and neuraminidase genetic sequences published in GenBank (<ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/GenBank/">http://www.ncbi.nlm.nih.gov/GenBank/</ext-link>) and in the Influenza Sequence Database (<ext-link ext-link-type="uri" xlink:href="http://www.flu.lanl.gov">http://www.flu.lanl.gov</ext-link>) [<xref ref-type="bibr" rid="ref25">25</xref>]. We chose this period in order to include strains that circulated just before the pandemic until the first major postpandemic antigenic change (A/Victoria/75) [<xref ref-type="bibr" rid="ref11">11</xref>]. We analyzed 38 sequences for the hemagglutinin H3 gene and 53 sequences for the neuraminidase N2 gene</p>
</sec>
<sec id="SS1.2">
<title>Analytic Approach</title>
<p>To evaluate the impact of the 2 pandemic seasons in the 6 countries, we calculated P&I and all-cause seasonal excess mortality and adjusted for age and nondemographic factors</p>
<p>
<bold>
<italic>Estimating P&I and all-cause seasonal excess mortality</italic>
</bold> P&I and all-cause seasonal excess mortality were computed for 2 age categories (all ages and <65 years old) as the increase in mortality above a seasonal baseline, during epidemic months, for both the 1968/1969 and the 1969/1970 pandemic seasons. We used a Serfling-type regression model [<xref ref-type="bibr" rid="ref26">26</xref>] and identified influenza epidemic months from the time series of deaths specifically attributed to influenza</p>
<p>We adjusted excess mortality using the mid-1969 population of England as the reference population, to account for differences in age structure between countries. To compensate for nondemographic differences (e.g., access to health care and coding for underlying cause of death [<xref ref-type="bibr" rid="ref27">27</xref>, <xref ref-type="bibr" rid="ref28">28</xref>]), we calculated the percentage increase in mortality as the excess mortality divided by the baseline mortality during winter (expected mortality) for both P&I and all-cause seasonal excess mortality. This measure was introduced by Serfling, for comparison of influenza mortality in different age groups [<xref ref-type="bibr" rid="ref29">29</xref>]</p>
<p>Exposure to influenza during the last A/H2N2 epidemic season (1967/1968) may have reduced the impact of the A/H3N2 pandemic by granting protection against neuraminidase [<xref ref-type="bibr" rid="ref3">3</xref>, <xref ref-type="bibr" rid="ref11">11</xref>]. We also analyzed the age-standardized excess mortality and corresponding percentage increase for this epidemic season</p>
<p>
<bold>
<italic>Proportion of deaths, illnesses, and infections during each pandemic season (1968/1969 and 1969/1970)</italic>
</bold>To estimate the relative mortality during each pandemic season, we summed the excess mortality for 1968/1969 and 1969/1970 and computed the proportion occurring during each pandemic season separately for each country. We compared the resulting estimates with those of previous studies of mortality [<xref ref-type="bibr" rid="ref5">5</xref>, <xref ref-type="bibr" rid="ref9">9</xref>, <xref ref-type="bibr" rid="ref24">24</xref>, <xref ref-type="bibr" rid="ref30">30</xref>
<xref ref-type="bibr" rid="ref31"></xref>
<xref ref-type="bibr" rid="ref32"></xref>
<xref ref-type="bibr" rid="ref33"></xref>
<xref ref-type="bibr" rid="ref34"></xref>–<xref ref-type="bibr" rid="ref35">35</xref>]. Similarly, we computed the proportion of clinical illnesses and infections identified by serologic tests during each pandemic season from the available published literature [<xref ref-type="bibr" rid="ref9">9</xref>, <xref ref-type="bibr" rid="ref17">17</xref>, <xref ref-type="bibr" rid="ref20">20</xref>
<xref ref-type="bibr" rid="ref21"></xref>
<xref ref-type="bibr" rid="ref22"></xref>
<xref ref-type="bibr" rid="ref23"></xref>–<xref ref-type="bibr" rid="ref24">24</xref>]</p>
</sec>
</sec>
<sec id="S2">
<title>Results</title>
<sec id="SS2.1">
<title>Timing of the First 2 A/H3N2 Pandemic Seasons</title>
<p>In most countries, the pandemic strain was isolated shortly after its appearance in Hong Kong in July 1968 (<xref ref-type="fig" rid="Fig1">figure 1</xref>), with several months of sporadic activity before the epidemic took off. There was no documented cocirculation of A/H3N2 and A/H2N2 viruses in the same geographical area; the last reported isolation of A/H2N2 was in August 1968 in Australia [<xref ref-type="bibr" rid="ref14">14</xref>, <xref ref-type="bibr" rid="ref36">36</xref>]</p>
</sec>
<sec id="SS2.2">
<title>Mortality</title>
<p>
<bold>
<italic>Epidemic pattern and impact of the first 2 A/H3N2 pandemic seasons (all ages)</italic>
</bold>The epidemic patterns of the 2 pandemic seasons were different in the 6 countries studied (<xref ref-type="fig" rid="Fig2">figure 2</xref>). The P&I mortality time series reveals a large epidemic in the United States in 1968/1969, followed by a milder one in 1969/1970, late in the winter season. In Canada, the 2 epidemic patterns were similar in amplitude and timing. In the other 4 countries, entirely different patterns emerged. The first epidemic was mild, followed by a much more intense epidemic the next season. Similar patterns were observed from all-cause mortality time series (data not shown)</p>
<p>Of the sum of P&I excess deaths that occurred during 1968/1969 and 1969/1970, in the United States, 70% occurred during the first pandemic season; in Canada, 54%; in Japan, 32%; in England, 23%; in Australia, 22%; and, in France, 15% (<xref ref-type="table" rid="tb1">table 1</xref>). The same trend was obtained for all-cause excess mortality, which supports a 1-year delay in the major impact in England, France, Japan, and Australia</p>
<p>Age standardization and computation of the percentage increase reduced but did not eliminate the intercountry differences in the sum of excess deaths that occurred during 1968/1969 and 1969/1970, for both P&I and all causes (<xref ref-type="table" rid="tb1">table 1</xref>). For instance, P&I excess mortality was 2–3-fold higher in England and France than elsewhere. All-cause excess mortality was 2–5-fold lower in North America than elsewhere, and the corresponding percentage increase remained lower, suggesting that the total pandemic mortality was substantially lower in North America than in other countries</p>
<p>
<bold>
<italic>Last epidemic season of the A/H2N2 era (1967/1968)</italic>
</bold> Similar intercountry differences were found for the last A/H2N2 epidemic season (<xref ref-type="table" rid="tb1">table 1</xref>). P&I excess mortality was 2–3-fold higher in England and France than elsewhere. All-cause excess mortality was lower in North America than in other countries. The percentage increase in P&I and all-cause mortality was consistently lower in North America than elsewhere, supporting a lower impact for the last A/H2N2 epidemic season in this region. Interestingly, in all countries, all-cause excess mortality during the last A/H2N2 epidemic season was greater than or equal to that during the major A/H3N2 pandemic season</p>
<p>
<bold>
<italic>Pandemic “age shift” and impact in persons <65 years old (1968/1969 and 1969/1970)</italic>
</bold>For all countries studied, the proportion of excess P&I mortality in persons <65 years old increased substantially (by 2.2–4.6-fold) during the first A/H3N2 pandemic season, compared with that during the last A/H2N2 epidemic season (<xref ref-type="table" rid="tb1">table 1</xref>). This signature age shift of a novel virus subtype, taken together with virus surveillance data that indicated exclusive A/H3N2 circulation, clearly supports pandemic virus activity in all countries throughout the first A/H3N2 season</p>
<p>Intercountry differences in the relative impact of each pandemic season reported for all ages also existed for persons <65 years old (<xref ref-type="table" rid="tb2">table 2</xref>). In this age group, the majority of P&I and all-cause mortality occurred during the first pandemic season in North America but during the second pandemic season in England, France, and Australia. Regarding the sum of deaths during the 2 pandemic seasons, all of our mortality measures showed a lower impact in North America in persons <65 years old than in Europe and Asia</p>
<p>
<bold>
<italic>Geographically distinct pandemic patterns</italic>
</bold>For the Hong Kong A/H3N2 pandemic, 2 geographically distinct mortality patterns emerged. The North American pattern (United States and Canada) was characterized by a first pandemic season that was more severe than the second, although, the impact of each pandemic season was more balanced in Canada than in the United States. There were minimal geographical variations in local pandemic patterns across the United States (Appendix). By contrast, local pandemic patterns were heterogeneous in Canada, which explains the more-balanced impact in the national analysis</p>
<p>The “smoldering” pattern in Europe and Asia (England, France, Japan, and Australia) was characterized by a second pandemic season 2–5 times more severe than the first. The last A/H2N2 epidemic season was less severe in North America than elsewhere</p>
</sec>
<sec id="SS2.3">
<title>Review of the Literature for Proportion of Deaths, Illnesses, and Infections during Each Pandemic Season (1968/1969 and 1969/1970)</title>
<p>On average, across all mortality studies, including the present one, in the United States, an estimated 70% of influenza-related deaths occurred during the first pandemic season; in Canada, 57%; in England, 30%; and, in Australia, 31% (<xref ref-type="table" rid="tb3">table 3</xref>). These studies gave fairly consistent estimates, although they did not use the same approach for estimating excess mortality. No study other than ours included France and Japan</p>
<p>Morbidity time-series analysis revealed a pattern similar to the mortality time series in the United States, England, and Australia, in terms of amplitude and timing (<xref ref-type="fig" rid="Fig3">figure 3<italic>A–</italic>3<italic>C</italic>
</xref>). In these 3 countries, the relative morbidity and mortality of each pandemic season were very close (<xref ref-type="table" rid="tb3">table 3</xref>), ruling out potential differences in case fatalities. In all countries, high morbidity was associated with high mortality</p>
<p>General-population seroepidemiological surveys reported that the majority of influenza infections occurred during the first pandemic season in the United States and Canada, closely matching the pattern of deaths and clinical illnesses (<xref ref-type="table" rid="tb3">table 3</xref>). Conversely, in England, patterns of serological infections were discordant with mortality and morbidity patterns. Infections during the first pandemic season were nearly as frequent as were those during the second pandemic season, whereas the large majority of deaths and clinical illnesses occurred during the second pandemic season. These discordances imply that asymptomatic (subclinical) infections were frequent during the first pandemic season in England. Similarly, in the other countries in Europe and Asia that were studied, high rates of asymptomatic infections during the first pandemic season were reported [<xref ref-type="bibr" rid="ref15">15</xref>, <xref ref-type="bibr" rid="ref17">17</xref>, <xref ref-type="bibr" rid="ref37">37</xref>]. From the combined analysis of mortality, morbidity, and serological studies, we concluded that asymptomatic infections were frequent during the first pandemic season in Europe and Asia and were less frequent in North America</p>
</sec>
<sec id="SS2.4">
<title>Phylogenetic Studies</title>
<p>We searched for temporal and/or geographical differences in the genes of influenza surface antigens. The hemagglutinin H3 gene sequences available from the 2 pandemic seasons clustered in a single group in the hemagglutinin tree (n=13 for 1968/1969–1969/1970) (<xref ref-type="fig" rid="FG1">figure 4<italic>A</italic>
</xref>). A drift in this gene appeared in 1971/1972, which was later than our period of interest. Taken together with the single antigenic cluster defined by Smith et al. for the hemagglutinin between July 1968 and late 1970 [<xref ref-type="bibr" rid="ref1">1</xref>], the single genetic cluster found here suggests that there was no significant evolution in this antigen during the 2 pandemic seasons</p>
<p>Phylogenetic analysis of the neuraminidase N2 gene highlighted similarities in this gene between late A/H2N2 and early A/H3N2 viruses (<xref ref-type="fig" rid="FG1">figure 4<italic>B</italic>
</xref>). The neuraminidase gene of A/H2N2 viruses from 1967/1968 formed 2 distinct clusters (clusters I and II in <xref ref-type="fig" rid="FG1">figure 4<italic>B</italic>
</xref>). The neuraminidase gene of A/H3N2 viruses from 1968/1969 formed a single cluster, genetically close to the A/H2N2 cluster I. Although few sequences were available for A/H3N2 viruses from 1969/1970, they all formed a distinct cluster comprising strains from England and Canada, genetically close to the A/H2N2 cluster II. For A/H3N2 viruses, the 1968/1969 genetic cluster differed from the 1969/1970 genetic cluster by 29 nt. The clusters were supported by bootstrap values >90%. The neuraminidase genes of more-recent A/H3N2 viruses were derived from the 1969/1970 genetic cluster. In addition, we predicted and compared the protein sequence of neuraminidase. Similar to the nucleotide analysis, the protein analysis revealed 2 distinct clusters for 1968/1969 and 1969/1970. The clusters differed by 11 amino acid changes, 3 of them located in characterized antigenic sites [<xref ref-type="bibr" rid="ref38">38</xref>]. These findings are in agreement with those of a recent study showing that neuraminidase had an increased rate of change immediately after the emergence of A/H3N2 viruses, compared with that during the more-recent interpandemic period [<xref ref-type="bibr" rid="ref38">38</xref>]. These results highlight temporal differences in the neuraminidases of influenza viruses circulating during the 2 pandemic seasons, whereas the hemagglutinins remained unchanged</p>
</sec>
</sec>
<sec id="S3">
<title>Discussion</title>
<p>The present study is based on data from 6 countries and demonstrates distinct differences in mortality patterns for the Hong Kong A/H3N2 pandemic. The United States and Canada displayed the expected pattern—high mortality during the first pandemic season (1968/1969), when the emerging virus first circulated, followed by a relatively mild second pandemic season (1969/1970). This pattern was observed only in North America. For the 4 other countries in Europe and Asia that were studied, we identified an opposite mortality pattern: more than two-thirds of all influenza-related deaths that occurred during 1968/1969–1969/1970 occurred during the second pandemic season. Although this smoldering pattern had previously been reported for England [<xref ref-type="bibr" rid="ref9">9</xref>], the present study is the first multinational study to carefully compare and quantify the mortality and temporal pattern of the Hong Kong A/H3N2 pandemic. Published mortality time series for at least 8 additional countries in Europe and elsewhere support the idea that the 1-year delay in mortality might be the most common experience in continents other than North America [<xref ref-type="bibr" rid="ref7">7</xref>, <xref ref-type="bibr" rid="ref31">31</xref>, <xref ref-type="bibr" rid="ref39">39</xref>
<xref ref-type="bibr" rid="ref40"></xref>–<xref ref-type="bibr" rid="ref41">41</xref>]</p>
<p>We next entertained a possible hypothesis to explain the unexpected smoldering pattern in Europe and Asia (<xref ref-type="fig" rid="Fig5">figure 5</xref>) that combines (1) the effect of geographical differences in preexisting immunity to neuraminidase at the time of emergence of A/H3N2 (remaining from the A/H2N2 era) and (2) the effect of genetic drift in the neuraminidase antigen during 1969/1970. Preexisting immunity to the neuraminidase N2 gene may have contributed to the differential impact of the first pandemic season in the 2 regions. It is believed that exposure to A/H2N2 viruses during 1967/1968 attenuated the impact of the 1968 pandemic [<xref ref-type="bibr" rid="ref3">3</xref>, <xref ref-type="bibr" rid="ref11">11</xref>]. A study showed that individuals infected by A/H2N2 during 1967/1968 were protected against influenza infection during the first A/H3N2 pandemic season, and infections in persons with prior antineuraminidase antibodies were more frequently asymptomatic, compared with those in persons without prior antineuraminidase antibodies [<xref ref-type="bibr" rid="ref20">20</xref>]</p>
<p>The smoldering pattern in Europe and Asia is consistent with high preexisting immunity to neuraminidase. The greater mortality of the last A/H2N2 epidemic season in this region suggests greater exposure to late A/H2N2 viruses (<xref ref-type="fig" rid="Fig5">figure 5</xref>). Hence, immunity to neuraminidase may have been greater in Europe and Asia during the fall of 1968, when the A/H3N2 virus started to circulate. Furthermore, the neuraminidase of late A/H2N2 viruses circulating in Europe and Asia may have been closer to that of early A/H3N2 viruses [<xref ref-type="bibr" rid="ref14">14</xref>, <xref ref-type="bibr" rid="ref16">16</xref>, <xref ref-type="bibr" rid="ref42">42</xref>]</p>
<p>A drift in the neuraminidase antigen found in our phylogenetic analysis coincided with the severe second A/H3N2 pandemic season in Europe and Asia (<xref ref-type="fig" rid="Fig5">figure 5</xref>). This analysis is in agreement with antigenic studies conducted by the World Influenza Center (London, UK) in Europe and Japan. In 1968/1969, influenza viruses were antigenically similar to the first A/H3N2 virus identified in Hong Kong, in both hemagglutinin and neuraminidase [<xref ref-type="bibr" rid="ref42">42</xref>, <xref ref-type="bibr" rid="ref43">43</xref>]. In 1969/1970, the neuraminidase antigen had changed, but the hemagglutinin antigen had not [<xref ref-type="bibr" rid="ref41">41</xref>
<xref ref-type="bibr" rid="ref42"></xref>–<xref ref-type="bibr" rid="ref43">43</xref>]. Accordingly, Lindstrom et al. recently found that 2 distinct neuraminidase lineages circulated during 1968/1969 and 1969/1970 and hypothesized that such genetic diversity could be due to multiple reassortments with A/H2N2 viruses [<xref ref-type="bibr" rid="ref38">38</xref>]</p>
<p>We were unfortunately unable to study geographical heterogeneity in the neuraminidase gene, since very few North American viral sequences from 1968/1969 to 1969/1970 were available in the public domain. Rapid fluxes in international populations [<xref ref-type="bibr" rid="ref8">8</xref>] and the available sequences would suggest that the same viruses circulated in North America and in Europe and Asia</p>
<p>Assuming that the same viruses circulated in all continents studied, differences in prior immunity followed by a drift in the neuraminidase antigen could explain the intercountry differences in mortality patterns. What sets North America apart epidemiologically is the severity of the first pandemic season, which included frequent influenza illness and death (<xref ref-type="fig" rid="Fig5">figure 5</xref>). Hence, at the end of the first pandemic season, a substantial proportion of the North American population had antibodies to the novel hemagglutinin H3 gene. Since the hemagglutinin did not change between the 2 pandemic seasons, these antibodies would have protected this population during the second pandemic season</p>
<p>One of the other factors we considered was immunity to the hemagglutinin H3 gene in the very elderly, which remained from childhood exposure to H3-like viruses before 1892 [<xref ref-type="bibr" rid="ref10">10</xref>, <xref ref-type="bibr" rid="ref32">32</xref>, <xref ref-type="bibr" rid="ref44">44</xref>
<xref ref-type="bibr" rid="ref45"></xref>–<xref ref-type="bibr" rid="ref46">46</xref>]. However, such immunity would not account for the intercountry differences in mortality found in persons <65 years old. Furthermore, influenza vaccination coverage was too limited during this time to explain these differences [<xref ref-type="bibr" rid="ref9">9</xref>]. Finally, environmental differences and weather could have played a role—but this explanation is unlikely, given the geographical heterogeneity of the countries studied [<xref ref-type="bibr" rid="ref47">47</xref>]. The A/H3N2 pandemic strain appeared early during the winter season in all countries. Certainly, weather did not hamper the full potential for causing widespread epidemics and mortality in every country during the 1968/1969 pandemic season</p>
<p>Despite the geographical differences in the timing of the major mortality, the A/H3N2 pandemic was relatively mild in all countries, compared with surrounding severe epidemics [<xref ref-type="bibr" rid="ref48">48</xref>], including the last A/H2N2 epidemic season. The mildness of the 1968 pandemic is perhaps not entirely unexpected, considering preexisting immunity to the neuraminidase antigen in all age groups [<xref ref-type="bibr" rid="ref3">3</xref>, <xref ref-type="bibr" rid="ref11">11</xref>] and to the hemagglutinin antigen in the elderly [<xref ref-type="bibr" rid="ref10">10</xref>, <xref ref-type="bibr" rid="ref32">32</xref>, <xref ref-type="bibr" rid="ref44">44</xref>
<xref ref-type="bibr" rid="ref45"></xref>–<xref ref-type="bibr" rid="ref46">46</xref>]</p>
<p>It has been reported that, for the 1950s and 1960s, both P&I excess mortality and all-cause crude excess mortality (unadjusted) were systematically 2–3-fold higher in Europe than in North America [<xref ref-type="bibr" rid="ref27">27</xref>, <xref ref-type="bibr" rid="ref28">28</xref>, <xref ref-type="bibr" rid="ref31">31</xref>]. Adjusting for differences in age structure and mortality outside influenza periods (data not shown) reduced but did not eliminate these differences. Therefore, we studied the percentage increase in mortality above the winter baseline, which further reduced intercountry differences [<xref ref-type="bibr" rid="ref29">29</xref>]. A more thorough investigation of the intercountry differences in absolute mortality was beyond the scope of the present study; factors such as population density, demographics, climate, country size, and health care systems could affect influenza transmission and disease outcome and, in turn, mortality [<xref ref-type="bibr" rid="ref27">27</xref>, <xref ref-type="bibr" rid="ref28">28</xref>, <xref ref-type="bibr" rid="ref31">31</xref>, <xref ref-type="bibr" rid="ref49">49</xref>]. In the present study, the smoldering pattern relies on the unbiased comparison of the relative impact of each pandemic season</p>
<p>The present study was based on analysis of both P&I (as an underlying cause of death) and all-cause mortality. Analysis of P&I data could potentially have been biased as a result of intercountry differences in coding of the underlying cause of death and the transition to a new system of classification of deaths around 1968 (Appendix). However, because our analysis of all-cause mortality data was not affected by such possible bias and because it produced similar results in terms of temporal and geographical differences in patterns, nosological bias was not an issue in the present study</p>
<p>Another limitation of the present study was the poor temporal and geographical resolution of influenza genetic sequences from this pandemic, both in terms of the overall number of sequences and the lack of systematic sampling (outliers were preferentially sequenced [<xref ref-type="bibr" rid="ref1">1</xref>]). This bias tends to preclude the use of phylogenetic studies to derive the epidemiological importance of each strain. However, in this work, analyses at the amino acid level and antigenic studies support the significance of the drift in the neuraminidase antigen [<xref ref-type="bibr" rid="ref38">38</xref>, <xref ref-type="bibr" rid="ref41">41</xref>
<xref ref-type="bibr" rid="ref42"></xref>–<xref ref-type="bibr" rid="ref43">43</xref>]</p>
<p>Why should we care about studying the geographical and temporal impact of pandemic influenza? The pattern in Europe and Asia during the 1968/1969–1969/1970 period suggests a possible favorable opportunity for pandemic response should a future pandemic be like the one in 1968. The smoldering first pandemic season observed in 4 of the 6 countries suggests that a pandemic vaccine available 1 year after the emergence of the new subtype could have prevented the majority of deaths and illnesses associated with the emerging pandemic strain. The exact role that neuraminidase played in driving the mortality of the 1968 pandemic remains to be confirmed, but it seems that the 1968 pattern, unique in its conservation of the neuraminidase antigen, allowed ample time to produce and distribute a pandemic vaccine. In the meantime, vaccination targeted against neuraminidase could be complementary to treatment and prophylaxis by antiviral agents, which would probably be available in short supply in most countries during a pandemic situation [<xref ref-type="bibr" rid="ref50">50</xref>]. Unfortunately, given our limited experience with pandemic influenza—only 3 pandemics occurred during the 20th century—our ability to predict the likelihood of a 1968-like pandemic in the future is quite limited</p>
</sec>
<sec id="S4">
<title>Multinational Influenza Seasonal Mortality Study (MISMS) Group</title>
<p>MISMS group members (other than the authors already listed) are as follows: J. Dushoff (Princeton University, Princeton), D. M. Fleming (Birmingham Research Unit of the Royal College of General Practitioners, Birmingham, UK), A. W. Hampson (World Health Organization Collaborating Centre for Reference and Research on Influenza, Melbourne, Australia), N. Sugaya (Keiyu Hospital, Yokohama, Japan), T. W. Tam (Health Canada, Ottawa, Canada), A. J. Valleron (Institut National de la Santé et de la Recherche Médicale, Paris, France), and J. Watkins (University of Wales College of Medicine, Cardiff, UK)</p>
</sec>
</body>
<back>
<ack>
<title>Acknowledgments</title>
<p>We thank O. T. Bjørnstad, B. T. Grenfell, D. L. Smith, F. E. McKenzie, and J. Dushoff for fruitful discussions on this study</p>
</ack>
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<title>Figures and Tables</title>
<fig id="Fig1" position="float">
<label>Figure 1</label>
<caption>
<p>Timing of the first 2 pandemic seasons of A/H3N2 influenza virus in 6 countries. Shown are isolation, sporadic, and epidemic activities, as defined by virus surveillance reports [<xref ref-type="bibr" rid="ref13">13</xref>
<xref ref-type="bibr" rid="ref14"></xref>
<xref ref-type="bibr" rid="ref15"></xref>
<xref ref-type="bibr" rid="ref16"></xref>
<xref ref-type="bibr" rid="ref17"></xref>
<xref ref-type="bibr" rid="ref18"></xref>–<xref ref-type="bibr" rid="ref19">19</xref>]</p>
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<graphic mimetype="image" xlink:href="192-2-233-fig001.tif"></graphic>
</fig>
<fig id="Fig2" position="float">
<label>Figure 2</label>
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<p>Influenza epidemic mortality curves for the first 2 pandemic seasons of A/H3N2 virus in 6 countries. Pneumonia and influenza (P&I) monthly mortality time series/100,000 persons are represented for the United States, England and Wales, Canada, France, Japan, and Australia. Note the geographical differences in the relative mortality of each pandemic season. First pandemic season, 1968/1969; second pandemic season, 1969/1970. In Australia, the first pandemic season was in 1969, and the second pandemic season was in 1970 (<xref ref-type="fig" rid="Fig1">figure 1</xref>)</p>
</caption>
<graphic mimetype="image" xlink:href="192-2-233-fig002.tif"></graphic>
</fig>
<fig id="Fig3" position="float">
<label>Figure 3</label>
<caption>
<p>Influenza epidemic morbidity curves for the first 2 pandemic seasons of A/H3N2 virus. <italic>A</italic> Weekly no. of influenza A isolates in England [<xref ref-type="bibr" rid="ref9">9</xref>]. <italic>B</italic> Weekly no. of influenza-like illnesses (ILIs) in Michigan [<xref ref-type="bibr" rid="ref20">20</xref>
<xref ref-type="bibr" rid="ref21"></xref>
<xref ref-type="bibr" rid="ref22"></xref>–<xref ref-type="bibr" rid="ref23">23</xref>]. <italic>C</italic> Weekly no. of influenza A isolates in New South Wales, Australia [<xref ref-type="bibr" rid="ref17">17</xref>]</p>
</caption>
<graphic mimetype="image" xlink:href="192-2-233-fig003.tif"></graphic>
</fig>
<fig-group id="FG1">
<fig id="Fig4" position="float">
<label>Figure 4</label>
<caption>
<p>Phylogenetic relationships of the hemagglutinin H3 gene (1968–75) <italic>(A)</italic> and the neuraminidase N2 gene (1967–72) <italic>(B)</italic> of influenza virus. For the hemagglutinin gene, black dots indicate the antigenic clusters <italic>(A)</italic> as defined elsewhere [<xref ref-type="bibr" rid="ref1">1</xref>]. For the neuraminidase gene, black dots denote the genetic clusters corresponding to the 1968/1969 and 1969/1970 sequences <italic>(B);</italic> clusters were supported by bootstrap values >90%. Braces indicate earlier or later clusters. Italic font indicates neuraminidase genes from A/H2N2 viruses; boldface font indicates neuraminidase genes from A/H3N2 viruses. Hemagglutinin and neuraminidase sequences (nt 49–960 and 1–1310, respectively) were aligned by use of the Clustal W program of MacVector (version 7.2.2). Phylogenetic analysis was performed by use of the neighbor-joining method, with Kimura’s 2-parameter distance (1000 bootstrap replicates). A/Hong-Kong/1/68 was used as the root for the hemagglutinin tree, and A/Singapore/1/57 was used as the root for the neuraminidase tree. The first A/H3N2 virus isolated was A/Hong Kong/1/68</p>
</caption>
<graphic mimetype="image" xlink:href="192-2-233-fig004.tif"></graphic>
<graphic mimetype="image" xlink:href="192-2-233-fig005.tif"></graphic>
</fig>
</fig-group>
<fig id="Fig5" position="float">
<label>Figure 5</label>
<caption>
<p>Hypotheses for explaining the differences in influenza pandemic patterns between Europe and Asia and North America. The genetic evolution of hemagglutinin and neuraminidase are indicated from the first pandemic season of A/H2N2 viruses (1957/1958) to the second pandemic season of A/H3N2 viruses (1969/1970). * and †, successive drifts; •, virus circulation and impact in each region (•, low; ••, high)</p>
</caption>
<graphic mimetype="image" xlink:href="192-2-233-fig006.tif"></graphic>
</fig>
<fig id="tb1" position="float">
<label>Table 1</label>
<caption>
<p>Influenza mortality impact of the last A/H2N2 epidemic season and the first 2 A/H3N2 pandemic seasons</p>
</caption>
<graphic mimetype="image" xlink:href="192-2-233-tab001.tif"></graphic>
</fig>
<fig id="tb2" position="float">
<label>Table 2</label>
<caption>
<p>Influenza mortality of the first 2 A/H3N2 pandemic seasons in persons <65 years old</p>
</caption>
<graphic mimetype="image" xlink:href="192-2-233-tab002.tif"></graphic>
</fig>
<fig id="tb3" position="float">
<label>Table 3</label>
<caption>
<p>Relative impact of the first 2 influenza A/H3N2 pandemic seasons on mortality, morbidity, and serological infections in the United States, Canada, England, and Australia</p>
</caption>
<graphic mimetype="image" xlink:href="192-2-233-tab003.tif"></graphic>
</fig>
<fig id="tb4" position="float">
<label>Table A1</label>
<caption>
<p>Average intercountry differences in age-adjusted excess mortality related to influenza</p>
</caption>
<graphic mimetype="image" xlink:href="192-2-233-tab004.tif"></graphic>
</fig>
<fig id="tb5" position="float">
<label>Table A2</label>
<caption>
<p>Change in summer pneumonia and influenza (P&I) mortality at the transition of International Classification of Diseases (ICD) and in later years, by country (1967–1978)</p>
</caption>
<graphic mimetype="image" xlink:href="192-2-233-tab005.tif"></graphic>
</fig>
</sec>
<fn-group>
<fn id="fn1">
<p>Financial support: National Institutes of Health</p>
</fn>
<fn id="fn2">
<p>R.F.G. is under contract to Fogarty International Center</p>
</fn>
<fn id="fn3">
<p>Study group members are listed <xref ref-type="sec" rid="S4">after the text</xref>
</p>
</fn>
</fn-group>
</back>
</article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Multinational Impact of the 1968 Hong Kong Influenza Pandemic: Evidence for a Smoldering Pandemic</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Multinational Impact of the 1968 Hong Kong Influenza Pandemic: Evidence for a Smoldering Pandemic</title></titleInfo><name type="personal"><namePart type="given">Cécile</namePart><namePart type="family">Viboud</namePart><affiliation>Fogarty International Center and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Rebecca F.</namePart><namePart type="family">Grais</namePart><affiliation>Fogarty International Center and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Bernard A. P.</namePart><namePart type="family">Lafont</namePart><affiliation>National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mark A.</namePart><namePart type="family">Miller</namePart><affiliation>Fogarty International Center and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Lone</namePart><namePart type="family">Simonsen</namePart><affiliation>National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland</affiliation><description>for the Multinational Influenza Seasonal Mortality Study Group</description><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>The University of Chicago Press</publisher><dateIssued encoding="w3cdtf">2005-07-15</dateIssued><dateCreated encoding="w3cdtf">2005-01-31</dateCreated><copyrightDate encoding="w3cdtf">2005</copyrightDate></originInfo><abstract>BackgroundThe first pandemic season of A/H3N2 influenza virus (1968/1969) resulted in significant mortality in the United States, but it was the second pandemic season of A/H3N2 influenza virus (1969/1970) that caused the majority of deaths in England. We further explored the global pattern of mortality caused by the pandemic during this period MethodsWe estimated the influenza-related excess mortality in 6 countries (United States, Canada, England and Wales, France, Japan, and Australia) using national vital statistics by age for 1967–1978. Geographical and temporal pandemic patterns in mortality were compared with the genetic drift of the influenza viruses by analyzing hemagglutinin and neuraminidase sequences from GenBank ResultsIn North America, the majority of influenza-related deaths in 1968/1969 and 1969/1970 occurred during the first pandemic season (United States, 70%; Canada, 54%). Conversely, in Europe and Asia, the pattern was reversed: 70% of deaths occurred during the second pandemic season. The second pandemic season coincided with a drift in the neuraminidase antigen ConclusionWe found a consistent pattern of mortality being delayed until the second pandemic season of A/H3N2 circulation in Europe and Asia. 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