Prior H1N1 Influenza Infection and Susceptibility of Cleveland Family Study Participants during the H2N2 Pandemic of 1957: An Experiment of Nature
Identifieur interne : 000255 ( Istex/Corpus ); précédent : 000254; suivant : 000256Prior H1N1 Influenza Infection and Susceptibility of Cleveland Family Study Participants during the H2N2 Pandemic of 1957: An Experiment of Nature
Auteurs : Suzanne L. EpsteinSource :
- The Journal of Infectious Diseases [ 0022-1899 ] ; 2006.
Abstract
During a pandemic, influenza vaccines that rely on neutralizing antibodies to protect against matched viruses might not be available early enough. Much broader (heterosubtypic) immune protection is seen in animals. Do humans also have cross-subtype immunity? To investigate this issue, archival records from the Cleveland Family Study, which was conducted before and during the 1957 pandemic (during which a shift from subtype H1N1 to H2N2 occurred), were analyzed. Only 5.6% of the adults who had had symptomatic influenza A in earlier study years developed influenza during the pandemic, despite living in households with participants who had influenza. In contrast, 55.2% of the children who had had symptomatic influenza A contracted it again. These findings suggest an impact of accumulated heterosubtypic immunity during a pandemic. Such immunity, as well as its implications for vaccination, should be further investigated
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DOI: 10.1086/498980
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Epstein</name><affiliation><mods:affiliation>Laboratory of Immunology and Developmental Biology, Division of Cellular and Gene Therapies, Office of Cellular, Tissue, and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, 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="2006-01-01">2006</date><biblScope unit="vol">193</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="49">49</biblScope><biblScope unit="page" to="53">53</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">During a pandemic, influenza vaccines that rely on neutralizing antibodies to protect against matched viruses might not be available early enough. Much broader (heterosubtypic) immune protection is seen in animals. Do humans also have cross-subtype immunity? To investigate this issue, archival records from the Cleveland Family Study, which was conducted before and during the 1957 pandemic (during which a shift from subtype H1N1 to H2N2 occurred), were analyzed. Only 5.6% of the adults who had had symptomatic influenza A in earlier study years developed influenza during the pandemic, despite living in households with participants who had influenza. In contrast, 55.2% of the children who had had symptomatic influenza A contracted it again. These findings suggest an impact of accumulated heterosubtypic immunity during a pandemic. 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Only 5.6% of the adults who had had symptomatic influenza A in earlier study years developed influenza during the pandemic, despite living in households with participants who had influenza. In contrast, 55.2% of the children who had had symptomatic influenza A contracted it again. These findings suggest an impact of accumulated heterosubtypic immunity during a pandemic. 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<article-title>Prior H1N1 Influenza Infection and Susceptibility of Cleveland Family Study Participants during the H2N2 Pandemic of 1957: An Experiment of Nature<xref ref-type="fn" rid="fn1"></xref>
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<surname>Epstein</surname>
<given-names>Suzanne L.</given-names>
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<aff>Laboratory of Immunology and Developmental Biology, Division of Cellular and Gene Therapies, Office of Cellular, Tissue, and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland</aff>
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<corresp id="cor1">Reprints or correspondence: Dr. Suzanne L. Epstein, FDA, CBER, OCTGT, DCGT, 1401 Rockville Pike, HFM-730, Rockville, MD 20852-1448 (<email>epsteins@cber.fda.gov</email>)</corresp>
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<day>15</day>
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<day>20</day>
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<copyright-year>2006</copyright-year>
<abstract>
<p>During a pandemic, influenza vaccines that rely on neutralizing antibodies to protect against matched viruses might not be available early enough. Much broader (heterosubtypic) immune protection is seen in animals. Do humans also have cross-subtype immunity? To investigate this issue, archival records from the Cleveland Family Study, which was conducted before and during the 1957 pandemic (during which a shift from subtype H1N1 to H2N2 occurred), were analyzed. Only 5.6% of the adults who had had symptomatic influenza A in earlier study years developed influenza during the pandemic, despite living in households with participants who had influenza. In contrast, 55.2% of the children who had had symptomatic influenza A contracted it again. These findings suggest an impact of accumulated heterosubtypic immunity during a pandemic. Such immunity, as well as its implications for vaccination, should be further investigated</p>
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<p>Influenza vaccination is problematic, because the virus evolves rapidly and antigens differ between virus strains. In animals, exposure to influenza A virus of one subtype can induce immunity that is protective against challenge with other subtypes (termed “heterosubtypic immunity” or “cross-protection”). Vaccination with conserved antigens can also induce this kind of immunity, which does not completely prevent infection but limits viral replication and accelerates clearance. Heterosubtypic immunity reduces viral titers and prevents mortality in mice (reviewed in [<xref ref-type="bibr" rid="ref1">1</xref>]) and chickens [<xref ref-type="bibr" rid="ref2">2</xref>]; it also reduces titers of shed virus during nonlethal infection of ferrets [<xref ref-type="bibr" rid="ref3">3</xref>] and pigs [<xref ref-type="bibr" rid="ref4">4</xref>]. The protection conferred can be long lasting</p>
<p>Can immunity to conserved antigens provide a basis for human vaccination? Human immunity to influenza A virus is often considered to be subtype specific [<xref ref-type="bibr" rid="ref5">5</xref>], as would be expected for neutralizing antibody (hereafter, “influenza” will be used in this report to refer to influenza A, except for the mention of influenza B in <xref ref-type="fig" rid="tb1">table 1</xref>). There is some evidence of human heterosubtypic immunity [<xref ref-type="bibr" rid="ref7">7</xref>], but it is considered to be weak and has not been investigated thoroughly. In a clinical study of live attenuated vaccines, prior infection did not interfere with infection by virus of a differing subtype [<xref ref-type="bibr" rid="ref8">8</xref>]. Although this was interpreted as indicating a lack of cross-protection in humans, the participants were children <3 years old</p>
<p>In animals, live influenza virus infection generally induces more potent immune cross-protection than do vaccines. Thus, evidence of such immunity in humans could potentially be found in the impact that infection with one subtype would have on subsequent susceptibility to infection with another subtype. Most informative would be a pandemic in which both hemagglutinin (HA) and neuraminidase shifted. This occurred in 1957, with a shift from H1N1 to H2N2. One Russian study, by Slepushkin, suggested that recent infection conferred partial protection during the 1957 pandemic [<xref ref-type="bibr" rid="ref9">9</xref>], but the study was based on symptom reporting, not laboratory-confirmed influenza</p>
<p>If laboratory confirmations of influenza in the same population before and during a pandemic were available, with data individually identified to link histories and outcomes, it would be possible to look for evidence of cross-protection. Such data were collected in the Cleveland Family Study, but they were not examined at the time for evidence of cross-protection (W. S. Jordan, personal communication); animal studies of heterosubtypic immunity had not yet been conducted (they began in the 1960s [<xref ref-type="bibr" rid="ref10">10</xref>]). To evaluate the possible impact of heterosubtypic immunity during a pandemic, I conducted a study using archival records from the Cleveland Family Study</p>
<p>
<bold>
<italic>Participants, materials, and methods</italic>
</bold>Individual archival case records were examined at the Stanley A. Ferguson Archives of University Hospitals of Cleveland (UHC), under a protocol approved by the Food and Drug Administration Research Involving Human Subjects Committee and the Institutional Review Board of UHC. Consent of the patients was obtained during the original study. For statistical analysis, comparisons of tabulated data were performed by the χ<sup>2</sup> test and Fisher’s exact test, using SigmaStat software (version 3.0; Systat Software)</p>
<p>
<bold>
<italic>Results</italic>
</bold>The Cleveland Family Study was an active surveillance study conducted at what was then Western Reserve University. For the study, illnesses of members of ∼60 families were monitored from 1947 to 1957. The design called for the inclusion of young couples with children and, thus, did not incorporate the elderly</p>
<p>The planned 10 years of observation were completed in the spring of 1957. When an outbreak of a new influenza strain in Asia was reported in May 1957, plans were made to extend the study. The study was reactivated by September, just in time to capture information as the pandemic swept through Cleveland [<xref ref-type="bibr" rid="ref11">11</xref>]. From late September to late November, detailed observations were made and specimens (throat swabs and sera) again were collected for testing. There were no deaths in the study population</p>
<p>Influenza was, of course, more common during the pandemic than it had been during earlier epidemics (<xref ref-type="fig" rid="tb1">table 1</xref>). Case-report forms for virus isolation–positive participants were found in the archives for 1950, 1951, 1953, and 1957, the years in which influenza epidemics occurred in Cleveland, and were confirmed to represent virtually all influenza case reports for those years (<xref ref-type="fig" rid="tb2">table 2</xref>) [<xref ref-type="bibr" rid="ref6">6</xref>, <xref ref-type="bibr" rid="ref11">11</xref>]. A difference in influenza frequency by age was noted at the time (<xref ref-type="fig" rid="tb1">table 1</xref>) [<xref ref-type="bibr" rid="ref11">11</xref>]. In prepandemic years, the numbers of cases were small, and differences between adults and children were not significant. In 1957, children were, on a percentage basis, 3-fold more likely to contract influenza than were adults, a highly significant difference (P<.001, χ<sup>2</sup> test). <xref ref-type="fig" rid="Fig1">Figure 1</xref> is based on case-report forms and illustrates the intense pandemic wave and the bimodal age distribution in the study population</p>
<p>The design of the Cleveland Family Study called for intensive active surveillance, with mothers keeping diaries of any symptoms for each family member and reporting new illnesses by telephone at onset. Relevant to influenza ascertainment, a physician examined anyone with respiratory symptoms and obtained pharyngeal specimens for virus isolation</p>
<p>For the present analysis, entry and dropout dates were found and used to identify participating families who were monitored throughout the period from 1950 to 1957, to avoid false negatives. Of the 42 families meeting this criterion, only 2 were untouched by influenza in all years. (Three children in included families dropped out before 1957 and so were excluded.) Within this monitored population, participants with culture-proven influenza in 1950, 1951, or 1953 were further examined for influenza in 1957. The relationship between prior infection and susceptibility in 1957 is shown in the rows of <xref ref-type="fig" rid="tb3">table 3</xref> in boldface. Although many of the children who had had influenza in earlier study years were infected again in 1957 (16/29 [55.2%]), the adults with a history of influenza almost never were (1/18 [5.6%]). With respect to the apparent protective effect of prior infection, the adults differed dramatically from the children (P=.002, χ<sup>2</sup> test)</p>
<p>Exposure was widespread during such an intense outbreak, but did the adults with apparent protection escape exposure simply by chance? Of these 17 adults, all lived with schoolchildren, and 12 lived in households with 1 or more participants with culture-proven influenza during the pandemic. Anecdotally, the sole adult with apparent failure of protection lived in a household in which both adults and all 4 children became infected</p>
<p>Data were also compared for participants who did not have influenza in earlier study years (shown in the rows of <xref ref-type="fig" rid="tb3">table 3</xref> not in boldface). The adults who had not been infected in earlier study years were ∼3-fold more susceptible than those who had been infected (16.7% vs. 5.6%), which is in agreement with Slepushkin’s symptom reporting–based findings [<xref ref-type="bibr" rid="ref9">9</xref>]. Among children, the 2 groups were similar (52.0% vs. 55.2%). The trend observed in adults is not statistically significant, but the total number of study adults with influenza in 1957 was low, which could in itself reflect immunity. It is likely that none of the study adults were truly naive to influenza; no data on either infections before 1950 or subclinical infections are available</p>
<p>Some participants (both adults and children) were given a vaccine of unknown efficacy late during the pandemic, and, despite an extensive search, records indicating which participants received vaccine were not found. Analysis of the expected versus the observed number of cases, done at the time of the original study on the basis of person-days of exposure [<xref ref-type="bibr" rid="ref11">11</xref>], showed that a reduction of only 7 cases could be attributed to vaccination. Even if it is assumed that all 7 cases occurred in adults in the group who were apparently protected and, therefore, are removed, the difference in the effect of prior infection between adults and children remains highly significant (P=.012, Fisher’s exact test). Note also that, among the total Cleveland Family Study population, 24% of vaccinated adults had influenza in 1957, whereas 18.5% of unvaccinated adults did [<xref ref-type="bibr" rid="ref11">11</xref>]. Thus, vaccination cannot account for the findings of the present analysis</p>
<p>Could the lower susceptibility of adults be attributed to preexisting antibodies to H2N2? On the basis of serological testing of elderly adults, the virus that circulated in humans in 1889–1890 was suggested to have been H2N2 [<xref ref-type="bibr" rid="ref12">12</xref>], but more-recent evidence points to H3N2 [<xref ref-type="bibr" rid="ref13">13</xref>, <xref ref-type="bibr" rid="ref14">14</xref>]. Regardless, all of the parents in the Cleveland Family Study were too young for the 1889–1890 outbreak; the oldest adult was born in 1905 [<xref ref-type="bibr" rid="ref15">15</xref>]. Also, participant serum samples collected before the pandemic were tested and were found to react with the 1957 H2N2 virus either marginally or, in almost all cases, not at all [<xref ref-type="bibr" rid="ref11">11</xref>]</p>
<p>With regard to the possibility that influenza was transmitted to adults by family members, to search for clues, the sequence and timing of cases in 1957 was examined within each monitored family. Among 10 families, 11 cases occurred in adults after other cases had occurred in the family. For 10 of these cases, the dates of onset were 1–6 days after the onset of a prior case in the family; for 1 case, the onset interval was 9 days. Only 1 adult had the first case in a family</p>
<p>In the present analysis, the children with prior influenza who contracted it again in 1957 and the children with prior influenza who did not were compared in additional ways. The mean number of siblings was not significantly different between the 2 groups. There was a trend toward children who did not contract influenza again in 1957 being slightly older than those who did, but this difference was not statistically significant</p>
<p>With regard to cumulative effects, only 1 participant (an adult) had 2 symptomatic cases of influenza during 1950–1953. This likely was a result of the similarity of HAs during a short H1N1 period. Even children were apparently protected against repeat infections in the prepandemic years by antibody to H1N1. Other infections that might have contributed to a cumulative effect in adults would have occurred before study initiation</p>
<p>
<bold>
<italic>Discussion</italic>
</bold>The age difference in influenza frequency in 1957 was noted by the Cleveland Family Study investigators, who suggested that “unknown factors … apart from possession of antibody” influenced rates of infection [<xref ref-type="bibr" rid="ref11">11</xref>, p. 210]. Given the findings of animal studies that have been conducted since 1965, the unknown factors could be immunity to viral epitopes that are conserved among subtypes. Possibilities include immune protection mediated by T cells [<xref ref-type="bibr" rid="ref2">2</xref>, <xref ref-type="bibr" rid="ref16">16</xref>] and/or mucosal antibody [<xref ref-type="bibr" rid="ref17">17</xref>]. Immunological maturation and/or a need for multiple exposures to establish a sufficiently potent immunological response and sufficient immunological memory could explain the age difference. The adults had decades to accumulate exposures, some of them resulting in asymptomatic infection</p>
<p>Other explanations can be considered for the difference between adults and children. School outbreaks are common, and the high exposure of children has been proposed as an explanation for their high rates of illness, including in 1957. Indeed, children are often the vectors that introduce influenza into a household, and, among the overall adult population, many do not come into contact with children acting as vectors. However, without exception the adults in the Cleveland Family Study lived in households with school-age children, and, in 1957, most lived in households with participants who had culture-proven influenza. Thus, the exposure of the adults in the study population was considerable</p>
<p>Transmission of influenza within families is demonstrated by several lines of evidence. Vaccination of children reduces cases in their parents [<xref ref-type="bibr" rid="ref18">18</xref>], and treatment of 1 family member with antiviral drugs reduces additional cases in the family [<xref ref-type="bibr" rid="ref19">19</xref>]. In a study of viral sequences, HA1 domain sequences of the HA gene differed among families in a community but were identical within each family [<xref ref-type="bibr" rid="ref20">20</xref>]. In the monitored Cleveland Family Study population, the high attack rate in children 0–4 years old, who would not have been in school during the 1950s, suggests exposure by school-age siblings, and almost all cases in adults occurred several days after a case in another family member</p>
<p>Do human immune responses to influenza include mediators that have the potential to provide heterosubtypic immunity? Human CD4<sup>+</sup> and CD8<sup>+</sup> T cells have been found to recognize epitopes of several conserved proteins [<xref ref-type="bibr" rid="ref21">21</xref>]. Human memory T cells have been found to react with antigens from avian and swine viruses, including H5N1 [<xref ref-type="bibr" rid="ref22">22</xref>]. Because the humans who provided the T cells for these studies had been exposed to circulating H1N1 or H3N2, these broad cross-reactivities are encouraging. Also, antibody to the conserved antigen M2 has been found in serum from some convalescent individuals [<xref ref-type="bibr" rid="ref23">23</xref>]</p>
<p>Would a vaccine based on heterosubtypic immunity be useful? It would if cross-protection lasted for a few years, as is suggested by the greater susceptibility of study adults whose last infection preceded the study years—especially for a disease that is currently managed via annual vaccination. Furthermore, if children were to require 2 doses for initial priming, then that is no less practical than the 2-dose recommendation for children that is in place for current influenza vaccines</p>
<p>These historical data alone cannot prove the existence of cross-protection in humans or establish its mechanism, but the findings of the present analysis suggest that it plays a role. No larger data set that is from a pandemic and that has comparably detailed and individually linked records is available for analysis. The importance of the present analysis is to highlight the outcomes in this unusually well-documented population. The findings are consistent with the existence of human heterosubtypic immunity and call for further investigation. If such immunity is confirmed in humans, new vaccines that are designed to optimize its induction will be valuable. Clinical studies to evaluate its potential in the control of influenza could use contemporary analytical methods and end points rather than traditional serological testing. Such vaccines could be used off the shelf as a first line of defense early during an epidemic or pandemic to reduce morbidity and mortality, complementing efforts in surveillance and the time-consuming preparation of strain-matched vaccines</p>
</body>
<back>
<ack>
<title>Acknowledgments</title>
<p>Special thanks are due to Dr. William S. Jordan, one of the investigators in the original Cleveland Family Study who is now affiliated with the National Institute of Allergy and Infectious Diseases, National Institutes of Health, for valuable discussions. Thanks also to Dianne O’Malia, archivist, and Nancy Erdey, former archivist, Stanley A. Ferguson Archives of University Hospitals of Cleveland, for assistance; and to Cecile Viboud, Ira Berkower, Fred Miller, Julia Misplon, and Chia-Yun Lo, for critical review of the manuscript</p>
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<sec sec-type="display-objects">
<title>Figures and Tables</title>
<fig id="Fig1" position="float">
<label>Figure 1</label>
<caption>
<p>The 1957 pandemic wave in the Cleveland Family Study population, reconstructed from individual archival case records; each dot represents 1 participant with influenza. The plot shows all participants with influenza in the Cleveland Family Study, not only the subset who met the inclusion criteria for the analysis shown in <xref ref-type="fig" rid="tb3">table 3</xref>
</p>
</caption>
<graphic mimetype="image" xlink:href="193-1-49-fig001.tif"></graphic>
</fig>
<fig id="tb1" position="float">
<label>Table 1</label>
<caption>
<p>Influenza virus infections, as measured by virus isolation</p>
</caption>
<graphic mimetype="image" xlink:href="193-1-49-tab001.tif"></graphic>
</fig>
<fig id="tb2" position="float">
<label>Table 2</label>
<caption>
<p>Completeness of individual case records</p>
</caption>
<graphic mimetype="image" xlink:href="193-1-49-tab002.tif"></graphic>
</fig>
<fig id="tb3" position="float">
<label>Table 3</label>
<caption>
<p>Susceptibility in 1957 for all participants monitored from 1950 to 1957</p>
</caption>
<graphic mimetype="image" xlink:href="193-1-49-tab003.tif"></graphic>
</fig>
</sec>
<fn-group>
<fn id="fn2">
<p>(See the editorial commentary by <ext-link ext-link-type="uri" xlink:href="/cgi-bin/resolve?JID35340">Kilbourne</ext-link>, on pages 7–8.)</p>
</fn>
<fn id="fn1">
<p>Presented in part: Experimental Biology 2004 (Federation of American Societies for Experimental Biology conference), Washington, DC, 17 April 2004 (abstract 2699)</p>
<p>Potential conflicts of interest: none reported</p>
<p>Financial support: Center for Biologics Evaluation and Research, Food and Drug Administration</p>
<p>This report does not present an official position of the Food and Drug Administration</p>
</fn>
</fn-group>
</back>
</article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Prior H1N1 Influenza Infection and Susceptibility of Cleveland Family Study Participants during the H2N2 Pandemic of 1957: An Experiment of Nature</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Prior H1N1 Influenza Infection and Susceptibility of Cleveland Family Study Participants during the H2N2 Pandemic of 1957: An Experiment of Nature</title></titleInfo><name type="personal"><namePart type="given">Suzanne L.</namePart><namePart type="family">Epstein</namePart><affiliation>Laboratory of Immunology and Developmental Biology, Division of Cellular and Gene Therapies, Office of Cellular, Tissue, and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland</affiliation></name><typeOfResource>text</typeOfResource><genre type="brief-communication" displayLabel="brief-report" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-S9SX2MFS-0">brief-communication</genre><originInfo><publisher>The University of Chicago Press</publisher><dateIssued encoding="w3cdtf">2006-01-01</dateIssued><dateCreated encoding="w3cdtf">2005-07-20</dateCreated><copyrightDate encoding="w3cdtf">2006</copyrightDate></originInfo><abstract>During a pandemic, influenza vaccines that rely on neutralizing antibodies to protect against matched viruses might not be available early enough. Much broader (heterosubtypic) immune protection is seen in animals. Do humans also have cross-subtype immunity? To investigate this issue, archival records from the Cleveland Family Study, which was conducted before and during the 1957 pandemic (during which a shift from subtype H1N1 to H2N2 occurred), were analyzed. Only 5.6% of the adults who had had symptomatic influenza A in earlier study years developed influenza during the pandemic, despite living in households with participants who had influenza. In contrast, 55.2% of the children who had had symptomatic influenza A contracted it again. These findings suggest an impact of accumulated heterosubtypic immunity during a pandemic. 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