Antiviral Resistance and the Control of Pandemic Influenza
Identifieur interne : 000E11 ( Pmc/Checkpoint ); précédent : 000E10; suivant : 000E12Antiviral Resistance and the Control of Pandemic Influenza
Auteurs : Marc Lipsitch [États-Unis] ; Ted Cohen [États-Unis] ; Megan Murray [États-Unis] ; Bruce R. Levin [États-Unis]Source :
- PLoS Medicine [ 1549-1277 ] ; 2007.
Abstract
The response to the next influenza pandemic will likely include extensive use of antiviral drugs (mainly oseltamivir), combined with other transmission-reducing measures. Animal and in vitro studies suggest that some strains of influenza may become resistant to oseltamivir while maintaining infectiousness (fitness). Use of antiviral agents on the scale anticipated for the control of pandemic influenza will create an unprecedented selective pressure for the emergence and spread of these strains. Nonetheless, antiviral resistance has received little attention when evaluating these plans.
We designed and analyzed a deterministic compartmental model of the transmission of oseltamivir-sensitive and -resistant influenza infections during a pandemic. The model predicts that even if antiviral treatment or prophylaxis leads to the emergence of a transmissible resistant strain in as few as 1 in 50,000 treated persons and 1 in 500,000 prophylaxed persons, widespread use of antivirals may strongly promote the spread of resistant strains at the population level, leading to a prevalence of tens of percent by the end of a pandemic. On the other hand, even in circumstances in which a resistant strain spreads widely, the use of antivirals may significantly delay and/or reduce the total size of the pandemic. If resistant strains carry some fitness cost, then, despite widespread emergence of resistance, antivirals could slow pandemic spread by months or more, and buy time for vaccine development; this delay would be prolonged by nondrug control measures (e.g., social distancing) that reduce transmission, or use of a stockpiled suboptimal vaccine. Surprisingly, the model suggests that such nondrug control measures would increase the proportion of the epidemic caused by resistant strains.
The benefits of antiviral drug use to control an influenza pandemic may be reduced, although not completely offset, by drug resistance in the virus. Therefore, the risk of resistance should be considered in pandemic planning and monitored closely during a pandemic.
Url:
DOI: 10.1371/journal.pmed.0040015
PubMed: 17253900
PubMed Central: 1779817
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Antiviral Resistance and the Control of Pandemic Influenza</title><author><name sortKey="Lipsitch, Marc" sort="Lipsitch, Marc" uniqKey="Lipsitch M" first="Marc" last="Lipsitch">Marc Lipsitch</name><affiliation wicri:level="2"><nlm:aff id="aff1"> Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="aff2"> Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Cohen, Ted" sort="Cohen, Ted" uniqKey="Cohen T" first="Ted" last="Cohen">Ted Cohen</name><affiliation wicri:level="2"><nlm:aff id="aff1"> Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="aff3"> Division of Social Medicine and Health Inequalities, Harvard Medical School, Boston, Massachusetts, United States of America</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Division of Social Medicine and Health Inequalities, Harvard Medical School, Boston, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Murray, Megan" sort="Murray, Megan" uniqKey="Murray M" first="Megan" last="Murray">Megan Murray</name><affiliation wicri:level="2"><nlm:aff id="aff1"> Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="aff3"> Division of Social Medicine and Health Inequalities, Harvard Medical School, Boston, Massachusetts, United States of America</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Division of Social Medicine and Health Inequalities, Harvard Medical School, Boston, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="aff4"> Division of Infectious Diseases and General Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Division of Infectious Diseases and General Medicine, Massachusetts General Hospital, Boston, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Levin, Bruce R" sort="Levin, Bruce R" uniqKey="Levin B" first="Bruce R" last="Levin">Bruce R. Levin</name><affiliation wicri:level="2"><nlm:aff id="aff5"> Department of Biology, Emory University, Atlanta, Georgia, United States of America</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Department of Biology, Emory University, Atlanta, Georgia</wicri:regionArea><placeName><region type="state">Géorgie (États-Unis)</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">17253900</idno><idno type="pmc">1779817</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1779817</idno><idno type="RBID">PMC:1779817</idno><idno type="doi">10.1371/journal.pmed.0040015</idno><date when="2007">2007</date><idno type="wicri:Area/Pmc/Corpus">000C26</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000C26</idno><idno type="wicri:Area/Pmc/Curation">000C26</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000C26</idno><idno type="wicri:Area/Pmc/Checkpoint">000E11</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000E11</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Antiviral Resistance and the Control of Pandemic Influenza</title><author><name sortKey="Lipsitch, Marc" sort="Lipsitch, Marc" uniqKey="Lipsitch M" first="Marc" last="Lipsitch">Marc Lipsitch</name><affiliation wicri:level="2"><nlm:aff id="aff1"> Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="aff2"> Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Cohen, Ted" sort="Cohen, Ted" uniqKey="Cohen T" first="Ted" last="Cohen">Ted Cohen</name><affiliation wicri:level="2"><nlm:aff id="aff1"> Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="aff3"> Division of Social Medicine and Health Inequalities, Harvard Medical School, Boston, Massachusetts, United States of America</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Division of Social Medicine and Health Inequalities, Harvard Medical School, Boston, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Murray, Megan" sort="Murray, Megan" uniqKey="Murray M" first="Megan" last="Murray">Megan Murray</name><affiliation wicri:level="2"><nlm:aff id="aff1"> Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="aff3"> Division of Social Medicine and Health Inequalities, Harvard Medical School, Boston, Massachusetts, United States of America</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Division of Social Medicine and Health Inequalities, Harvard Medical School, Boston, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="aff4"> Division of Infectious Diseases and General Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Division of Infectious Diseases and General Medicine, Massachusetts General Hospital, Boston, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Levin, Bruce R" sort="Levin, Bruce R" uniqKey="Levin B" first="Bruce R" last="Levin">Bruce R. Levin</name><affiliation wicri:level="2"><nlm:aff id="aff5"> Department of Biology, Emory University, Atlanta, Georgia, United States of America</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Department of Biology, Emory University, Atlanta, Georgia</wicri:regionArea><placeName><region type="state">Géorgie (États-Unis)</region></placeName></affiliation></author></analytic><series><title level="j">PLoS Medicine</title><idno type="ISSN">1549-1277</idno><idno type="eISSN">1549-1676</idno><imprint><date when="2007">2007</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="st1"><title>Background</title><p>The response to the next influenza pandemic will likely include extensive use of antiviral drugs (mainly oseltamivir), combined with other transmission-reducing measures. Animal and in vitro studies suggest that some strains of influenza may become resistant to oseltamivir while maintaining infectiousness (fitness). Use of antiviral agents on the scale anticipated for the control of pandemic influenza will create an unprecedented selective pressure for the emergence and spread of these strains. Nonetheless, antiviral resistance has received little attention when evaluating these plans.</p></sec><sec id="st2"><title>Methods and Findings</title><p>We designed and analyzed a deterministic compartmental model of the transmission of oseltamivir-sensitive and -resistant influenza infections during a pandemic. The model predicts that even if antiviral treatment or prophylaxis leads to the emergence of a transmissible resistant strain in as few as 1 in 50,000 treated persons and 1 in 500,000 prophylaxed persons, widespread use of antivirals may strongly promote the spread of resistant strains at the population level, leading to a prevalence of tens of percent by the end of a pandemic. On the other hand, even in circumstances in which a resistant strain spreads widely, the use of antivirals may significantly delay and/or reduce the total size of the pandemic. If resistant strains carry some fitness cost, then, despite widespread emergence of resistance, antivirals could slow pandemic spread by months or more, and buy time for vaccine development; this delay would be prolonged by nondrug control measures (e.g., social distancing) that reduce transmission, or use of a stockpiled suboptimal vaccine. Surprisingly, the model suggests that such nondrug control measures would increase the proportion of the epidemic caused by resistant strains.</p></sec><sec id="st3"><title>Conclusions</title><p>The benefits of antiviral drug use to control an influenza pandemic may be reduced, although not completely offset, by drug resistance in the virus. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Med</journal-id><journal-id journal-id-type="iso-abbrev">PLoS Med</journal-id><journal-id journal-id-type="publisher-id">pmed</journal-id><journal-id journal-id-type="publisher-id">plme</journal-id><journal-id journal-id-type="pmc">plosmed</journal-id><journal-title-group><journal-title>PLoS Medicine</journal-title></journal-title-group><issn pub-type="ppub">1549-1277</issn><issn pub-type="epub">1549-1676</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">17253900</article-id><article-id pub-id-type="pmc">1779817</article-id><article-id pub-id-type="doi">10.1371/journal.pmed.0040015</article-id><article-id pub-id-type="publisher-id">06-PLME-RA-0490R2</article-id><article-id pub-id-type="sici">plme-04-01-17</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline"><subject>Infectious Diseases</subject><subject>Non-Clinical Medicine</subject><subject>Public Health and Epidemiology</subject><subject>Virology</subject></subj-group><subj-group subj-group-type="System Taxonomy"><subject>Infectious Diseases</subject><subject>Epidemiology</subject><subject>Public Health</subject><subject>Drugs and adverse drug reactions</subject><subject>Health Policy</subject></subj-group></article-categories><title-group><article-title>Antiviral Resistance and the Control of Pandemic Influenza</article-title><alt-title alt-title-type="running-head">Influenza Drug Resistance</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Lipsitch</surname><given-names>Marc</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib><contrib contrib-type="author"><name><surname>Cohen</surname><given-names>Ted</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Murray</surname><given-names>Megan</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff3">3</xref><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Levin</surname><given-names>Bruce R</given-names></name><xref ref-type="aff" rid="aff5">5</xref></contrib></contrib-group><aff id="aff1"><label>1</label> Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America</aff><aff id="aff2"><label>2</label> Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America</aff><aff id="aff3"><label>3</label> Division of Social Medicine and Health Inequalities, Harvard Medical School, Boston, Massachusetts, United States of America</aff><aff id="aff4"><label>4</label> Division of Infectious Diseases and General Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America</aff><aff id="aff5"><label>5</label> Department of Biology, Emory University, Atlanta, Georgia, United States of America</aff><contrib-group><contrib contrib-type="editor"><name><surname>Simonsen</surname><given-names>Lone</given-names></name><role>Academic Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1">National Institutes of Health, United States of America</aff><author-notes><corresp id="cor1">* To whom correspondence should be addressed. E-mail: <email>mlipsitc@hsph.harvard.edu</email></corresp></author-notes><pub-date pub-type="ppub"><month>1</month><year>2007</year></pub-date><pub-date pub-type="epub"><day>23</day><month>1</month><year>2007</year></pub-date><volume>4</volume><issue>1</issue><elocation-id>e15</elocation-id><history><date date-type="received"><day>29</day><month>6</month><year>2006</year></date><date date-type="accepted"><day>14</day><month>11</month><year>2006</year></date></history><permissions><copyright-statement> © 2007 Lipsitch et al.</copyright-statement><copyright-year>2007</copyright-year><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.</license-p></license></permissions><abstract><sec id="st1"><title>Background</title><p>The response to the next influenza pandemic will likely include extensive use of antiviral drugs (mainly oseltamivir), combined with other transmission-reducing measures. Animal and in vitro studies suggest that some strains of influenza may become resistant to oseltamivir while maintaining infectiousness (fitness). Use of antiviral agents on the scale anticipated for the control of pandemic influenza will create an unprecedented selective pressure for the emergence and spread of these strains. Nonetheless, antiviral resistance has received little attention when evaluating these plans.</p></sec><sec id="st2"><title>Methods and Findings</title><p>We designed and analyzed a deterministic compartmental model of the transmission of oseltamivir-sensitive and -resistant influenza infections during a pandemic. The model predicts that even if antiviral treatment or prophylaxis leads to the emergence of a transmissible resistant strain in as few as 1 in 50,000 treated persons and 1 in 500,000 prophylaxed persons, widespread use of antivirals may strongly promote the spread of resistant strains at the population level, leading to a prevalence of tens of percent by the end of a pandemic. On the other hand, even in circumstances in which a resistant strain spreads widely, the use of antivirals may significantly delay and/or reduce the total size of the pandemic. If resistant strains carry some fitness cost, then, despite widespread emergence of resistance, antivirals could slow pandemic spread by months or more, and buy time for vaccine development; this delay would be prolonged by nondrug control measures (e.g., social distancing) that reduce transmission, or use of a stockpiled suboptimal vaccine. Surprisingly, the model suggests that such nondrug control measures would increase the proportion of the epidemic caused by resistant strains.</p></sec><sec id="st3"><title>Conclusions</title><p>The benefits of antiviral drug use to control an influenza pandemic may be reduced, although not completely offset, by drug resistance in the virus. Therefore, the risk of resistance should be considered in pandemic planning and monitored closely during a pandemic.</p></sec></abstract><abstract abstract-type="toc"><p>Emergence of oseltamivir-resistant influenza strains during a pandemic is likely given the heightened selective pressure if the drug is widely used. Marc Lipsitch and colleagues suggest that resistance would reduce but not completely offset the drug's benefits for pandemic control.</p></abstract><abstract abstract-type="editor"><title>Editors' Summary</title><sec id="sb1a"><title>Background.</title><p>Governments and health authorities worldwide are planning how they would best prepare for and deal with a future influenza pandemic. Seasonal influenza is thought to affect between 5% and 15% of the population worldwide each year. Most people who get influenza recover within a couple of weeks without lasting effects, but a small proportion of patients, mostly young children and elderly people, experience serious complications that can be fatal. An influenza pandemic happens when new variants of the influenza virus emerge against which little immunity exists in the general population. Pandemic influenza strains are transmitted more rapidly than seasonal strains, often sweep across several countries or continents, and make more people ill. There are drugs that can treat and prevent influenza. One of them, oseltamivir (Tamiflu) is an antiviral drug that works by preventing viral particles from being released by infected human cells. Stockpiling large amounts of oseltamivir and related drugs with the intent to treat a large fraction of the population is a key part of pandemic preparedness of many countries. However, it is known that influenza viruses can develop resistance to these drugs.</p></sec><sec id="sb1b"><title>Why Was This Study Done?</title><p>It is not clear how the emergence of oseltamivir-resistant influenza strains would affect the course of any future influenza pandemic. Much research in this area has focused on how likely the new strains are to emerge in the first place, rather than on how they might spread once they had emerged. In the context of an influenza pandemic, antiviral drugs would be used in a large proportion of the population, likely driving the selection and spread of resistant viruses. For this study, the researchers wanted to estimate the likely impact of resistant strains during an influenza pandemic.</p></sec><sec id="sb1c"><title>What Did the Researchers Do and Find?</title><p>These researchers set up a mathematical model (i.e., simulations done on a computer) to mimic the spread of influenza. They then fed a set of assumptions into the computer. These included information about the rate of transmission of influenza from one person to another; what proportion of people would receive antiviral drugs for prophylaxis or treatment; how likely the drugs would be to successfully treat or prevent infection; and in what proportion of people the virus might become resistant to drugs. The modeling led to three main predictions. First, it predicted that widespread use of antiviral drugs such as oseltamivir could quickly lead to the spread of resistant viruses, even if resistant strains emerged only rarely. Second, even with resistant strains circulating, prophylaxis and treatment with oseltamivir would still delay the spread of the pandemic and reduce its total size. Third, nondrug interventions (such as social isolation and school closures) would further reduce the number of cases, but a higher proportion of cases would be caused by resistant strains if these control measures were used.</p></sec><sec id="sb1d"><title>What Do These Findings Mean?</title><p>These findings suggest that, in the event of a future influenza pandemic for which antiviral drugs are used, there is a risk of resistance emerging and resistant strains causing illness in a substantial number of people. This would counteract the benefits of antiviral drugs but not eliminate those benefits entirely. Like all modeling studies, this one relies on realistic assumptions being entered into the model, and it is hard to know closely the model will mimic a real-life situation until the properties of an actual pandemic strain are known. Most studies, including this one, suggest that in the event of a pandemic, antiviral drugs will have an overall beneficial impact on reducing death rates and adverse health outcomes. However, given the sizeable effects of resistance suggested here, its role should be considered in pandemic planning. This includes surveillance that can detect emergence and spread of resistant strains.</p></sec><sec id="sb1e"><title>Additional Information.</title><p>Please access these Web sites via the online version of this summary at <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/doi:10.1371/journal.pmed.0040015">http://dx.doi.org/doi:10.1371/journal.pmed.0040015</ext-link>.</p><list list-type="bullet"><list-item><p>World Health Organization: <ext-link ext-link-type="uri" xlink:href="http://www.who.int/csr/disease/influenza/pandemic/en/">information on pandemic preparedness</ext-link></p></list-item><list-item><p>World Health Organization: <ext-link ext-link-type="uri" xlink:href="http://www.who.int/topics/influenza/en/">fact sheets on influenza</ext-link></p></list-item><list-item><p>Information from the <ext-link ext-link-type="uri" xlink:href="http://www.hpa.org.uk/infections/topics_az/influenza/pandemic/default.htm">UK Health Protection Agency</ext-link> on pandemic influenza</p></list-item><list-item><p>US government website on both <ext-link ext-link-type="uri" xlink:href="http://www.pandemicflu.gov/">pandemic flu and avian flu</ext-link> (information provided by the US Department of Health and Human Services)</p></list-item></list></sec></abstract><counts><page-count count="11"></page-count></counts><custom-meta-group><custom-meta><meta-name>citation</meta-name><meta-value>Lipsitch M, Cohen T, Murray M, Levin BR (2007) Antiviral resistance and the control of pandemic influenza. PLoS Med 4(1): e15. doi:<ext-link ext-link-type="doi" xlink:href="10.1371/journal.pmed.0040015">10.1371/journal.pmed.0040015</ext-link></meta-value></custom-meta></custom-meta-group></article-meta></front></pmc><affiliations><list><country><li>États-Unis</li></country><region><li>Géorgie (États-Unis)</li><li>Massachusetts</li></region></list><tree><country name="États-Unis"><region name="Massachusetts"><name sortKey="Lipsitch, Marc" sort="Lipsitch, Marc" uniqKey="Lipsitch M" first="Marc" last="Lipsitch">Marc Lipsitch</name></region><name sortKey="Cohen, Ted" sort="Cohen, Ted" uniqKey="Cohen T" first="Ted" last="Cohen">Ted Cohen</name><name sortKey="Cohen, Ted" sort="Cohen, Ted" uniqKey="Cohen T" first="Ted" last="Cohen">Ted Cohen</name><name sortKey="Levin, Bruce R" sort="Levin, Bruce R" uniqKey="Levin B" first="Bruce R" last="Levin">Bruce R. Levin</name><name sortKey="Lipsitch, Marc" sort="Lipsitch, Marc" uniqKey="Lipsitch M" first="Marc" last="Lipsitch">Marc Lipsitch</name><name sortKey="Murray, Megan" sort="Murray, Megan" uniqKey="Murray M" first="Megan" last="Murray">Megan Murray</name><name sortKey="Murray, Megan" sort="Murray, Megan" uniqKey="Murray M" first="Megan" last="Murray">Megan Murray</name><name sortKey="Murray, Megan" sort="Murray, Megan" uniqKey="Murray M" first="Megan" last="Murray">Megan Murray</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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