Evaluation of the Immune Response to a 2-Dose Measles Vaccination Schedule Administered at 6 and 9 Months of Age to HIV-Infected and HIV-Uninfected Children in Malawi
Identifieur interne : 004363 ( Istex/Corpus ); précédent : 004362; suivant : 004364Evaluation of the Immune Response to a 2-Dose Measles Vaccination Schedule Administered at 6 and 9 Months of Age to HIV-Infected and HIV-Uninfected Children in Malawi
Auteurs : Rita F. Helfand ; Desiree Witte ; Ashley Fowlkes ; Philip Garcia ; Chunfu Yang ; Richard Fudzulani ; Laura Walls ; Sun Bae ; Peter Strebel ; Robin Broadhead ; William J. Bellini ; Felicity CuttsSource :
- The Journal of Infectious Diseases [ 0022-1899 ] ; 2008-11-15.
Abstract
Background. The World Health Organization recommends that infants at high risk for developing measles before 9 months of age, including human immunodeficiency virus (HIV)-infected infants, receive measles vaccination (MV) at 6 and 9 months of age. Methods. Children born to HIV-infected mothers received MV at 6 and 9 months, and children of HIV-uninfected mothers were randomized to receive MV at 6 and 9 months, MV at 9 months, or routine MV without follow-up. Blood samples were obtained before and 3 months after each MV. Data were collected on adverse events for 21 days after each MV, at all clinic visits, on any hospitalization, and for subjects who died. HIV-infection status was determined by antibody assays and polymerase chain reaction; the presence of measles IgG was determined by EIA. Results. Twenty-two hundred mother-infant pairs were enrolled. After the first and second doses of measles vaccine, respectively, the percentages of children who were measles seropositive were 59% (36 of 61) and 64% (29 of 45) among HIV-infected children, 68% (152 of 223) and 94% (189 of 202) among HIV-exposed but uninfected children, and 62% (288 of 467) and 92% (385 of 417) among HIV-unexposed children. Of 521 HIV-unexposed children vaccinated only at 9 months, 398 (76%) were measles seropositive at 12 months. No serious vaccine-related adverse events were identified. Conclusions. An early, 2-dose MV schedule was immunogenic, but a higher proportion of HIV-infected children remained susceptible to measles, compared with HIV-uninfected children (whether HIV exposed or HIV unexposed).
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DOI: 10.1086/592756
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Helfand</name><affiliation><mods:affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: rzh7@cdc.gov</mods:affiliation></affiliation><affiliation><mods:affiliation>Reprints or correspondence: Dr. Rita Helfand, Centers for Disease Control and Prevention, 1600 Clifton Road, MS C-12, Atlanta, GA 30333</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: rzh7@cdc.gov</mods:affiliation></affiliation></author><author><name sortKey="Witte, Desiree" sort="Witte, Desiree" uniqKey="Witte D" first="Desiree" last="Witte">Desiree Witte</name><affiliation><mods:affiliation>College of Medicine, University of Malawi, Blantyre, Malawi</mods:affiliation></affiliation></author><author><name sortKey="Fowlkes, Ashley" sort="Fowlkes, Ashley" uniqKey="Fowlkes A" first="Ashley" last="Fowlkes">Ashley Fowlkes</name><affiliation><mods:affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</mods:affiliation></affiliation></author><author><name sortKey="Garcia, Philip" sort="Garcia, Philip" uniqKey="Garcia P" first="Philip" last="Garcia">Philip Garcia</name><affiliation><mods:affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</mods:affiliation></affiliation></author><author><name sortKey="Yang, Chunfu" sort="Yang, Chunfu" uniqKey="Yang C" first="Chunfu" last="Yang">Chunfu Yang</name><affiliation><mods:affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</mods:affiliation></affiliation></author><author><name sortKey="Fudzulani, Richard" sort="Fudzulani, Richard" uniqKey="Fudzulani R" first="Richard" last="Fudzulani">Richard Fudzulani</name><affiliation><mods:affiliation>College of Medicine, University of Malawi, Blantyre, Malawi</mods:affiliation></affiliation></author><author><name sortKey="Walls, Laura" sort="Walls, Laura" uniqKey="Walls L" first="Laura" last="Walls">Laura Walls</name><affiliation><mods:affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</mods:affiliation></affiliation></author><author><name sortKey="Bae, Sun" sort="Bae, Sun" uniqKey="Bae S" first="Sun" last="Bae">Sun Bae</name><affiliation><mods:affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</mods:affiliation></affiliation></author><author><name sortKey="Strebel, Peter" sort="Strebel, Peter" uniqKey="Strebel P" first="Peter" last="Strebel">Peter Strebel</name><affiliation><mods:affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</mods:affiliation></affiliation><affiliation><mods:affiliation>World Health Organization, Geneva, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Broadhead, Robin" sort="Broadhead, Robin" uniqKey="Broadhead R" first="Robin" last="Broadhead">Robin Broadhead</name><affiliation><mods:affiliation>College of Medicine, University of Malawi, Blantyre, Malawi</mods:affiliation></affiliation></author><author><name sortKey="Bellini, William J" sort="Bellini, William J" uniqKey="Bellini W" first="William J." last="Bellini">William J. Bellini</name><affiliation><mods:affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</mods:affiliation></affiliation></author><author><name sortKey="Cutts, Felicity" sort="Cutts, Felicity" uniqKey="Cutts F" first="Felicity" last="Cutts">Felicity Cutts</name><affiliation><mods:affiliation>London School of Hygiene and Tropical Medicine, London, United Kingdom</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:CFD5984CBF1AA060E20D8976678E8D21AEB82FBE</idno><date when="2008" year="2008">2008</date><idno type="doi">10.1086/592756</idno><idno type="url">https://api.istex.fr/document/CFD5984CBF1AA060E20D8976678E8D21AEB82FBE/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">004363</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">004363</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">Evaluation of the Immune Response to a 2-Dose Measles Vaccination Schedule Administered at 6 and 9 Months of Age to HIV-Infected and HIV-Uninfected Children in Malawi</title><author><name sortKey="Helfand, Rita F" sort="Helfand, Rita F" uniqKey="Helfand R" first="Rita F." last="Helfand">Rita F. Helfand</name><affiliation><mods:affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: rzh7@cdc.gov</mods:affiliation></affiliation><affiliation><mods:affiliation>Reprints or correspondence: Dr. Rita Helfand, Centers for Disease Control and Prevention, 1600 Clifton Road, MS C-12, Atlanta, GA 30333</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: rzh7@cdc.gov</mods:affiliation></affiliation></author><author><name sortKey="Witte, Desiree" sort="Witte, Desiree" uniqKey="Witte D" first="Desiree" last="Witte">Desiree Witte</name><affiliation><mods:affiliation>College of Medicine, University of Malawi, Blantyre, Malawi</mods:affiliation></affiliation></author><author><name sortKey="Fowlkes, Ashley" sort="Fowlkes, Ashley" uniqKey="Fowlkes A" first="Ashley" last="Fowlkes">Ashley Fowlkes</name><affiliation><mods:affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</mods:affiliation></affiliation></author><author><name sortKey="Garcia, Philip" sort="Garcia, Philip" uniqKey="Garcia P" first="Philip" last="Garcia">Philip Garcia</name><affiliation><mods:affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</mods:affiliation></affiliation></author><author><name sortKey="Yang, Chunfu" sort="Yang, Chunfu" uniqKey="Yang C" first="Chunfu" last="Yang">Chunfu Yang</name><affiliation><mods:affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</mods:affiliation></affiliation></author><author><name sortKey="Fudzulani, Richard" sort="Fudzulani, Richard" uniqKey="Fudzulani R" first="Richard" last="Fudzulani">Richard Fudzulani</name><affiliation><mods:affiliation>College of Medicine, University of Malawi, Blantyre, Malawi</mods:affiliation></affiliation></author><author><name sortKey="Walls, Laura" sort="Walls, Laura" uniqKey="Walls L" first="Laura" last="Walls">Laura Walls</name><affiliation><mods:affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</mods:affiliation></affiliation></author><author><name sortKey="Bae, Sun" sort="Bae, Sun" uniqKey="Bae S" first="Sun" last="Bae">Sun Bae</name><affiliation><mods:affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</mods:affiliation></affiliation></author><author><name sortKey="Strebel, Peter" sort="Strebel, Peter" uniqKey="Strebel P" first="Peter" last="Strebel">Peter Strebel</name><affiliation><mods:affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</mods:affiliation></affiliation><affiliation><mods:affiliation>World Health Organization, Geneva, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Broadhead, Robin" sort="Broadhead, Robin" uniqKey="Broadhead R" first="Robin" last="Broadhead">Robin Broadhead</name><affiliation><mods:affiliation>College of Medicine, University of Malawi, Blantyre, Malawi</mods:affiliation></affiliation></author><author><name sortKey="Bellini, William J" sort="Bellini, William J" uniqKey="Bellini W" first="William J." last="Bellini">William J. Bellini</name><affiliation><mods:affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</mods:affiliation></affiliation></author><author><name sortKey="Cutts, Felicity" sort="Cutts, Felicity" uniqKey="Cutts F" first="Felicity" last="Cutts">Felicity Cutts</name><affiliation><mods:affiliation>London School of Hygiene and Tropical Medicine, London, United Kingdom</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">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 type="published" when="2008-11-15">2008-11-15</date><biblScope unit="volume">198</biblScope><biblScope unit="issue">10</biblScope><biblScope unit="page" from="1457">1457</biblScope><biblScope unit="page" to="1465">1465</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">Background. The World Health Organization recommends that infants at high risk for developing measles before 9 months of age, including human immunodeficiency virus (HIV)-infected infants, receive measles vaccination (MV) at 6 and 9 months of age. Methods. Children born to HIV-infected mothers received MV at 6 and 9 months, and children of HIV-uninfected mothers were randomized to receive MV at 6 and 9 months, MV at 9 months, or routine MV without follow-up. Blood samples were obtained before and 3 months after each MV. Data were collected on adverse events for 21 days after each MV, at all clinic visits, on any hospitalization, and for subjects who died. HIV-infection status was determined by antibody assays and polymerase chain reaction; the presence of measles IgG was determined by EIA. Results. Twenty-two hundred mother-infant pairs were enrolled. After the first and second doses of measles vaccine, respectively, the percentages of children who were measles seropositive were 59% (36 of 61) and 64% (29 of 45) among HIV-infected children, 68% (152 of 223) and 94% (189 of 202) among HIV-exposed but uninfected children, and 62% (288 of 467) and 92% (385 of 417) among HIV-unexposed children. Of 521 HIV-unexposed children vaccinated only at 9 months, 398 (76%) were measles seropositive at 12 months. No serious vaccine-related adverse events were identified. Conclusions. An early, 2-dose MV schedule was immunogenic, but a higher proportion of HIV-infected children remained susceptible to measles, compared with HIV-uninfected children (whether HIV exposed or HIV unexposed).</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Rita F. Helfand</name><affiliations><json:string>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</json:string><json:string>E-mail: rzh7@cdc.gov</json:string></affiliations></json:item><json:item><name>Desiree Witte</name><affiliations><json:string>College of Medicine, University of Malawi, Blantyre, Malawi</json:string></affiliations></json:item><json:item><name>Ashley Fowlkes</name><affiliations><json:string>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</json:string></affiliations></json:item><json:item><name>Philip Garcia</name><affiliations><json:string>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</json:string></affiliations></json:item><json:item><name>Chunfu Yang</name><affiliations><json:string>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</json:string></affiliations></json:item><json:item><name>Richard Fudzulani</name><affiliations><json:string>College of Medicine, University of Malawi, Blantyre, Malawi</json:string></affiliations></json:item><json:item><name>Laura Walls</name><affiliations><json:string>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</json:string></affiliations></json:item><json:item><name>Sun Bae</name><affiliations><json:string>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</json:string></affiliations></json:item><json:item><name>Peter Strebel</name><affiliations><json:string>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</json:string><json:string>World Health Organization, Geneva, Switzerland</json:string></affiliations></json:item><json:item><name>Robin Broadhead</name><affiliations><json:string>College of Medicine, University of Malawi, Blantyre, Malawi</json:string></affiliations></json:item><json:item><name>William J. Bellini</name><affiliations><json:string>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</json:string></affiliations></json:item><json:item><name>Felicity Cutts</name><affiliations><json:string>London School of Hygiene and Tropical Medicine, London, United Kingdom</json:string></affiliations></json:item></author><language><json:string>unknown</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>Background. The World Health Organization recommends that infants at high risk for developing measles before 9 months of age, including human immunodeficiency virus (HIV)-infected infants, receive measles vaccination (MV) at 6 and 9 months of age. Methods. Children born to HIV-infected mothers received MV at 6 and 9 months, and children of HIV-uninfected mothers were randomized to receive MV at 6 and 9 months, MV at 9 months, or routine MV without follow-up. Blood samples were obtained before and 3 months after each MV. Data were collected on adverse events for 21 days after each MV, at all clinic visits, on any hospitalization, and for subjects who died. HIV-infection status was determined by antibody assays and polymerase chain reaction; the presence of measles IgG was determined by EIA. Results. Twenty-two hundred mother-infant pairs were enrolled. After the first and second doses of measles vaccine, respectively, the percentages of children who were measles seropositive were 59% (36 of 61) and 64% (29 of 45) among HIV-infected children, 68% (152 of 223) and 94% (189 of 202) among HIV-exposed but uninfected children, and 62% (288 of 467) and 92% (385 of 417) among HIV-unexposed children. Of 521 HIV-unexposed children vaccinated only at 9 months, 398 (76%) were measles seropositive at 12 months. No serious vaccine-related adverse events were identified. Conclusions. An early, 2-dose MV schedule was immunogenic, but a higher proportion of HIV-infected children remained susceptible to measles, compared with HIV-uninfected children (whether HIV exposed or HIV unexposed).</abstract><qualityIndicators><score>9.952</score><pdfWordCount>6110</pdfWordCount><pdfCharCount>37458</pdfCharCount><pdfVersion>1.3</pdfVersion><pdfPageCount>9</pdfPageCount><pdfPageSize>594 x 783 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractWordCount>246</abstractWordCount><abstractCharCount>1596</abstractCharCount><keywordCount>0</keywordCount></qualityIndicators><title>Evaluation of the Immune Response to a 2-Dose Measles Vaccination Schedule Administered at 6 and 9 Months of Age to HIV-Infected and HIV-Uninfected Children in Malawi</title><genre><json:string>research-article</json:string></genre><host><title>The Journal of Infectious 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HIV-Uninfected Children in Malawi</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher scheme="https://publisher-list.data.istex.fr">The University of Chicago Press</publisher><availability><licence><p>© 2008 by the Infectious Diseases Society of America</p></licence><p scheme="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-GTWS0RDP-M">oup</p></availability><date>2008</date></publicationStmt><notesStmt><note type="research-article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</note><note type="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Evaluation of the Immune Response to a 2-Dose Measles Vaccination Schedule Administered at 6 and 9 Months of Age to HIV-Infected and HIV-Uninfected Children in Malawi</title><author xml:id="author-0000" corresp="yes"><persName><forename type="first">Rita F.</forename><surname>Helfand</surname></persName><email>rzh7@cdc.gov</email><email>rzh7@cdc.gov</email><affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</affiliation><affiliation>Reprints or correspondence: Dr. Rita Helfand, Centers for Disease Control and Prevention, 1600 Clifton Road, MS C-12, Atlanta, GA 30333</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Desiree</forename><surname>Witte</surname></persName><affiliation>College of Medicine, University of Malawi, Blantyre, Malawi</affiliation></author><author xml:id="author-0002"><persName><forename type="first">Ashley</forename><surname>Fowlkes</surname></persName><affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</affiliation></author><author xml:id="author-0003"><persName><forename type="first">Philip</forename><surname>Garcia</surname></persName><affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</affiliation></author><author xml:id="author-0004"><persName><forename type="first">Chunfu</forename><surname>Yang</surname></persName><affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</affiliation></author><author xml:id="author-0005"><persName><forename type="first">Richard</forename><surname>Fudzulani</surname></persName><affiliation>College of Medicine, University of Malawi, Blantyre, Malawi</affiliation></author><author xml:id="author-0006"><persName><forename type="first">Laura</forename><surname>Walls</surname></persName><affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</affiliation></author><author xml:id="author-0007"><persName><forename type="first">Sun</forename><surname>Bae</surname></persName><affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</affiliation></author><author xml:id="author-0008"><persName><forename type="first">Peter</forename><surname>Strebel</surname></persName><affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</affiliation><affiliation>World Health Organization, Geneva, Switzerland</affiliation></author><author xml:id="author-0009"><persName><forename type="first">Robin</forename><surname>Broadhead</surname></persName><affiliation>College of Medicine, University of Malawi, Blantyre, Malawi</affiliation></author><author xml:id="author-0010"><persName><forename type="first">William J.</forename><surname>Bellini</surname></persName><affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</affiliation></author><author xml:id="author-0011"><persName><forename type="first">Felicity</forename><surname>Cutts</surname></persName><affiliation>London School of Hygiene and Tropical Medicine, London, United Kingdom</affiliation></author><idno type="istex">CFD5984CBF1AA060E20D8976678E8D21AEB82FBE</idno><idno type="ark">ark:/67375/HXZ-J33LWC4G-D</idno><idno type="DOI">10.1086/592756</idno></analytic><monogr><title level="j">The Journal of Infectious Diseases</title><title level="j" type="abbrev">The Journal of Infectious Diseases</title><idno type="pISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><idno type="publisher-id">jid</idno><idno type="PublisherID-hwp">jinfdis</idno><imprint><publisher>The University of Chicago Press</publisher><date type="published" when="2008-11-15"></date><biblScope unit="volume">198</biblScope><biblScope unit="issue">10</biblScope><biblScope unit="page" from="1457">1457</biblScope><biblScope unit="page" to="1465">1465</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2008</date></creation><abstract><p>Background. The World Health Organization recommends that infants at high risk for developing measles before 9 months of age, including human immunodeficiency virus (HIV)-infected infants, receive measles vaccination (MV) at 6 and 9 months of age. Methods. Children born to HIV-infected mothers received MV at 6 and 9 months, and children of HIV-uninfected mothers were randomized to receive MV at 6 and 9 months, MV at 9 months, or routine MV without follow-up. Blood samples were obtained before and 3 months after each MV. Data were collected on adverse events for 21 days after each MV, at all clinic visits, on any hospitalization, and for subjects who died. HIV-infection status was determined by antibody assays and polymerase chain reaction; the presence of measles IgG was determined by EIA. Results. Twenty-two hundred mother-infant pairs were enrolled. After the first and second doses of measles vaccine, respectively, the percentages of children who were measles seropositive were 59% (36 of 61) and 64% (29 of 45) among HIV-infected children, 68% (152 of 223) and 94% (189 of 202) among HIV-exposed but uninfected children, and 62% (288 of 467) and 92% (385 of 417) among HIV-unexposed children. Of 521 HIV-unexposed children vaccinated only at 9 months, 398 (76%) were measles seropositive at 12 months. No serious vaccine-related adverse events were identified. Conclusions. An early, 2-dose MV schedule was immunogenic, but a higher proportion of HIV-infected children remained susceptible to measles, compared with HIV-uninfected children (whether HIV exposed or HIV unexposed).</p></abstract></profileDesc><revisionDesc><change when="2008-11-15">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/CFD5984CBF1AA060E20D8976678E8D21AEB82FBE/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"</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">
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<contrib-group>
<contrib contrib-type="author" corresp="yes">
<name><surname>Helfand</surname><given-names>Rita F.</given-names></name><xref ref-type="aff" rid="AU1"><sup>1</sup></xref><xref ref-type="corresp" rid="COR1"></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Witte</surname><given-names>Desiree</given-names></name><xref ref-type="aff" rid="AU2"><sup>2</sup></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Fowlkes</surname><given-names>Ashley</given-names></name><xref ref-type="aff" rid="AU1"><sup>1</sup></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Garcia</surname><given-names>Philip</given-names></name><xref ref-type="aff" rid="AU1"><sup>1</sup></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Yang</surname><given-names>Chunfu</given-names></name><xref ref-type="aff" rid="AU1"><sup>1</sup></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Fudzulani</surname><given-names>Richard</given-names></name><xref ref-type="aff" rid="AU2"><sup>2</sup></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Walls</surname><given-names>Laura</given-names></name><xref ref-type="aff" rid="AU1"><sup>1</sup></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Bae</surname><given-names>Sun</given-names></name><xref ref-type="aff" rid="AU1"><sup>1</sup></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Strebel</surname><given-names>Peter</given-names></name><xref ref-type="aff" rid="AU1"><sup>1</sup></xref><xref ref-type="aff" rid="AU3"><sup>3</sup></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Broadhead</surname><given-names>Robin</given-names></name><xref ref-type="aff" rid="AU2"><sup>2</sup></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Bellini</surname><given-names>William J.</given-names></name><xref ref-type="aff" rid="AU1"><sup>1</sup></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Cutts</surname><given-names>Felicity</given-names></name><xref ref-type="aff" rid="AU4"><sup>4</sup></xref>
</contrib>
<aff id="AU1"><label>1</label><institution>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention</institution>, <addr-line>Altanta, Georgia</addr-line></aff>
<aff id="AU2"><label>2</label><institution>College of Medicine, University of Malawi</institution>, <addr-line>Blantyre, Malawi</addr-line></aff>
<aff id="AU3"><label>3</label><institution>World Health Organization</institution>, <addr-line>Geneva, Switzerland</addr-line></aff>
<aff id="AU4"><label>4</label><institution>London School of Hygiene and Tropical Medicine</institution>, <addr-line>London, United Kingdom</addr-line></aff>
</contrib-group>
<author-notes>
<corresp id="COR1">Reprints or correspondence: Dr. Rita Helfand, Centers for Disease Control and Prevention, 1600 Clifton Road, MS C-12, Atlanta, GA 30333 (<email>rzh7@cdc.gov</email>).</corresp>
</author-notes>
<pub-date pub-type="ppub">
<day>15</day>
<month>11</month>
<year>2008</year>
</pub-date>
<volume>198</volume>
<issue>10</issue>
<fpage>1457</fpage>
<lpage>1465</lpage>
<history>
<date date-type="received">
<day>14</day>
<month>3</month>
<year>2008</year>
</date>
<date date-type="accepted">
<day>9</day>
<month>6</month>
<year>2008</year>
</date>
</history>
<copyright-statement>© 2008 by the Infectious Diseases Society of America</copyright-statement>
<copyright-year>2008</copyright-year>
<abstract>
<p><bold><italic>Background.</italic></bold> The World Health Organization recommends that infants at high risk for developing measles before 9 months of age, including human immunodeficiency virus (HIV)-infected infants, receive measles vaccination (MV) at 6 and 9 months of age.</p>
<p><bold><italic>Methods.</italic></bold> Children born to HIV-infected mothers received MV at 6 and 9 months, and children of HIV-uninfected mothers were randomized to receive MV at 6 and 9 months, MV at 9 months, or routine MV without follow-up. Blood samples were obtained before and 3 months after each MV. Data were collected on adverse events for 21 days after each MV, at all clinic visits, on any hospitalization, and for subjects who died. HIV-infection status was determined by antibody assays and polymerase chain reaction; the presence of measles IgG was determined by EIA.</p>
<p><bold><italic>Results.</italic></bold> Twenty-two hundred mother-infant pairs were enrolled. After the first and second doses of measles vaccine, respectively, the percentages of children who were measles seropositive were 59% (36 of 61) and 64% (29 of 45) among HIV-infected children, 68% (152 of 223) and 94% (189 of 202) among HIV-exposed but uninfected children, and 62% (288 of 467) and 92% (385 of 417) among HIV-unexposed children. Of 521 HIV-unexposed children vaccinated only at 9 months, 398 (76%) were measles seropositive at 12 months. No serious vaccine-related adverse events were identified.</p>
<p><bold><italic>Conclusions.</italic></bold> An early, 2-dose MV schedule was immunogenic, but a higher proportion of HIV-infected children remained susceptible to measles, compared with HIV-uninfected children (whether HIV exposed or HIV unexposed).</p>
</abstract>
</article-meta>
</front>
<body>
<p>Although measles morbidity and mortality have been reduced significantly, measles is still a leading vaccine-preventable cause of death, especially among children, causing an estimated 242,000 deaths worldwide in 2006 [<xref ref-type="bibr" rid="R1">1</xref>]. Approximately 36,000 of these deaths occur annually in sub-Saharan Africa, where approximately 2.1 million HIV-related deaths occurred in 2006 [<xref ref-type="bibr" rid="R2">2</xref>].</p>
<p>The World Health Organization (WHO) currently recommends that infants in developing countries receive measles vaccine at 9 months of age. However, they recommend that infants at high risk of developing measles before 9 months of age, including those living in areas with measles outbreaks and those with HIV infection, receive 2 doses of measles vaccine at 6 and 9 months of age [<xref ref-type="bibr" rid="R3">3</xref>]. Because the HIV status of mothers is usually unknown, most children are vaccinated once at 9 months of age, regardless of HIV status.</p>
<p>The decision to give measles vaccine at 9 months of age is based on balancing the risk of developing measles at a young age with the increased rate of primary vaccine failure at younger ages because of interference by maternal antibodies and the child's immature immune system. Several studies have suggested that infants born to HIV-infected mothers have lower levels of maternal antibodies and may be susceptible to measles infection at a younger age [<xref ref-type="bibr" rid="R4">4</xref>–<xref ref-type="bibr" rid="R7">7</xref>]. Most studies of antibody responses after standard-titer measles vaccination (MV) have shown a lower response in HIV-infected children than in HIV-uninfected children [<xref ref-type="bibr" rid="R4">4</xref>, <xref ref-type="bibr" rid="R8">8</xref>–<xref ref-type="bibr" rid="R14">14</xref>], although a recent study in Zambia demonstrated an equivalent initial response to vaccination [<xref ref-type="bibr" rid="R5">5</xref>].</p>
<p>There has also been variation in response relative to age. For example, in HIV-infected children, Arpadi et al. [<xref ref-type="bibr" rid="R9">9</xref>] found a higher rate of measles seropositivity when subjects were vaccinated at <1 year of age, compared with subjects vaccinated at an older age. Furthermore, the level of measles antibodies waned sooner, especially in those vaccinated at >1 year of age, presumably because they were vaccinated when they were more severely immunocompromised [<xref ref-type="bibr" rid="R8">8</xref>, <xref ref-type="bibr" rid="R9">9</xref>, <xref ref-type="bibr" rid="R15">15</xref>]. Two doses of vaccine are recommended for HIV-infected infants at 6 and 9 months of age to give earlier protection, but standard-titer measles vaccines have not been evaluated in HIV-infected infants <9 months old. We compared measles antibody responses to a 2-dose schedule administered at 6 and 9 months of age in HIV-infected and HIV-uninfected children (both exposed and unexposed) with responses in a control group of HIV-unexposed children vaccinated only at 9 months of age to help assess the optimal vaccination schedules for areas with a high prevalence of HIV infection.</p>
<sec sec-type="methods">
<title>Methods</title>
<p><bold><italic>Study site and population.</italic></bold> The study was conducted in Ndirande, a densely populated area in Blantyre, Malawi. Malawi has a high prevalence of HIV infection in women of child-bearing age (15%–33%) [<xref ref-type="bibr" rid="R2">2</xref>, <xref ref-type="bibr" rid="R16">16</xref>] and a very low incidence of measles—following the implementation of measles-elimination strategies [<xref ref-type="bibr" rid="R17">17</xref>]—so measles-specific antibodies in infants would likely be the result of vaccination and not of exposure to wild-type measles. During the time of the study, antiretroviral therapy for HIV infection was not available in the public sector, and the national infant-feeding guidelines encouraged breastfeeding, irrespective of the mother's HIV infection status.</p>
<p><bold><italic>Enrollment, vaccination, and follow-up methods.</italic></bold> From August 2000 through March 2002, mother-infant pairs presenting to Ndirande Health Center for the infant's 14-week routine immunization visit were screened for eligibility. Exclusion criteria were as follows: residing somewhere other than Ndirande, intent to move out of Ndirande within 3 months, and child age <2 months or >6 months. Witnessed, written informed consent was obtained; pretest HIV counseling was provided by trained study personnel; basic clinical and demographic information was recorded; and a sample of the mother's blood was obtained by finger stick for HIV and measles testing. Posttest HIV counseling was offered and encouraged. All children of HIV-infected mothers were assigned to be vaccinated at 6 and 9 months of age. Block randomization was used to assign the children of HIV-uninfected mothers to 1 of 3 groups (at a ratio of 4:5:3, respectively): MV at 6 and 9 months; MV at 9 months only; or routine MV without follow-up. Subjects in the last group were no longer followed up in the study, and they were vaccinated per Malawi's schedule; however, they were offered the option of attending the study clinic for sick visits (<xref ref-type="fig" rid="F1">figure 1</xref>). Children followed up in the study were given appointments at 6, 9, 12, 16–18, and 20–24 months, and, for a subset of children, at 30–36 months of age. This manuscript focuses on results observed through 12 months of age.</p>
<p>At each study visit, clinical and nutritional information (see below) was collected. Approximately 1 mL of blood was obtained by finger stick using sterile technique before each subcutaneously administered MV and at 12 months. Children were followed up at home 7 and 21 days after MV for adverse events, and a subset of HIV-unexposed children in the 9-month vaccination group were followed up 7 and 21 days after their 6-month visit (at which there was no MV) to serve as controls. All children were eligible to receive outpatient medical care (including vaccination, nutrition, and sick visits) at the study clinic. Vitamin A was administered at 6 and 12 months of age, in accordance with the country protocol.</p>
<p><bold><italic>Data collection.</italic></bold> At enrollment, a standard questionnaire was administered to record baseline demographic information. Additionally, at the initial visit and all follow-up visits, study nurses and clinical officers used standard questionnaires to record the child's clinical information and physical exam results (<xref ref-type="fig" rid="F3">table 1</xref>). All hospitalizations and deaths were recorded, with clinical information on symptoms and diagnoses included when possible.</p>
<p>Parents were asked to complete daily logs of any illnesses for 21 days after MV and encouraged to contact or visit the study clinic if any symptoms occurred during this time. Axillary temperature was measured during the 7- and 21-day postvaccination home visits, and a standard questionnaire captured information from parents on any history of fever, rash, diarrhea, cough, runny nose, red eyes, and other symptoms.</p>
<p><bold><italic>Measles vaccine.</italic></bold> One lot of single-dose Edmonston-Zagreb measles vaccine was donated for this study (by Berna Biotech, formerly Swiss Serum and Vaccine Institute). The vaccine was stored at 4°C–8°C until use. Potency testing of the vaccine before and during the study at the US Centers for Disease Control and Prevention (CDC) demonstrated a titer of 3.1 log<sup>10</sup> pfu of virus, without loss of titer over time. Malawi held a measles supplemental immunization activity (SIA) for children aged 9–59 months in June 2002; in general, children's participation in the study was deferred until age 20–24 months. Study children who were vaccinated in the SIA or outside the study before 12 months old were censored from further analyses.</p>
<p><bold><italic>Specimen processing, HIV tests, and related tests.</italic></bold> HIV infection status was determined from analysis of whole blood in Malawi by using 2 commercially available, rapid HIV-1 antibody tests (Determine, from Iverness Medical Innovations; and Unigold, from Trinity Biotech). Preliminary HIV infection status was assessed for children at 12 months of age, with confirmation at or after 18 months of age. Discrepant HIV test results were verified by ELISA and/or Western blot analysis. After performing HIV antibody testing, serum or plasma was separated from the remaining blood clot and stored at −70°C (or −20°C if space in the −70°C freezer was limited) until shipment to the CDC in liquid nitrogen containers.</p>
<p>After study completion, an in-house, semiquantitative, HIV-1 real-time reverse-transcriptase polymerase chain reaction (RT-PCR) was performed on samples from every study visit (to determine the timing of HIV infection) if the child's HIV antibody test results from samples collected on or after 18 months of age were unavailable or positive. This test detects HIV-1 viral RNA and proviral DNA in whole blood samples, with a detection limit of ≥10 copies of proviral DNA per RT-PCR reaction, and was performed on the stored blood clots by using a procedure [<xref ref-type="bibr" rid="R18">18</xref>] that was validated for use with blood clots [<xref ref-type="bibr" rid="R19">19</xref>]. If blood clots were unavailable, serum or plasma was used. Confirmed HIV test results (positive or negative) were defined according to either 2 concordant rapid antibody tests results after 18 months of age or real-time RT-PCR results concordant for the last 2 consecutive blood samples. Probable HIV test results were defined as 1 positive or negative real-time RT-PCR result (for the last or only sample available) without antibody testing on or after 18 months of age. Probable and confirmed HIV test results were combined during analyses. Children who became HIV infected after 12 months of age (presumably through breastfeeding) were excluded from analyses.</p>
<p><bold><italic>Measles serology.</italic></bold> Serum or plasma samples from mothers and from children through 12 months of age were tested in the same run for measles antibody at the CDC by using a commercially available indirect IgG EIA (Trinity Biotech), and results were initially defined as positive, indeterminate, or negative in accordance with the package insert. Tests with indeterminate results were repeated, and the result of the repeated test was used. Repeated indeterminate EIA results were included with positive results after performance of a modified plaque-reduction neutralization assay (PRN) [<xref ref-type="bibr" rid="R20">20</xref>] on a subset of samples validated this approach (48 of 52 randomly chosen samples with indeterminate results were positive by PRN [defined as >120 mIU neutralizing antibody/mL]). As 97%–99% of samples in all groups were measles seronegative prior to vaccination, response to MV was defined as a seropositive result after vaccination.</p>
<p><bold><italic>Sample size and statistical analysis.</italic></bold> Sample size determinations were made with the aim of having 80% power to detect differences of ≥15% between HIV-infected and HIV-uninfected children vaccinated at 6 and 9 months old and ≥10% between HIV-unexposed children vaccinated at 6 and 9 months and HIV-unexposed children vaccinated at 9 months old. Assumptions included measles seropositivity rates in HIV-uninfected children of 85% and 90% after 1 and 2 doses of MV, respectively, with a 95% significance level (2-tailed). The sample size of 2200 was selected with the goal of enrolling >60 HIV-infected children (assuming a 50% dropout rate by 1 year of age, 20% HIV-infected mothers, and 28% maternal-fetal transmission), >200 HIV-exposed but uninfected children, and >400 children of HIV-uninfected mothers randomized to be vaccinated either at both 6 and 9 months or only at 9 months of age.</p>
<p>All questionnaire data were double-entered and validated by using EpiInfo (version 6.04; CDC). Statistical analyses were performed by using SAS (SAS version 9.1; SAS Institute). The proportion of children in each group who were measles seropositive was compared by using a χ<sup>2</sup> test. Additional potential factors associated with seropositivity were assessed by using a Fisher's exact test for categorical variables or a Wilcoxon rank sum test for continuous variables. Wasting, being underweight, and stunting were defined in terms of weight-for-height, weight-for-age, and height-for-age, respectively, with a <italic>z</italic> score of ≥2 SDs below the reference population mean, compared with CDC growth curves [<xref ref-type="bibr" rid="R21">21</xref>]. Because the risk-factor assessment was considered hypothesis generating, variables that had an association with measles seropositivity resulting in <italic>P</italic> values ≤.10 were included in multivariable logistic regression models. Kaplan-Meier survival curves and the Cox proportional hazards model were used to show and compare rates of all-cause mortality between groups.</p>
<p><bold><italic>Ethical considerations.</italic></bold> Ethical approval was obtained from the College of Medicine (University of Malawi), the London School of Hygiene and Tropical Medicine, and the CDC. The protocol was also reviewed by the World Health Organization (WHO) and the Malawi Ministry of Health. Funding was provided by the WHO and the CDC. A data safety monitoring board was assembled to review morbidity and mortality data throughout the study. The WHO measles steering committee advised researchers on the measles vaccine strain to use in the study.</p>
</sec>
<sec sec-type="results">
<title>Results</title>
<p><bold><italic>Enrollment figures and demographic characteristics.</italic></bold> Of 2173 mothers screened for HIV, 421 (19%) were HIV infected. Twenty-two hundred children were enrolled (including 27 sets of twins); 1756 children were followed up prospectively (444 children were randomized to the “no follow-up” group). There were no statistically significant differences in demographic traits between the groups of children born to HIV-uninfected mothers (<xref ref-type="fig" rid="F3">table 1</xref>). Children born to HIV-infected mothers were significantly more likely to have a birth weight <3 kg (282 [66%] of 429) and to be both underweight (48 [11%] of 423) and stunted (134 [32%] of 423) at enrollment, compared with children born to HIV-uninfected mothers</p>
<p><xref ref-type="fig" rid="F1">Figure 1</xref> shows the number of children who attended each study visit; the number of subjects varied between visits because of families traveling and because of inadequate blood samples for a small percentage of children at each study visit. The HIV-infected cohort included 85 children with probable (55) or confirmed (30) HIV infection at or before 12 months of age; the first HIV-positive blood sample was obtained at 6 months for 75 children, at 9 months for 6 children, and at 12 months for 4 children. Ten children who became HIV infected after 12 months of age were excluded from analysis. At 12 months of age, 1185 children were included in analyses: 45 (53%) of 85 HIV-infected children; 202 (60%) of 334 HIV-exposed but uninfected children; 417 (70%) of 593 of HIV-unexposed children vaccinated at 6 and 9 months, and 521 (71%) of 734 HIV-unexposed children vaccinated at 9 months.</p>
<p>The frequency of study dropout was significantly higher among children born to HIV-infected mothers, compared to children born to HIV-uninfected mothers (odds ratio [OR], 1.9 [95% confidence interval {CI}, 2.4–1.5]; <italic>P</italic> < .001). HIV-negative mothers whose children dropped out before 12 months of age were significantly more likely (<italic>P</italic> < .01) not to own their homes, to have had fewer pregnancies and births, and have had no more than primary education. Among HIV-exposed children who dropped out, both parents were significantly more likely (<italic>P</italic> < .01) to have no more than primary education, and children were significantly more likely to be HIV infected, have had birth weight <3 kg, and have had symptoms and/or signs of illness at enrollment (including fever, thrush, or respiratory infections; data not shown).</p>
<p><bold><italic>Measles antibody prevalence before and after vaccination.</italic></bold> Nearly all mothers in the study population had detectable levels of measles antibody (≥95% of mothers in all groups). Only 1%–3% of the children tested before MV had detectable levels of measles IgG by EIA (<xref ref-type="fig" rid="F4">table 2</xref>).</p>
<p>At the 9-month visit, 59%–68% of children vaccinated at 6 months were measles seropositive (<xref ref-type="fig" rid="F4">table 2</xref>). At 12 months of age, HIV-infected children who received a second dose of measles vaccine at 9 months were significantly less likely to be measles seropositive than HIV-uninfected children (whether HIV-exposed or unexposed) who received a second dose at 9 months (29 [64%] of 45 versus 189 [94%] of 202 and 385 [92%] of 417; <italic>P</italic> < .001). Of 521 HIV-unexposed children vaccinated at 9 months only, 398 (76%) were measles seropositive at 12 months of age; there was a trend toward this value being higher than that for the group of HIV-infected children (<italic>P</italic> = .07), but the percentage of measles seropositive, HIV-unexposed children vaccinated at 9 months only was significantly lower than the percentage of measles seropositive, HIV-unexposed children vaccinated with 2 doses at 6 and 9 months of age (<italic>P</italic> < .001).</p>
<p>Forty-four HIV-infected children had blood samples available for both the 9- and 12-month visits. Of these 44 children, 10 (23%) remained measles seronegative at both 9 and 12 months, 19 (43%) remained measles seropositive at both visits, 6 (14%) went from measles seropositive to seronegative, and 9 (20%) went from measles seronegative to seropositive.</p>
<p><xref ref-type="fig" rid="F5">Table 3</xref> shows the results of univariable and multivariable analysis of factors associated with seropositivity after MV for children who received 2 doses of vaccine. After the first dose of vaccine, female sex and low birth weight were significantly associated with measles seropositivity in multivariable analysis; after 2 doses of vaccine, lack of HIV infection and lack of stunting at the time the blood sample was obtained were significantly associated with measles seropositivity (<italic>P</italic> < .001 and <italic>P</italic> < .05, respectively). For HIV-unexposed children vaccinated at 9 months only, female sex was the only factor significantly associated with measles seropositivity after MV (<italic>P</italic> = .02).</p>
<p><bold><italic>Adverse events.</italic></bold> There were no statistically significant differences in the prevalence of parental reports of fever, cough, conjunctivitis, or rash in the 21 days after the 6-month study visit across all groups (<xref ref-type="fig" rid="F6">table 4</xref>). After the 9-month visit, the HIV-unexposed children vaccinated with their first dose at 9 months had a significantly lower reported rate of rhinorrhea, compared with the HIV-unexposed children vaccinated at both 6 and 9 months. The HIV-infected children had a significantly higher reported rate of diarrhea, compared with all other study groups.</p>
<p>We found no significant differences among the 4 four groups in the rates of clinic sick visits in either the month before or after the vaccination visits. However, all 4 groups (including the children not vaccinated at 6 months of age who served as controls) had higher rates of clinic sick visits in the month following the 6-month (but not the 9-month) study visit, compared with the month before the visit (<italic>P</italic> < .001).</p>
<p>Twelve hospitalizations and 4 deaths occurred within 4 weeks before the 6- or 9-month MV, whereas 13 hospitalizations and 6 deaths occurred within 4 weeks after the 6- or 9-month MV. The data safety monitoring board did not interpret any of these events as vaccine related. No significant differences were seen in the number of deaths across the groups of HIV-uninfected children (exposed or unexposed) throughout the study, and no spike was seen around the time of vaccination (<xref ref-type="fig" rid="F2">figure 2</xref> and <xref ref-type="fig" rid="F7">table 5</xref>). However, mortality among HIV-infected children was significantly higher throughout the study, compared with each of the other groups (<italic>P</italic> < .001). The 2 leading causes of death (primary and secondary diagnoses) for both HIV-exposed and HIV-unexposed children were pneumonia and gastroenteritis.</p>
</sec>
<sec sec-type="discussion">
<title>Discussion</title>
<p>A 2-dose MV schedule has long been recommended by the WHO for HIV-infected infants but, to our knowledge, has not previously been evaluated. We found that at 12 months of age, HIV-infected children vaccinated at both 6 and 9 months were less likely to have detectable levels of measles antibodies than HIV-uninfected children who received 2 doses of measles vaccine at 6 and 9 months of age or 1 dose at 9 months of age. HIV-infected children showed little increase in overall measles seropositivity rates after the second dose, in contrast to HIV-uninfected children, although some HIV-infected children did become measles seropositive and others seroreverted. The proportion of HIV-infected children who were measles seropositive after 2 doses of measles vaccine in this study (29 [64%] of 45) was similar to that reported after receipt of a single MV at 9 months in the Democratic Republic of Congo (65% of 37 children) and Thailand (57% of 14 children) [<xref ref-type="bibr" rid="R12">12</xref>, <xref ref-type="bibr" rid="R22">22</xref>]. In contrast, a recent study in Zambia that used the same lot of measles vaccine as the present study found that 88% of 50 HIV-infected children were measles seropositive when tested between 1 and 6 months after MV at age 9 months, although there was rapid waning of measles antibody levels over time [<xref ref-type="bibr" rid="R5">5</xref>]. The Zambia study used the gold standard measles PRN assay, and although children with known clinical measles were excluded from analyses, measles was endemic during the study, subclinical infections could not be ruled out after MV, and some evidence was provided (i.e., asymptomatic boosting of antibody levels) that this occurred. In contrast, ours is the first study in Africa conducted in a setting without identified measles transmission, so measles antibody levels were presumably only the result of MV. Of note, the number of HIV-infected children evaluated after MV was low in all of these studies. The higher mortality rate observed among HIV-infected children supports previous assumptions that the effect of HIV-infected children who are not receiving antiretroviral therapy on the overall population immunity to measles may be relatively low, as a result of their increased mortality rate [<xref ref-type="bibr" rid="R23">23</xref>].</p>
<p>It was reassuring that we did not find any increase in serious adverse events among HIV-infected children who were vaccinated early (at age 6 months), although this study design could not detect any rare potential longer-term adverse events, such as vaccine virus pneumonitis. Although our study included a small number of HIV-infected children, our findings are consistent with those of other studies, supporting the WHO policy that HIV infection without severe immune suppression is not a contraindication to MV (reviewed in Moss et al. [<xref ref-type="bibr" rid="R4">4</xref>]) and suggesting that early vaccination appears to be safe for both HIV-infected and uninfected children. The finding that most HIV-infected mothers were measles seropositive would help explain how it has been possible to eliminate indigenous transmission of measles in settings with high rates of HIV infection. It will be important to see whether this finding persists when most mothers have antibodies due to vaccination without subclinical boosting.</p>
<p>Among HIV-uninfected children (both HIV exposed and HIV unexposed), we found a significantly higher prevalence of measles antibodies at 12 months of age after 2 doses of measles vaccine administered at 6 and 9 months of age, compared with 1 dose administered at 9 months of age. This is consistent with studies conducted in Guinea Bissau and Niger [<xref ref-type="bibr" rid="R24">24</xref>, <xref ref-type="bibr" rid="R25">25</xref>]. Evaluation at 2 and 3 years of age will be important to determine whether antibody levels persist over time in a setting like this one, where the rate of measles transmission is low.</p>
<p>The response to a single MV given at 9 months of age to HIV-negative children was lower than the anticipated 85% [<xref ref-type="bibr" rid="R26">26</xref>, <xref ref-type="bibr" rid="R27">27</xref>]. The vaccine potency (3.1 log<sub>10</sub> TCID<sub>50</sub> of virus) was just above the minimum recommended titer of 3.0 log<sub>10</sub> TCID<sub>50</sub> of virus [<xref ref-type="bibr" rid="R28">28</xref>]. However, the same lot was used in the Zambia study that found a 94% response 1–3 months after MV of HIV-uninfected children at 9 months of age, although again, measles infections could not be ruled out in that study. It is possible that the lower measles positivity rate in our study was the result of using an EIA test that may have had slightly reduced sensitivity, relative to the PRN assay. Although nutritional status was not strongly associated with nonresponse in this group, it is still possible that some unmeasured nutritional factor, such as a micronutrient deficiency, was important. It is noteworthy that despite this lower rate of measles seropositivity, measles was effectively eliminated in Malawi by using a routine dose of vaccine at 9 months of age along with a supplemental dose during SIAs.</p>
<p>In summary, an early first dose of measles vaccine at 6 months of age appeared to be safe and immunogenic for both HIV-infected and HIV-uninfected children, suggesting that it may be valuable for children under 9 months old who are at risk of developing measles. However, the percentage of HIV-infected children who were measles seropositive at 12 months of age was no higher than in previous studies of MV at 9 months only. Among HIV-uninfected children, a 2-dose schedule was more immunogenic than a single-dose schedule, but follow-up of children in all study groups will be important to determine the persistence of antibody levels at 2–3 years of age. Finally, further study will be necessary to determine the effect of antiretroviral therapy on the response to measles vaccination and the mortality rate among HIV-infected children.</p>
</sec>
</body>
<back>
<ack>
<title>Acknowledgments</title>
<p>We would like to thank the following people and organizations for their technical guidance and support: Drs. Robin Biellik, Peggi Henderson, Samuel Katz, Renu Lal, and Cathy Wilfert; the Measles Steering Committee of the World Health Organization; the members of the Data Safety Monitoring Board, and the Malawi Ministry of Health and Expanded Programme of Immunization. We would also like to acknowledge Larry Marum and Carl Campbell for their logistic support, and Aaron Curns for his statistical advice. Finally, we acknowledge the hard work and compassion of the study team at Ndirande Health Centre.</p></ack>
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<sec sec-type="display-objects">
<title>Figures and Tables</title>
<fig id="F1" position="float">
<label>Figure 1</label>
<caption>
<p>Flowchart showing enrollment and follow-up profile of study population: “bloods” denotes laboratory blood work data; extravax, children who received an additional dose of vaccine prior to 12 months of age (a second dose for the 9-month group and a third dose for the 6- and 9-month group); LTF, lost to follow-up; 9-month group, children randomized to be vaccinated at 9 months of age only; 6- and 9-month group, children randomized to be vaccinated at 6 and 9 months of age; vaxhome, vaccinated at home.</p>
</caption>
<graphic mimetype="image" xlink:href="198-10-1457-fig001.tif"></graphic>
</fig>
<fig id="F2" position="float">
<label>Figure 2</label>
<caption>
<p>Kaplan-Meier survival estimates by children's vaccination group and HIV status. Sample sizes for each time point were based on the time points when children were still considered enrolled in the study. With the exception of mothers who withdrew their children shortly after enrollment, children were not considered defaulters until after they failed to show up for study visits, so the samples sizes in this figure may be slightly greater at each time point than the actual number of children who attended each study visit.</p>
</caption>
<graphic mimetype="image" xlink:href="198-10-1457-fig002.tif"></graphic>
</fig>
<fig id="F3" position="float">
<label>Table 1</label>
<caption>
<p>Demographic and clinical characteristics of study population at time of enrollment.</p>
</caption>
<graphic mimetype="image" xlink:href="198-10-1457-tbl001.tif"></graphic>
</fig>
<fig id="F4" position="float">
<label>Table 2</label>
<caption>
<p>Infant and maternal measles EIA results through 12-month visit.</p>
</caption>
<graphic mimetype="image" xlink:href="198-10-1457-tbl002.tif"></graphic>
</fig>
<fig id="F5" position="float">
<label>Table 3</label>
<caption>
<p>Univariate and multivariable analyses of factors associated with measles seropositivity after measles vaccination among children vaccinated at 6 and 9 months of age.</p>
</caption>
<graphic mimetype="image" xlink:href="198-10-1457-tbl003.tif"></graphic>
</fig>
<fig id="F6" position="float">
<label>Table 4</label>
<caption>
<p>Parental reports of symptoms during the 21 days after measles vaccination.</p>
</caption>
<graphic mimetype="image" xlink:href="198-10-1457-tbl004.tif"></graphic>
</fig>
<fig id="F7" position="float">
<label>Table 5</label>
<caption>
<p>Changes in sample size during the study period used for Kaplan-Meier survival estimates.</p>
</caption>
<graphic mimetype="image" xlink:href="198-10-1457-tbl005.tif"></graphic>
</fig>
</sec>
<fn-group>
<fn fn-type="other">
<p>Potential conflicts of interest: none reported.</p>
</fn>
<fn fn-type="presented-by">
<p>Presented in part: 43rd Annual Meeting of the Infectious Diseases Society of America, San Francisco, California, 6–9 October 2005 (poster 1018).</p>
</fn>
<fn fn-type="financial-disclosure">
<p>Financial support: World Health Organization (grant V21/181/130 to R.B.); Centers for Disease Control and Prevention; Berna Biotech (formerly Swiss Serum and Vaccine Institute; donation of measles vaccine).</p>
</fn>
<fn fn-type="other">
<p>The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Use of trade names and commercial sources is for identification only and does not imply endorsement by the US Department of Health and Human Services.</p>
<p>One author is a staff member of the World Health Organization. The author alone is responsible for the views expressed in this publication, and they do not necessarily represent the decisions, policy, or views of the World Health Organization.</p>
</fn>
</fn-group>
</back>
</article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Evaluation of the Immune Response to a 2-Dose Measles Vaccination Schedule Administered at 6 and 9 Months of Age to HIV-Infected and HIV-Uninfected Children in Malawi</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Evaluation of the Immune Response to a 2-Dose Measles Vaccination Schedule Administered at 6 and 9 Months of Age to HIV-Infected and HIV-Uninfected Children in Malawi</title></titleInfo><name type="personal" displayLabel="corresp"><namePart type="given">Rita F.</namePart><namePart type="family">Helfand</namePart><affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</affiliation><affiliation>E-mail: rzh7@cdc.gov</affiliation><affiliation>Reprints or correspondence: Dr. Rita Helfand, Centers for Disease Control and Prevention, 1600 Clifton Road, MS C-12, Atlanta, GA 30333</affiliation><affiliation>E-mail: rzh7@cdc.gov</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Desiree</namePart><namePart type="family">Witte</namePart><affiliation>College of Medicine, University of Malawi, Blantyre, Malawi</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ashley</namePart><namePart type="family">Fowlkes</namePart><affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Philip</namePart><namePart type="family">Garcia</namePart><affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Chunfu</namePart><namePart type="family">Yang</namePart><affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Richard</namePart><namePart type="family">Fudzulani</namePart><affiliation>College of Medicine, University of Malawi, Blantyre, Malawi</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Laura</namePart><namePart type="family">Walls</namePart><affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sun</namePart><namePart type="family">Bae</namePart><affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Peter</namePart><namePart type="family">Strebel</namePart><affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</affiliation><affiliation>World Health Organization, Geneva, Switzerland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Robin</namePart><namePart type="family">Broadhead</namePart><affiliation>College of Medicine, University of Malawi, Blantyre, Malawi</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">William J.</namePart><namePart type="family">Bellini</namePart><affiliation>Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Altanta, Georgia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Felicity</namePart><namePart type="family">Cutts</namePart><affiliation>London School of Hygiene and Tropical Medicine, London, United Kingdom</affiliation><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">2008-11-15</dateIssued><copyrightDate encoding="w3cdtf">2008</copyrightDate></originInfo><abstract>Background. The World Health Organization recommends that infants at high risk for developing measles before 9 months of age, including human immunodeficiency virus (HIV)-infected infants, receive measles vaccination (MV) at 6 and 9 months of age. Methods. Children born to HIV-infected mothers received MV at 6 and 9 months, and children of HIV-uninfected mothers were randomized to receive MV at 6 and 9 months, MV at 9 months, or routine MV without follow-up. Blood samples were obtained before and 3 months after each MV. Data were collected on adverse events for 21 days after each MV, at all clinic visits, on any hospitalization, and for subjects who died. HIV-infection status was determined by antibody assays and polymerase chain reaction; the presence of measles IgG was determined by EIA. Results. Twenty-two hundred mother-infant pairs were enrolled. After the first and second doses of measles vaccine, respectively, the percentages of children who were measles seropositive were 59% (36 of 61) and 64% (29 of 45) among HIV-infected children, 68% (152 of 223) and 94% (189 of 202) among HIV-exposed but uninfected children, and 62% (288 of 467) and 92% (385 of 417) among HIV-unexposed children. Of 521 HIV-unexposed children vaccinated only at 9 months, 398 (76%) were measles seropositive at 12 months. No serious vaccine-related adverse events were identified. Conclusions. An early, 2-dose MV schedule was immunogenic, but a higher proportion of HIV-infected children remained susceptible to measles, compared with HIV-uninfected children (whether HIV exposed or HIV unexposed).</abstract><relatedItem type="host"><titleInfo><title>The Journal of Infectious Diseases</title></titleInfo><titleInfo type="abbreviated"><title>The Journal of Infectious Diseases</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><identifier type="ISSN">0022-1899</identifier><identifier type="eISSN">1537-6613</identifier><identifier type="PublisherID">jid</identifier><identifier type="PublisherID-hwp">jinfdis</identifier><part><date>2008</date><detail type="volume"><caption>vol.</caption><number>198</number></detail><detail type="issue"><caption>no.</caption><number>10</number></detail><extent unit="pages"><start>1457</start><end>1465</end></extent></part></relatedItem><identifier type="istex">CFD5984CBF1AA060E20D8976678E8D21AEB82FBE</identifier><identifier type="DOI">10.1086/592756</identifier><accessCondition type="use and reproduction" contentType="copyright">© 2008 by the Infectious Diseases Society of America</accessCondition><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-GTWS0RDP-M">oup</recordContentSource><recordOrigin>© 2008 by the Infectious Diseases Society of America</recordOrigin></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/document/CFD5984CBF1AA060E20D8976678E8D21AEB82FBE/metadata/json</uri></json:item></metadata><covers><json:item><extension>tiff</extension><original>true</original><mimetype>image/tiff</mimetype><uri>https://api.istex.fr/document/CFD5984CBF1AA060E20D8976678E8D21AEB82FBE/covers/tiff</uri></json:item><json:item><extension>html</extension><original>true</original><mimetype>text/html</mimetype><uri>https://api.istex.fr/document/CFD5984CBF1AA060E20D8976678E8D21AEB82FBE/covers/html</uri></json:item></covers><annexes><json:item><extension>jpeg</extension><original>true</original><mimetype>image/jpeg</mimetype><uri>https://api.istex.fr/document/CFD5984CBF1AA060E20D8976678E8D21AEB82FBE/annexes/jpeg</uri></json:item><json:item><extension>gif</extension><original>true</original><mimetype>image/gif</mimetype><uri>https://api.istex.fr/document/CFD5984CBF1AA060E20D8976678E8D21AEB82FBE/annexes/gif</uri></json:item><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/CFD5984CBF1AA060E20D8976678E8D21AEB82FBE/annexes/pdf</uri></json:item></annexes><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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