Kinetics of Serologic Responses to MERS Coronavirus Infection in Humans, South Korea
Identifieur interne : 000012 ( Pmc/Corpus ); précédent : 000011; suivant : 000013Kinetics of Serologic Responses to MERS Coronavirus Infection in Humans, South Korea
Auteurs : Wan Beom Park ; Ranawaka A. P. M. Perera ; Pyoeng Gyun Choe ; Eric H. Y. Lau ; Seong Jin Choi ; June Young Chun ; Hong Sang Oh ; Kyoung-Ho Song ; Ji Hwan Bang ; Eu Suk Kim ; Hong Bin Kim ; Sang Won Park ; Nam Joong Kim ; Leo Lit Man Poon ; Malik Peiris ; Myoung-Don OhSource :
- Emerging Infectious Diseases [ 1080-6040 ] ; 2015.
Abstract
We investigated the kinetics of serologic responses to Middle East respiratory syndrome coronavirus (MERS-CoV) infection by using virus neutralization and MERS-CoV S1 IgG ELISA tests. In most patients, robust antibody responses developed by the third week of illness. Delayed antibody responses with the neutralization test were associated with more severe disease.
Url:
DOI: 10.3201/eid2112.151421
PubMed: 26583829
PubMed Central: 4672454
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Lau</name></author><author><name sortKey="Choi, Seong Jin" sort="Choi, Seong Jin" uniqKey="Choi S" first="Seong Jin" last="Choi">Seong Jin Choi</name></author><author><name sortKey="Chun, June Young" sort="Chun, June Young" uniqKey="Chun J" first="June Young" last="Chun">June Young Chun</name></author><author><name sortKey="Oh, Hong Sang" sort="Oh, Hong Sang" uniqKey="Oh H" first="Hong Sang" last="Oh">Hong Sang Oh</name></author><author><name sortKey="Song, Kyoung Ho" sort="Song, Kyoung Ho" uniqKey="Song K" first="Kyoung-Ho" last="Song">Kyoung-Ho Song</name></author><author><name sortKey="Bang, Ji Hwan" sort="Bang, Ji Hwan" uniqKey="Bang J" first="Ji Hwan" last="Bang">Ji Hwan Bang</name></author><author><name sortKey="Kim, Eu Suk" sort="Kim, Eu Suk" uniqKey="Kim E" first="Eu Suk" last="Kim">Eu Suk Kim</name></author><author><name sortKey="Kim, Hong Bin" sort="Kim, Hong Bin" uniqKey="Kim H" first="Hong Bin" last="Kim">Hong Bin Kim</name></author><author><name sortKey="Park, Sang Won" sort="Park, Sang Won" uniqKey="Park S" first="Sang Won" last="Park">Sang Won Park</name></author><author><name sortKey="Kim, Nam Joong" sort="Kim, Nam Joong" uniqKey="Kim N" first="Nam Joong" last="Kim">Nam Joong Kim</name></author><author><name sortKey="Man Poon, Leo Lit" sort="Man Poon, Leo Lit" uniqKey="Man Poon L" first="Leo Lit" last="Man Poon">Leo Lit Man Poon</name></author><author><name sortKey="Peiris, Malik" sort="Peiris, Malik" uniqKey="Peiris M" first="Malik" last="Peiris">Malik Peiris</name></author><author><name sortKey="Oh, Myoung Don" sort="Oh, Myoung Don" uniqKey="Oh M" first="Myoung-Don" last="Oh">Myoung-Don Oh</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26583829</idno><idno type="pmc">4672454</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4672454</idno><idno type="RBID">PMC:4672454</idno><idno type="doi">10.3201/eid2112.151421</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000012</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000012</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Kinetics of Serologic Responses to MERS Coronavirus Infection in Humans, South Korea</title><author><name sortKey="Park, Wan Beom" sort="Park, Wan Beom" uniqKey="Park W" first="Wan Beom" last="Park">Wan Beom Park</name></author><author><name sortKey="Perera, Ranawaka A P M" sort="Perera, Ranawaka A P M" uniqKey="Perera R" first="Ranawaka A. P. M." last="Perera">Ranawaka A. P. M. Perera</name></author><author><name sortKey="Choe, Pyoeng Gyun" sort="Choe, Pyoeng Gyun" uniqKey="Choe P" first="Pyoeng Gyun" last="Choe">Pyoeng Gyun Choe</name></author><author><name sortKey="Lau, Eric H Y" sort="Lau, Eric H Y" uniqKey="Lau E" first="Eric H. Y." last="Lau">Eric H. Y. Lau</name></author><author><name sortKey="Choi, Seong Jin" sort="Choi, Seong Jin" uniqKey="Choi S" first="Seong Jin" last="Choi">Seong Jin Choi</name></author><author><name sortKey="Chun, June Young" sort="Chun, June Young" uniqKey="Chun J" first="June Young" last="Chun">June Young Chun</name></author><author><name sortKey="Oh, Hong Sang" sort="Oh, Hong Sang" uniqKey="Oh H" first="Hong Sang" last="Oh">Hong Sang Oh</name></author><author><name sortKey="Song, Kyoung Ho" sort="Song, Kyoung Ho" uniqKey="Song K" first="Kyoung-Ho" last="Song">Kyoung-Ho Song</name></author><author><name sortKey="Bang, Ji Hwan" sort="Bang, Ji Hwan" uniqKey="Bang J" first="Ji Hwan" last="Bang">Ji Hwan Bang</name></author><author><name sortKey="Kim, Eu Suk" sort="Kim, Eu Suk" uniqKey="Kim E" first="Eu Suk" last="Kim">Eu Suk Kim</name></author><author><name sortKey="Kim, Hong Bin" sort="Kim, Hong Bin" uniqKey="Kim H" first="Hong Bin" last="Kim">Hong Bin Kim</name></author><author><name sortKey="Park, Sang Won" sort="Park, Sang Won" uniqKey="Park S" first="Sang Won" last="Park">Sang Won Park</name></author><author><name sortKey="Kim, Nam Joong" sort="Kim, Nam Joong" uniqKey="Kim N" first="Nam Joong" last="Kim">Nam Joong Kim</name></author><author><name sortKey="Man Poon, Leo Lit" sort="Man Poon, Leo Lit" uniqKey="Man Poon L" first="Leo Lit" last="Man Poon">Leo Lit Man Poon</name></author><author><name sortKey="Peiris, Malik" sort="Peiris, Malik" uniqKey="Peiris M" first="Malik" last="Peiris">Malik Peiris</name></author><author><name sortKey="Oh, Myoung Don" sort="Oh, Myoung Don" uniqKey="Oh M" first="Myoung-Don" last="Oh">Myoung-Don Oh</name></author></analytic><series><title level="j">Emerging Infectious Diseases</title><idno type="ISSN">1080-6040</idno><idno type="eISSN">1080-6059</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>We investigated the kinetics of serologic responses to Middle East respiratory syndrome coronavirus (MERS-CoV) infection by using virus neutralization and MERS-CoV S1 IgG ELISA tests. In most patients, robust antibody responses developed by the third week of illness. Delayed antibody responses with the neutralization test were associated with more severe disease.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><pmc article-type="brief-report"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Emerg Infect Dis</journal-id><journal-id journal-id-type="iso-abbrev">Emerging Infect. Dis</journal-id><journal-id journal-id-type="publisher-id">EID</journal-id><journal-title-group><journal-title>Emerging Infectious Diseases</journal-title></journal-title-group><issn pub-type="ppub">1080-6040</issn><issn pub-type="epub">1080-6059</issn><publisher><publisher-name>Centers for Disease Control and Prevention</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26583829</article-id><article-id pub-id-type="pmc">4672454</article-id><article-id pub-id-type="publisher-id">15-1421</article-id><article-id pub-id-type="doi">10.3201/eid2112.151421</article-id><article-categories><subj-group subj-group-type="heading"><subject>Dispatch</subject></subj-group><subj-group subj-group-type="article-type"><subject>Dispatch</subject></subj-group><subj-group subj-group-type="TOC-title"><subject>Kinetics of Serologic Responses to MERS Coronavirus Infection in Humans, South Korea</subject></subj-group></article-categories><title-group><article-title>Kinetics of Serologic Responses to MERS Coronavirus Infection in Humans, South Korea</article-title><alt-title alt-title-type="running-head">Serologic Responses to MERS-CoV Infection</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Park</surname><given-names>Wan Beom</given-names></name><xref ref-type="fn" rid="FN1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Perera</surname><given-names>Ranawaka A.P.M.</given-names></name><xref ref-type="fn" rid="FN1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Choe</surname><given-names>Pyoeng Gyun</given-names></name></contrib><contrib contrib-type="author"><name><surname>Lau</surname><given-names>Eric H.Y.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Choi</surname><given-names>Seong Jin</given-names></name></contrib><contrib contrib-type="author"><name><surname>Chun</surname><given-names>June Young</given-names></name></contrib><contrib contrib-type="author"><name><surname>Oh</surname><given-names>Hong Sang</given-names></name></contrib><contrib contrib-type="author"><name><surname>Song</surname><given-names>Kyoung-Ho</given-names></name></contrib><contrib contrib-type="author"><name><surname>Bang</surname><given-names>Ji Hwan</given-names></name></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Eu Suk</given-names></name></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Hong Bin</given-names></name></contrib><contrib contrib-type="author"><name><surname>Park</surname><given-names>Sang Won</given-names></name></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Nam Joong</given-names></name></contrib><contrib contrib-type="author"><name><surname>Man Poon</surname><given-names>Leo Lit</given-names></name></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Peiris</surname><given-names>Malik</given-names></name></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Oh</surname><given-names>Myoung-don</given-names></name></contrib><aff id="aff1">Seoul National University College of Medicine, Seoul, South Korea (W.B. Park, P.G. Choe, S.J. Choi, J.Y. Chun, H.S. Oh, K.-H. Song, J.H. Bang, E.S. Kim, H.B. Kim, S.W. Park, N.J. Kim, M.-d. Oh);</aff><aff id="aff2">The University of Hong Kong, Pokfulam, Hong Kong, China (R.A.P.M. Perera, E.H.Y. Lau, L.L.M. Poon);</aff><aff id="aff3">Hong Kong University–Pasteur Research Pole, Pokfulam (M. Peiris)</aff></contrib-group><author-notes><corresp id="cor1">Address for correspondence: Myoung-don Oh, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-799, South Korea; e-mail: <email xlink:href="mdohmd@snu.ac.kr">mdohmd@snu.ac.kr</email>; or Malik Peiris, School of Public Health, the University of Hong Kong, Pokfulam, Hong Kong, China; e-mail: <email xlink:href="malik@hku.hk">malik@hku.hk</email></corresp></author-notes><pub-date pub-type="ppub"><month>12</month><year>2015</year></pub-date><volume>21</volume><issue>12</issue><fpage>2186</fpage><lpage>2189</lpage><abstract><p>We investigated the kinetics of serologic responses to Middle East respiratory syndrome coronavirus (MERS-CoV) infection by using virus neutralization and MERS-CoV S1 IgG ELISA tests. In most patients, robust antibody responses developed by the third week of illness. Delayed antibody responses with the neutralization test were associated with more severe disease.</p></abstract><kwd-group kwd-group-type="author"><title>Keywords: </title><kwd>Middle East respiratory syndrome coronavirus</kwd><kwd>MERS-CoV</kwd><kwd>Middle East respiratory syndrome</kwd><kwd>MERS</kwd><kwd>coronavirus</kwd><kwd>antibody</kwd><kwd>kinetics</kwd><kwd>immunity</kwd><kwd>severity</kwd><kwd>viruses</kwd><kwd>South Korea</kwd><kwd>clinical correlates</kwd><kwd>serologic responses</kwd><kwd>diagnostics</kwd><kwd>seroepidemiologic data</kwd><kwd>humans</kwd></kwd-group></article-meta></front><body><p>Knowledge of the kinetics and clinical correlates of serologic responses to Middle East respiratory syndrome coronavirus (MERS-CoV) infection is essential for diagnosing the disease, interpreting seroepidemiologic data to define prevalence and risk factors for infection, understanding pathogenesis, and assessing a potential role for passive immunotherapy. To address this knowledge gap, we investigated serologic responses to MERS-CoV in 17 patients.</p><sec><title>The Study</title><p>During May–June 2015, an outbreak of MERS-CoV in South Korea resulted in 186 infections and 36 deaths (<xref rid="R1" ref-type="bibr"><italic>1</italic></xref>–<xref rid="R3" ref-type="bibr"><italic>3</italic></xref>); the outbreak strain was a clade B MERS-CoV closely related to viruses circulating in the Middle East (<xref rid="R1" ref-type="bibr"><italic>1</italic></xref>). Seventeen patients with reverse transcription PCR–confirmed MERS-CoV infections were included in this study; the patients were hospitalized at Seoul National University (SNU) Hospital or SNU Boramae Medical Center in Seoul, South Korea, or at SNU Bundang Hospital, in Bundang, South Korea. We investigated early serologic responses; thus, patients who were transferred to these facilities <underline>></underline>14 days after illness onset were excluded from study. Patients’ demographic and clinical profiles are shown in <xref ref-type="local-data" rid="SD1">Technical Appendix</xref> Table 1. Of the 17 patients, 9 had severe disease (4 required mechanical ventilation, 4 required supplemental oxygen; 1 died) and 8 had mild disease. Serial serum samples were collected and analyzed. The study was approved by the SNU Institutional Review Board.</p><p>Antibody to MERS-CoV was detected by using the plaque reduction neutralization test (PRNT) and MERS-CoV S1 IgG ELISA (EUROIMMUN, Lübeck, Germany) (<xref rid="R4" ref-type="bibr"><italic>4</italic></xref>,<xref rid="R5" ref-type="bibr"><italic>5</italic></xref>) (<xref ref-type="local-data" rid="SD1">Technical Appendix</xref>). MERS-CoV EMC was used for the PRNT assay; a 50% PRNT endpoint (PRNT<sub>50</sub>) was used because it was more sensitive than the 90% PRNT cutoff in detecting mild infections (<xref rid="R6" ref-type="bibr"><italic>6</italic></xref>). The ELISA was based on the recombinant spike S1 region of strain EMC because that region is sufficiently divergent between different coronavirus species and expected to lead to less cross-reaction (<xref rid="R4" ref-type="bibr"><italic>4</italic></xref>).</p><p>Overall, serologic responses were robust and were detected in most patients by week 3 of illness (<xref ref-type="fig" rid="F1">Figure</xref>). Of the 12 patients who had serum samples tested beyond day 18 of illness, 9 had PRNT<sub>50</sub> titers of 1:320 by day 21 and 2 more had titers >1:320 by day 28. Patient L, a 56-year-old woman with no underlying disease, had weakly positive PRNT<sub>50</sub> (1:20) and borderline ELISA responses (optical density ratio 1.0), even at day 32 of illness. A chest radiograph showed she had lung infiltrates, but she was not oxygen-dependent and was not administered antiviral drugs or corticosteroids; her recovery was uneventful.</p><fig id="F1" fig-type="figure" position="float"><label>Figure</label><caption><p>Antibody response kinetics in patients with Middle East respiratory syndrome coronavirus (MERS-CoV) infection, by days after illness onset, as determined by using a 50% endpoint plaque reduction neutralization test (PRNT<sub>50</sub>) (A) and an S1 IgG ELISA (B). Key indicates individual patients; Red indicates patients with severe illness requiring mechanical ventilation; blue indicates patients with severe illness requiring only supplemental oxygen therapy; and green indicates patients with mild illness. For better presentation, the PRNT<sub>50</sub> titers have been jittered vertically (random noise added to prevent overplotting) (<xref rid="R7" ref-type="bibr"><italic>7</italic></xref>) by adding random numbers to the titers within the range of −0.2 to 0.2 at the log scale. OD, optical density.</p></caption><graphic xlink:href="15-1421-F"></graphic></fig><p>Antibody responses in patient A, a 38-year-old man, were delayed up to 16–18 days after illness onset (<xref ref-type="fig" rid="F1">Figure</xref>). He required mechanical ventilation, and on illness day 14, he was given convalescent-phase plasma (200 mL; antibody titer unknown) from the outbreak index patient’s wife (<xref rid="R1" ref-type="bibr"><italic>1</italic></xref>). The next day, antibody responses were undetectable in the patient’s serum by PRNT or ELISA. By day 18, he had a PRNT<sub>50</sub> antibody titer of 1:10 and a negative ELISA response; strong antibody responses developed from day 21 onwards. We hypothesize that the data from the first 21 days of illness represent his own serologic response, unaffected by the passive transfusion with convalescent-phase plasma on day 14; thus, these data were included in the analysis. Patient A was given a second infusion of convalescent-phase plasma on day 24, and serologic data after day 21 were excluded from analysis.</p><p>We constructed a statistical model in which age, sex, incubation period, concomitant conditions, and therapy with corticosteroids or antiviral drugs were adjusted for disease severity. We assessed how these factors were associated with the time from illness onset to commencement of the log-phase antibody response (<xref ref-type="table" rid="T1">Table 1</xref>) and the time for the antibody response to reach a titer of 1:40 (PRNT<sub>50</sub>) or become positive in the ELISA (<xref ref-type="local-data" rid="SD1">Technical Appendix</xref><xref ref-type="table" rid="T2">Table 2</xref>). An accelerated failure model was used for a more natural interpretation of the median time from illness onset to the aforementioned antibody responses (<xref ref-type="local-data" rid="SD1">Technical Appendix</xref>). Because the increase in antibody titers exhibited an S-shaped pattern, we assessed the rate of change in antibody response after the commencement of the exponential phase by manually removing data from the steady state, thus restricting antibody data to the log-phase response (<xref ref-type="table" rid="T2">Table 2</xref>). A linear mixed model was used to test the potential difference in the rate of increase by the above factors (<xref ref-type="local-data" rid="SD1">Technical Appendix</xref>). Patients with severe disease had significant delays in the commencement of PRNT<sub>50</sub> antibody responses (<xref ref-type="table" rid="T1">Table 1</xref>) but had a steeper slope to the antibody response once it began (<xref ref-type="table" rid="T2">Table 2</xref>). Thus, a delayed adaptive immune response may contribute to increased severity, and passive therapy with convalescent-phase immune plasma may be clinically beneficial. In avian influenza A(H7N9) virus infection of humans, earlier antibody responses and a faster rate of increasing antibody titers were associated with milder disease (<xref rid="R8" ref-type="bibr"><italic>8</italic></xref>), but in SARS-CoV infection, earlier antibody responses were associated with an adverse outcome (<xref rid="R9" ref-type="bibr"><italic>9</italic></xref>).</p><table-wrap id="T1" position="float"><label>Table 1</label><caption><title>Associations and p values for different clinical factors with time from illness onset to commencement of log phase of antibody response in PRNT<sub>50</sub> and S1-ELISA*</title></caption><table frame="hsides" rules="groups"><col width="110" span="1"></col><col width="85" span="1"></col><col width="85" span="1"></col><col width="9" span="1"></col><col width="95" span="1"></col><col width="95" span="1"></col><thead><tr><th rowspan="2" valign="bottom" align="left" scope="col" colspan="1">Clinical factors</th><th colspan="5" valign="top" align="center" scope="colgroup" rowspan="1">Acceleration factor of time from illness onset to log phase of antibody response<hr></hr></th></tr><tr><th valign="bottom" colspan="1" align="center" scope="colgroup" rowspan="1">PRNT<sub>50</sub> titer</th><th valign="top" align="center" scope="col" rowspan="1" colspan="1">p value</th><th valign="top" align="left" scope="col" rowspan="1" colspan="1"></th><th valign="bottom" align="center" scope="col" rowspan="1" colspan="1">S1-ELISA OD ratio‡</th><th valign="top" align="center" scope="col" rowspan="1" colspan="1">p value</th></tr></thead><tbody><tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1">Severe disease</td><td valign="top" align="center" rowspan="1" colspan="1">1.61</td><td valign="top" align="center" rowspan="1" colspan="1"><0.001</td><td valign="top" align="left" rowspan="1" colspan="1"></td><td valign="top" align="center" rowspan="1" colspan="1">1.19</td><td valign="top" align="center" rowspan="1" colspan="1">0.21</td></tr><tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1">Male sex†</td><td valign="top" align="center" rowspan="1" colspan="1">0.90</td><td valign="top" align="center" rowspan="1" colspan="1">0.52</td><td valign="top" align="left" rowspan="1" colspan="1"></td><td valign="top" align="center" rowspan="1" colspan="1">0.90</td><td valign="top" align="center" rowspan="1" colspan="1">0.48</td></tr><tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1">Age <underline>></underline>60 y†</td><td valign="top" align="center" rowspan="1" colspan="1">0.95</td><td valign="top" align="center" rowspan="1" colspan="1">0.73</td><td valign="top" align="left" rowspan="1" colspan="1"></td><td valign="top" align="center" rowspan="1" colspan="1">1.08</td><td valign="top" align="center" rowspan="1" colspan="1">0.60</td></tr><tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1">Incubation period, d†</td><td valign="top" align="center" rowspan="1" colspan="1">0.97</td><td valign="top" align="center" rowspan="1" colspan="1">0.06</td><td valign="top" align="left" rowspan="1" colspan="1"></td><td valign="top" align="center" rowspan="1" colspan="1">0.95</td><td valign="top" align="center" rowspan="1" colspan="1"><0.001</td></tr><tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1">Use of corticosteroid†</td><td valign="top" align="center" rowspan="1" colspan="1">1.19</td><td valign="top" align="center" rowspan="1" colspan="1">0.33</td><td valign="top" align="left" rowspan="1" colspan="1"></td><td valign="top" align="center" rowspan="1" colspan="1">1.14</td><td valign="top" align="center" rowspan="1" colspan="1">0.47</td></tr><tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1">Use of antiviral drugs†</td><td valign="top" align="center" rowspan="1" colspan="1">1.07</td><td valign="top" align="center" rowspan="1" colspan="1">0.61</td><td valign="top" align="left" rowspan="1" colspan="1"></td><td valign="top" align="center" rowspan="1" colspan="1">0.76</td><td valign="top" align="center" rowspan="1" colspan="1">0.03</td></tr><tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1">Concomitant conditions†</td><td valign="top" align="center" rowspan="1" colspan="1">1.08</td><td valign="top" align="center" rowspan="1" colspan="1">0.57</td><td valign="top" align="left" rowspan="1" colspan="1"></td><td valign="top" align="center" rowspan="1" colspan="1">1.15</td><td valign="top" align="center" rowspan="1" colspan="1">0.30</td></tr></tbody></table><table-wrap-foot><p>*Accelerated failure time models were used; acceleration factor >1 means a longer interval to commencement of antibody response. OD, optical density; PRNT<sub>50</sub>, 50% endpoint plaque reduction neutralization test.
†Effects were adjusted for severity.
‡Increase over S1-ELISA OD <underline>></underline>0.8..</p></table-wrap-foot></table-wrap><table-wrap id="T2" position="float"><label>Table 2</label><caption><title>Testing potential difference in rates of change in antibody titers over day of illness during the exponential phase of the antibody response, accounting for sequential measurements taken at different days of illness and adjusted for severity*</title></caption><table frame="hsides" rules="groups"><col width="132" span="1"></col><col width="69" span="1"></col><col width="79" span="1"></col><col width="9" span="1"></col><col width="100" span="1"></col><col width="91" span="1"></col><thead><tr><th rowspan="2" valign="bottom" align="left" scope="col" colspan="1">Clinical factors</th><th colspan="5" valign="top" align="center" scope="colgroup" rowspan="1">Difference in rates of change in log antibody titers<hr></hr></th></tr><tr><th valign="bottom" colspan="1" align="center" scope="colgroup" rowspan="1">PRNT<sub>50</sub> titer</th><th valign="top" align="center" scope="col" rowspan="1" colspan="1">p value</th><th valign="top" align="left" scope="col" rowspan="1" colspan="1"></th><th valign="bottom" align="center" scope="col" rowspan="1" colspan="1">S1-ELISA OD ratio</th><th valign="top" align="center" scope="col" rowspan="1" colspan="1">p value</th></tr></thead><tbody><tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1">Severe disease</td><td valign="top" align="center" rowspan="1" colspan="1">0.09</td><td valign="top" align="center" rowspan="1" colspan="1">0.01</td><td valign="top" align="left" rowspan="1" colspan="1"></td><td valign="top" align="center" rowspan="1" colspan="1">0.08</td><td valign="top" align="center" rowspan="1" colspan="1">0.07</td></tr><tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1">Male sex†</td><td valign="top" align="center" rowspan="1" colspan="1">0.07</td><td valign="top" align="center" rowspan="1" colspan="1">0.05</td><td valign="top" align="left" rowspan="1" colspan="1"></td><td valign="top" align="center" rowspan="1" colspan="1">0.14</td><td valign="top" align="center" rowspan="1" colspan="1">0.01</td></tr><tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1">Age <underline>></underline>60 y†</td><td valign="top" align="center" rowspan="1" colspan="1">0.05</td><td valign="top" align="center" rowspan="1" colspan="1">0.22</td><td valign="top" align="left" rowspan="1" colspan="1"></td><td valign="top" align="center" rowspan="1" colspan="1">−0.03</td><td valign="top" align="center" rowspan="1" colspan="1">0.65</td></tr><tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1">Incubation period, d†</td><td valign="top" align="center" rowspan="1" colspan="1">0.01</td><td valign="top" align="center" rowspan="1" colspan="1">0.16</td><td valign="top" align="left" rowspan="1" colspan="1"></td><td valign="top" align="center" rowspan="1" colspan="1">0.02</td><td valign="top" align="center" rowspan="1" colspan="1">0.004</td></tr><tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1">Use of corticosteroid†</td><td valign="top" align="center" rowspan="1" colspan="1">0.06</td><td valign="top" align="center" rowspan="1" colspan="1">0.37</td><td valign="top" align="left" rowspan="1" colspan="1"></td><td valign="top" align="center" rowspan="1" colspan="1">−0.04</td><td valign="top" align="center" rowspan="1" colspan="1">0.58</td></tr><tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1">Use of antiviral drugs†</td><td valign="top" align="center" rowspan="1" colspan="1">0.06</td><td valign="top" align="center" rowspan="1" colspan="1">0.10</td><td valign="top" align="left" rowspan="1" colspan="1"></td><td valign="top" align="center" rowspan="1" colspan="1">0.05</td><td valign="top" align="center" rowspan="1" colspan="1">0.35</td></tr><tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1">Concomitant conditions†</td><td valign="top" align="center" rowspan="1" colspan="1">0.06</td><td valign="top" align="center" rowspan="1" colspan="1">0.06</td><td valign="top" align="left" rowspan="1" colspan="1"></td><td valign="top" align="center" rowspan="1" colspan="1">0.07 </td><td valign="top" align="center" rowspan="1" colspan="1">0.16</td></tr></tbody></table><table-wrap-foot><p>*Differences in rates of change and p values were estimated by using linear mixed models; positive value indicates a faster increase in antibody titer. Given that the antibody titers exhibited an S-shaped pattern, the analysis was restricted to data for log-phase antibody responses by manually removing data from the inductive/steady-state phase. Increases in antibody titers during the log phase were compared by different factors, adjusted for disease severity, by using a linear mixed model to account for repeated measurements, assuming a linear increasing trend by days since illness onset. PRNT<sub>50</sub> titers were first log-transformed (with base 10). OD, optical density; PRNT<sub>50</sub>, 50% endpoint plaque reduction neutralization test.
†Effects were adjusted for severity.</p></table-wrap-foot></table-wrap><p>Extensive contact tracing during the outbreak enabled us to determine the date of MERS-CoV exposure and incubation periods for patients (<xref ref-type="local-data" rid="SD1">Technical Appendix</xref><xref ref-type="table" rid="T1">Table 1</xref>). A longer incubation period was associated with earlier commencement of antibody responses detectable by ELISA (<xref ref-type="table" rid="T1">Table 1</xref>; <xref ref-type="local-data" rid="SD1">Technical Appendix</xref><xref ref-type="table" rid="T2">Table 2</xref>) and with a steeper slope to the response once it began (<xref ref-type="table" rid="T2">Table 2</xref>). Even after adjusting for disease severity, the use of interferon and antiviral drugs was associated with earlier commencement of antibody responses detectable by ELISA (<xref ref-type="table" rid="T1">Table 1</xref>). The time to commencement of response was similar for men and women, but the slope of the response was steeper for male patients (<xref ref-type="table" rid="T2">Table 2</xref>).</p></sec><sec sec-type="conclusions"><title>Conclusions</title><p>An understanding of MERS-CoV antibody response kinetics helps in defining the window during which passive antibody therapy may be useful. In our study, this window was the first 21 days of illness for most patients. However, some patients may not develop strong antibody responses even after 4 weeks of illness, so therapy must be individualized.</p><p>Our study has some limitations. First, no MERS-CoV isolates from the study patients were available, so MERS-CoV EMC was the basis of the serologic assays we used. Strain EMC is a clade A virus, and the outbreak in South Korea was caused by a clade B virus (<xref rid="R1" ref-type="bibr"><italic>1</italic></xref>). However, using serum from naturally infected camels, we previously showed that clade A and B viruses and genetically diverse MERS-CoVs from Egypt were serologically indistinguishable (<xref rid="R10" ref-type="bibr"><italic>10</italic></xref>). Another study reported that isolates of MERS-CoVs circulating in Saudi Arabia in 2014 were antigenically indistinguishable from the EMC strain in neutralization tests with human convalescent-phase serum (<xref rid="R5" ref-type="bibr"><italic>5</italic></xref>). Thus, it is unlikely that the use of MERS-CoV EMC in our study considerably affected the observed antibody titers. A second limitation was the small number of patients studied (n = 17) and that they were followed only through the acute stage of illness. Longer term follow-up is needed to define the duration of antibody responses. If MERS-CoV antibody responses wane, as has been reported with SARS (<xref rid="R11" ref-type="bibr">11</xref>), this is relevant for interpretation of seroepidemiologic studies and for finding convalescent-phase donors with high antibody titers for passive immunotherapy. It would be useful to investigate IgM antibody responses and antibody responses to other virus proteins, including the MERS-CoV nucleoprotein, especially in patient L, who had poor antibody responses.</p><p>In summary, our findings showed that an early MERS-CoV antibody response was associated with reduced disease severity. Robust neutralizing and S1 ELISA IgG antibody responses were mounted by the third week of illness in most patients. However, a robust response did not occur in a few patients, and infections in such patients may be undetectable by serologic and seroepidemiologic methods.</p></sec><sec sec-type="supplementary-material"><title></title><supplementary-material content-type="local-data" id="SD1"><caption><title>Technical Appendix</title><p>Demographic and clinical profiles for patients and serologic and statistical methods in a study of the kinetics of serologic responses to MERS-CoV infection in humans.</p></caption><media mimetype="application" mime-subtype="pdf" xlink:href="15-1421-Techapp-s1.pdf" xlink:type="simple" id="d36e663" position="anchor"></media></supplementary-material></sec></body><back><fn-group><fn fn-type="citation"><p><italic>Suggested citation for this article</italic>: Park WB, Perera RAPM, Choe PG, Lau EHY, Choi SJ, Chun JY, et al. Kinetics of serologic responses to MERS coronavirus infection in humans, South Korea. Emerg Infect Dis. 2015 Dec [<italic>date cited</italic>]. <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.3201/eid2112.151421">http://dx.doi.org/10.3201/eid2112.151421</ext-link></p></fn><fn id="FN1"><label>1</label><p>These authors contributed equally to this article.</p></fn></fn-group><ack><p>The study was supported by research grants from the Clinical Research Institute, Seoul National University Hospital (2015-1980), South Korea; the US National Institutes of Health (contract no. HHSN272201400006C); and the Health and Medical Research Fund, Food and Health Bureau, Government of Hong Kong Special Administrative Region (commissioned grant).</p></ack><bio id="d36e684"><p>Dr. Park is a clinical scientist at Seoul National University Hospital. 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