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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Immunization with inactivated Middle East Respiratory Syndrome coronavirus vaccine leads to lung immunopathology on challenge with live virus</title><author><name sortKey="Agrawal, Anurodh Shankar" sort="Agrawal, Anurodh Shankar" uniqKey="Agrawal A" first="Anurodh Shankar" last="Agrawal">Anurodh Shankar Agrawal</name><affiliation><nlm:aff id="af0001"><institution>Departments of Microbiology and Immunology, University of Texas Medical Branch</institution>, Galveston, TX,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Tao, Xinrong" sort="Tao, Xinrong" uniqKey="Tao X" first="Xinrong" last="Tao">Xinrong Tao</name><affiliation><nlm:aff id="af0001"><institution>Departments of Microbiology and Immunology, University of Texas Medical Branch</institution>, Galveston, TX,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Algaissi, Abdullah" sort="Algaissi, Abdullah" uniqKey="Algaissi A" first="Abdullah" last="Algaissi">Abdullah Algaissi</name><affiliation><nlm:aff id="af0001"><institution>Departments of Microbiology and Immunology, University of Texas Medical Branch</institution>, Galveston, TX,<country>USA</country></nlm:aff></affiliation><affiliation><nlm:aff id="af0005"><institution>Department of Medical Laboratories Technology, College of Applied Medical Sciences, Jazan University</institution>, Jazan,<country>Saudi Arabia</country></nlm:aff></affiliation></author><author><name sortKey="Garron, Tania" sort="Garron, Tania" uniqKey="Garron T" first="Tania" last="Garron">Tania Garron</name><affiliation><nlm:aff id="af0001"><institution>Departments of Microbiology and Immunology, University of Texas Medical Branch</institution>, Galveston, TX,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Narayanan, Krishna" sort="Narayanan, Krishna" uniqKey="Narayanan K" first="Krishna" last="Narayanan">Krishna Narayanan</name><affiliation><nlm:aff id="af0001"><institution>Departments of Microbiology and Immunology, University of Texas Medical Branch</institution>, Galveston, TX,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Peng, Bi Hung" sort="Peng, Bi Hung" uniqKey="Peng B" first="Bi-Hung" last="Peng">Bi-Hung Peng</name><affiliation><nlm:aff id="af0002"><institution>Pathology, University of Texas Medical Branch</institution>, Galveston, TX,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Couch, Robert B" sort="Couch, Robert B" uniqKey="Couch R" first="Robert B." last="Couch">Robert B. Couch</name><affiliation><nlm:aff id="af0003"><institution>Internal Medicine, Division of Infectious Disease, University of Texas Medical Branch</institution>, Galveston, TX,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Tseng, Chien Te K" sort="Tseng, Chien Te K" uniqKey="Tseng C" first="Chien-Te K." last="Tseng">Chien-Te K. Tseng</name><affiliation><nlm:aff id="af0001"><institution>Departments of Microbiology and Immunology, University of Texas Medical Branch</institution>, Galveston, TX,<country>USA</country></nlm:aff></affiliation><affiliation><nlm:aff id="af0004"><institution>Center for Biodefense and Emerging Infectious Disease, University of Texas Medical Branch</institution>, Galveston, TX,<country>USA</country></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27269431</idno><idno type="pmc">5027702</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027702</idno><idno type="RBID">PMC:5027702</idno><idno type="doi">10.1080/21645515.2016.1177688</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000883</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000883</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Immunization with inactivated Middle East Respiratory Syndrome coronavirus vaccine leads to lung immunopathology on challenge with live virus</title><author><name sortKey="Agrawal, Anurodh Shankar" sort="Agrawal, Anurodh Shankar" uniqKey="Agrawal A" first="Anurodh Shankar" last="Agrawal">Anurodh Shankar Agrawal</name><affiliation><nlm:aff id="af0001"><institution>Departments of Microbiology and Immunology, University of Texas Medical Branch</institution>, Galveston, TX,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Tao, Xinrong" sort="Tao, Xinrong" uniqKey="Tao X" first="Xinrong" last="Tao">Xinrong Tao</name><affiliation><nlm:aff id="af0001"><institution>Departments of Microbiology and Immunology, University of Texas Medical Branch</institution>, Galveston, TX,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Algaissi, Abdullah" sort="Algaissi, Abdullah" uniqKey="Algaissi A" first="Abdullah" last="Algaissi">Abdullah Algaissi</name><affiliation><nlm:aff id="af0001"><institution>Departments of Microbiology and Immunology, University of Texas Medical Branch</institution>, Galveston, TX,<country>USA</country></nlm:aff></affiliation><affiliation><nlm:aff id="af0005"><institution>Department of Medical Laboratories Technology, College of Applied Medical Sciences, Jazan University</institution>, Jazan,<country>Saudi Arabia</country></nlm:aff></affiliation></author><author><name sortKey="Garron, Tania" sort="Garron, Tania" uniqKey="Garron T" first="Tania" last="Garron">Tania Garron</name><affiliation><nlm:aff id="af0001"><institution>Departments of Microbiology and Immunology, University of Texas Medical Branch</institution>, Galveston, TX,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Narayanan, Krishna" sort="Narayanan, Krishna" uniqKey="Narayanan K" first="Krishna" last="Narayanan">Krishna Narayanan</name><affiliation><nlm:aff id="af0001"><institution>Departments of Microbiology and Immunology, University of Texas Medical Branch</institution>, Galveston, TX,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Peng, Bi Hung" sort="Peng, Bi Hung" uniqKey="Peng B" first="Bi-Hung" last="Peng">Bi-Hung Peng</name><affiliation><nlm:aff id="af0002"><institution>Pathology, University of Texas Medical Branch</institution>, Galveston, TX,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Couch, Robert B" sort="Couch, Robert B" uniqKey="Couch R" first="Robert B." last="Couch">Robert B. Couch</name><affiliation><nlm:aff id="af0003"><institution>Internal Medicine, Division of Infectious Disease, University of Texas Medical Branch</institution>, Galveston, TX,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Tseng, Chien Te K" sort="Tseng, Chien Te K" uniqKey="Tseng C" first="Chien-Te K." last="Tseng">Chien-Te K. Tseng</name><affiliation><nlm:aff id="af0001"><institution>Departments of Microbiology and Immunology, University of Texas Medical Branch</institution>, Galveston, TX,<country>USA</country></nlm:aff></affiliation><affiliation><nlm:aff id="af0004"><institution>Center for Biodefense and Emerging Infectious Disease, University of Texas Medical Branch</institution>, Galveston, TX,<country>USA</country></nlm:aff></affiliation></author></analytic><series><title level="j">Human Vaccines & Immunotherapeutics</title><idno type="ISSN">2164-5515</idno><idno type="eISSN">2164-554X</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>ABSTRACT</title><p>To determine if a hypersensitive-type lung pathology might occur when mice were given an inactivated MERS-CoV vaccine and challenged with infectious virus as was seen with SARS-CoV vaccines, we prepared and vaccinated mice with an inactivated MERS-CoV vaccine. Neutralizing antibody was induced by vaccine with and without adjuvant and lung virus was reduced in vaccinated mice after challenge. Lung mononuclear infiltrates occurred in all groups after virus challenge but with increased infiltrates that contained eosinophils and increases in the eosinophil promoting IL-5 and IL-13 cytokines only in the vaccine groups. Inactivated MERS-CoV vaccine appears to carry a hypersensitive-type lung pathology risk from MERS-CoV infection that is similar to that found with inactivated SARS-CoV vaccines from SARS-CoV infection.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Tseng, Ct" uniqKey="Tseng C">CT Tseng</name></author><author><name sortKey="Sbrana, E" uniqKey="Sbrana E">E Sbrana</name></author><author><name sortKey="Iwata Yoshikawa, N" uniqKey="Iwata Yoshikawa N">N Iwata-Yoshikawa</name></author><author><name sortKey="Newman, Pc" uniqKey="Newman P">PC Newman</name></author><author><name sortKey="Garron, T" uniqKey="Garron T">T Garron</name></author><author><name sortKey="Atmar, Rl" uniqKey="Atmar R">RL Atmar</name></author><author><name sortKey="Peters, Cj" uniqKey="Peters C">CJ Peters</name></author><author><name sortKey="Couch, Rb" uniqKey="Couch R">RB Couch</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bolles, M" uniqKey="Bolles M">M Bolles</name></author><author><name sortKey="Deming, D" uniqKey="Deming D">D Deming</name></author><author><name sortKey="Long, K" uniqKey="Long K">K Long</name></author><author><name sortKey="Agnihothram, S" uniqKey="Agnihothram S">S Agnihothram</name></author><author><name sortKey="Whitmore, A" uniqKey="Whitmore A">A Whitmore</name></author><author><name sortKey="Ferris, M" uniqKey="Ferris M">M Ferris</name></author><author><name sortKey="Funkhouser, W" uniqKey="Funkhouser W">W Funkhouser</name></author><author><name sortKey="Gralinski, L" uniqKey="Gralinski L">L Gralinski</name></author><author><name sortKey="Totura, A" uniqKey="Totura A">A Totura</name></author><author><name sortKey="Heise, M" uniqKey="Heise M">M Heise</name></author><author><name sortKey="Baric, Rs" uniqKey="Baric R">RS Baric</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Agrawal, As" uniqKey="Agrawal A">AS Agrawal</name></author><author><name sortKey="Garron, T" uniqKey="Garron T">T Garron</name></author><author><name sortKey="Tao, X" uniqKey="Tao X">X Tao</name></author><author><name sortKey="Peng, Bh" uniqKey="Peng B">BH Peng</name></author><author><name sortKey="Wakamiya, M" uniqKey="Wakamiya M">M Wakamiya</name></author><author><name sortKey="Chan, Ts" uniqKey="Chan T">TS Chan</name></author><author><name sortKey="Couch, Rb" uniqKey="Couch R">RB Couch</name></author><author><name sortKey="Tseng, Ct" uniqKey="Tseng C">CT Tseng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tao, X" uniqKey="Tao X">X Tao</name></author><author><name sortKey="Garron, T" uniqKey="Garron T">T Garron</name></author><author><name sortKey="Agrawal, As" uniqKey="Agrawal A">AS Agrawal</name></author><author><name sortKey="Algaissi, A" uniqKey="Algaissi A">A Algaissi</name></author><author><name sortKey="Peng, Bh" uniqKey="Peng B">BH Peng</name></author><author><name sortKey="Wakamiya, M" uniqKey="Wakamiya M">M Wakamiya</name></author><author><name sortKey="Chan, Ts" uniqKey="Chan T">TS Chan</name></author><author><name sortKey="Lu, L" uniqKey="Lu L">L Lu</name></author><author><name sortKey="Du, L" uniqKey="Du L">L Du</name></author><author><name sortKey="Jiang, S" uniqKey="Jiang S">S Jiang</name></author><author><name sortKey="Couch, Rb" uniqKey="Couch R">RB Couch</name></author><author><name sortKey="Tseng, Ct" uniqKey="Tseng C">CT Tseng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Huang, C" uniqKey="Huang C">C Huang</name></author><author><name sortKey="Peters, Cj" uniqKey="Peters C">CJ Peters</name></author><author><name sortKey="Makino, S" uniqKey="Makino S">S Makino</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tao, X" uniqKey="Tao X">X Tao</name></author><author><name sortKey="Mei, F" uniqKey="Mei F">F Mei</name></author><author><name sortKey="Agrawal, A" uniqKey="Agrawal A">A Agrawal</name></author><author><name sortKey="Peters, Cj" uniqKey="Peters C">CJ Peters</name></author><author><name sortKey="Ksiazek, Tg" uniqKey="Ksiazek T">TG Ksiazek</name></author><author><name sortKey="Cheng, X" uniqKey="Cheng X">X Cheng</name></author><author><name sortKey="Tseng, Ct" uniqKey="Tseng C">CT Tseng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Protheroe, C" uniqKey="Protheroe C">C Protheroe</name></author><author><name sortKey="Woodruff, Sa" uniqKey="Woodruff S">SA Woodruff</name></author><author><name sortKey="De Petris, G" uniqKey="De Petris G">G de Petris</name></author><author><name sortKey="Mukkada, V" uniqKey="Mukkada V">V Mukkada</name></author><author><name sortKey="Ochkur, Si" uniqKey="Ochkur S">SI Ochkur</name></author><author><name sortKey="Janarthanan, S" uniqKey="Janarthanan S">S Janarthanan</name></author><author><name sortKey="Lewis, Jc" uniqKey="Lewis J">JC Lewis</name></author><author><name sortKey="Pasha, S" uniqKey="Pasha S">S Pasha</name></author><author><name sortKey="Lunsford, T" uniqKey="Lunsford T">T Lunsford</name></author><author><name sortKey="Harris, L" uniqKey="Harris L">L Harris</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Locksley, Rm" uniqKey="Locksley R">RM Locksley</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wynn, Ta" uniqKey="Wynn T">TA Wynn</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhang, N" uniqKey="Zhang N">N Zhang</name></author><author><name sortKey="Channappanavar, R" uniqKey="Channappanavar R">R Channappanavar</name></author><author><name sortKey="Ma, C" uniqKey="Ma C">C Ma</name></author><author><name sortKey="Wang, L" uniqKey="Wang L">L Wang</name></author><author><name sortKey="Tang, 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Hum Vaccin Immunother</journal-id><journal-id journal-id-type="iso-abbrev">Hum Vaccin Immunother</journal-id><journal-id journal-id-type="publisher-id">KHVI</journal-id><journal-id journal-id-type="publisher-id">khvi20</journal-id><journal-title-group><journal-title>Human Vaccines & Immunotherapeutics</journal-title></journal-title-group><issn pub-type="ppub">2164-5515</issn><issn pub-type="epub">2164-554X</issn><publisher><publisher-name>Taylor & Francis</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27269431</article-id><article-id pub-id-type="pmc">5027702</article-id><article-id pub-id-type="publisher-id">1177688</article-id><article-id pub-id-type="doi">10.1080/21645515.2016.1177688</article-id><article-categories><subj-group subj-group-type="heading"><subject>Short Report</subject></subj-group></article-categories><title-group><article-title>Immunization with inactivated Middle East Respiratory Syndrome coronavirus vaccine leads to lung immunopathology on challenge with live virus</article-title><alt-title alt-title-type="running-authors">A. S. AGRAWAL ET AL.</alt-title><alt-title alt-title-type="running-title">HUMAN VACCINES & IMMUNOTHERAPEUTICS</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Agrawal</surname><given-names>Anurodh Shankar</given-names></name><xref ref-type="aff" rid="af0001"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tao</surname><given-names>Xinrong</given-names></name><xref ref-type="aff" rid="af0001"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Algaissi</surname><given-names>Abdullah</given-names></name><xref ref-type="aff" rid="af0001"><sup>a</sup></xref><xref ref-type="aff" rid="af0005"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Garron</surname><given-names>Tania</given-names></name><xref ref-type="aff" rid="af0001"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Narayanan</surname><given-names>Krishna</given-names></name><xref ref-type="aff" rid="af0001"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Peng</surname><given-names>Bi-Hung</given-names></name><xref ref-type="aff" rid="af0002"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Couch</surname><given-names>Robert B.</given-names></name><xref ref-type="aff" rid="af0003"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tseng</surname><given-names>Chien-Te K.</given-names></name><xref ref-type="aff" rid="af0001"><sup>a</sup></xref><xref ref-type="aff" rid="af0004"><sup>d</sup></xref><xref ref-type="corresp" rid="an0001"></xref></contrib><aff id="af0001"><label>a</label><institution>Departments of Microbiology and Immunology, University of Texas Medical Branch</institution>, Galveston, TX,<country>USA</country></aff><aff id="af0002"><label>b</label><institution>Pathology, University of Texas Medical Branch</institution>, Galveston, TX,<country>USA</country></aff><aff id="af0003"><label>c</label><institution>Internal Medicine, Division of Infectious Disease, University of Texas Medical Branch</institution>, Galveston, TX,<country>USA</country></aff><aff id="af0004"><label>d</label><institution>Center for Biodefense and Emerging Infectious Disease, University of Texas Medical Branch</institution>, Galveston, TX,<country>USA</country></aff><aff id="af0005"><label>e</label><institution>Department of Medical Laboratories Technology, College of Applied Medical Sciences, Jazan University</institution>, Jazan,<country>Saudi Arabia</country></aff></contrib-group><author-notes><corresp id="an0001"><bold>CONTACT</bold> Chien-Te K. Tseng <email xlink:href="sktseng@utmb.edu">sktseng@utmb.edu</email><institution>Department of Microbiology and Immunology, University of Texas Medical Branch</institution>, <addr-line>301 University Boulevard, Galveston National Laboratory 5.200Q</addr-line>, Galveston, TX 77555-0609, <country>USA</country>.</corresp><fn><p>Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/khvi.</p></fn></author-notes><pub-date pub-type="collection"><year>2016</year></pub-date><pub-date pub-type="epub"><day>07</day><month>6</month><year>2016</year></pub-date><volume>12</volume><issue>9</issue><fpage seq="20">2351</fpage><lpage>2356</lpage><history><date date-type="received"><day>08</day><month>2</month><year>2016</year></date><date date-type="rev-recd"><day>24</day><month>3</month><year>2016</year></date><date date-type="accepted"><day>07</day><month>4</month><year>2016</year></date></history><permissions><copyright-statement>© 2016 Taylor & Francis</copyright-statement><copyright-year>2016</copyright-year><copyright-holder>Taylor & Francis</copyright-holder><license><license-p>This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="KHVI_12_1177688.pdf"></self-uri><abstract><title>ABSTRACT</title><p>To determine if a hypersensitive-type lung pathology might occur when mice were given an inactivated MERS-CoV vaccine and challenged with infectious virus as was seen with SARS-CoV vaccines, we prepared and vaccinated mice with an inactivated MERS-CoV vaccine. Neutralizing antibody was induced by vaccine with and without adjuvant and lung virus was reduced in vaccinated mice after challenge. Lung mononuclear infiltrates occurred in all groups after virus challenge but with increased infiltrates that contained eosinophils and increases in the eosinophil promoting IL-5 and IL-13 cytokines only in the vaccine groups. Inactivated MERS-CoV vaccine appears to carry a hypersensitive-type lung pathology risk from MERS-CoV infection that is similar to that found with inactivated SARS-CoV vaccines from SARS-CoV infection.</p></abstract><kwd-group kwd-group-type="author"><title>Keywords</title><kwd>coronavirus; Eosinophils; immunopathology; Middle East Respiratory Syndrome; vaccination</kwd></kwd-group><counts><fig-count count="4"></fig-count><table-count count="1"></table-count><ref-count count="22"></ref-count><page-count count="6"></page-count></counts></article-meta></front><body><p>Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) emerged in 2002 and 2012 respectively and were shown to be caused by a new coronavirus (CoV), now designated as SARS-CoV and MERS-CoV, respectively.<xref rid="cit0001" ref-type="bibr"><sup>1,2</sup></xref> The SARS epidemic was brought under control by using infection control methods. Because of continued outbreaks, vaccines for MERS are urgently needed.</p><p>Preclinical evaluations of inactivated subunit and whole-virus vaccines for SARS have elicited serum neutralizing antibody and protection against infection in monkeys, ferrets and mice challenged with infectious SARS-CoV. However, challenged animals exhibited an immunopathologic-type lung reaction, and these results led to safety concerns relative to SARS-CoV vaccines.<xref rid="cit0003" ref-type="bibr"><sup>3,4</sup></xref> Moreover, due to the apparent epidemiologic control of SARS, along with these findings, clinical trials of SARS-CoV vaccines were placed on hold.</p><p>With the rise of MERS, we decided to revisit the vaccines prepared for SARS studies and initially prepared a small batch of whole inactivated virus (WIV) for evaluation. We then began tests to determine if vaccination with inactivated MERS-CoV vaccine would result in immunopathology in vaccinated hosts similar to that seen with SARS-CoV. A mouse model for studies of MERS-CoV was not initially available since mice and other small animals lack the MERS-CoV receptor. For this reason, we developed a transgenic mouse model containing the human DPP4 receptor.<xref rid="cit0005" ref-type="bibr"><sup>5,6</sup></xref> Availability of this model provided the opportunity to assess whether an inactivated MERS-CoV vaccine would induce protection against MERS-CoV infection but also induce an eosinophil-containing pulmonary immunopathology as had similar SARS-CoV vaccines. This is the first report that a similar risk for immunopathology appears to exist for MERS-CoV-inactivated vaccines despite an ability to protect against infection.</p><p>The WIV stock was prepared by gamma (γ) irradiating (5 mega-rads, cobalt-60) aliquots of Vero E6-derived, cell-free MERS-CoV (∼1.2 × 10<sup>8</sup> TCID<sub>50</sub>/ml). Inactivated supernatants, negative in rigorous isolation tests, were subjected to polyethylene glycol/salt precipitation, purified by sucrose density centrifugation,<xref rid="cit0007" ref-type="bibr"><sup>7</sup></xref> and diluted in PBS to an equivalent of ∼1 × 10<sup>7</sup> TCID<sub>50</sub>/ml. Western blot analysis by using a rabbit anti-MERS-CoV antibody demonstrated virus structural proteins including surface protein (S) and nucleoprotein (data not shown).<xref rid="cit0005" ref-type="bibr"><sup>5,8</sup></xref></p><p>For assessing the immunogenicity and protective efficacy of this WIV as well as its potential to elicit immunopathology upon live virus challenge of vaccinated animals, groups of six hCD26/DPP4 transgenic mice were immunized intramuscularly (I.M.) twice, three weeks apart. Mice received 100 µl of WIV only, WIV adjuvanted with alhydrogel 2% (alum) or with MF59 (Invivogen), or alum or MF59 only, according to protocols approved by the IACUC committee at the University of Texas Medical Branch. Sera were collected 21 days after the second immunization for micro-neutralization antibody tests; mice were then challenged intranasally (I.N.) with 10<sup>3</sup> TCID<sub>50</sub> (100 LD<sub>50</sub>) of MERS-CoV,<xref rid="cit0006" ref-type="bibr"><sup>6</sup></xref> and sacrificed on days 3 or 6 (3 from each group on each day) for assessing lung viral loads by Vero E6-based infection and quantitative (q) PCR assays targeting the UpE gene of MERS-CoV, and lung cytokines transcriptional profiling of TH1 (IFN-γ) and TH2 (IL-5 and IL-13) in qRT-PCR assays as previously described.<xref rid="cit0005" ref-type="bibr"><sup>5,6</sup></xref> Additionally, de-paraffinized sections were stained with either routine hematoxylin-and-eosin (H&E) for histopathologic evaluations or an antibody specific to eosinophil major basic protein (MBP), provided by the Lee Laboratory, for confirming eosinophil infiltrations, as described.<xref rid="cit0003" ref-type="bibr"><sup>3,9</sup></xref></p><p><xref ref-type="fig" rid="f0001">Figure 1</xref> shows that neither adjuvant alone group developed detectable neutralizing antibodies, whereas all vaccine groups developed significantly greater neutralizing antibody responses than the group with adjuvant alone (<italic>P</italic> < 0.01). Further, the mean titer for WIV/MF59 was higher than that for the WIV/Alum group (<italic>P</italic> < 0.01). Consistent with the absence of specific antibody response, infectious virus was readily detected in the lungs of three infected animals immunized with alum only (MF59 group not available) on days 3 and 6, with an average of 10<sup>3.1</sup> and 10<sup>2.8</sup> TCID<sub>50</sub>/gm, respectively, in which the limit of detection (LOD) in the Vero E6 cell-based infectivity assay was ∼10<sup>1.8</sup> TCID<sub>50</sub>/gm. In contrast, infectious virus remained undetectable in all of the vaccine groups at either time (<xref ref-type="fig" rid="f0002">Fig. 2A–B</xref>). Titers of viral RNA, as revealed by qRT-PCR assays and expressed as TCID<sub>50</sub> equivalents, were also compared among the groups. All groups exhibited detectable viral RNAs (<xref ref-type="fig" rid="f0002">Fig. 2C–D</xref>). The titers were lower in all vaccine groups on day 3 but none were significantly lower than those of the controls (<xref ref-type="fig" rid="f0002">Fig. 2C</xref>); however, the titer for each vaccine group on day 6 was significantly lower than those of either adjuvant only group (<italic>P</italic> < 0.01) (<xref ref-type="fig" rid="f0002">Fig. 2D</xref>). The titers in the WIV/MF59 group were also significantly lower than those in either of the other 2 vaccine groups (<italic>P</italic> < 0.01).
<fig id="f0001" orientation="portrait" position="float"><label>Figure 1.</label><caption><p>Mean serum-neutralizing antibody titers to MERS-CoV of vaccinated mice 3 weeks after the second immunization. Alum and MF59 are adjuvant only groups, WIV is whole inactivated vaccine (WIV) only, Alum/WIV is WIV formulated with Alum adjuvant, MF59/WIV is WIV formulated with MF59 adjuvant. The serum neutralizing antibody titers are expressed as Geometric Mean Titer (GMT) based on a 2-fold dilution sequence beginning at 1:2 (Log<sub>2</sub>). * Significantly different (<italic>P</italic> < 0.01) after correcting for multiple comparisons.</p></caption><graphic content-type="black-white" xlink:href="KHVI_A_1177688_F0001_B"></graphic></fig><fig id="f0002" orientation="portrait" position="float"><label>Figure 2.</label><caption><p>Mean viral titers of MERS-CoV on days 3 and 6 after intranasal challenge of vaccinated mice with 100 LD<sub>50</sub> of MERS-CoV. Lung homogenates and total RNAs extracted from tissues of vaccinated mice at days 3 and 6 post challenge with MERS-CoV were subjected to Vero E6 cell-based infectivity assay and one-step real-time RT-PCR analyses targeting the upE gene of MERS-CoV for assessing viral loads, as previously described (5,6). A serial 10-fold diluted MERS-CoV stock with a titer of 10<sup>7</sup> TCID<sub>50</sub>/ml was included in parallel during the quantitative PCR assays to calculate and express the levels of upE gene expression in individual specimens as log<sub>10</sub> TCID<sub>50</sub> equivalents per gram of tissue. Alum and MF59 are adjuvant-only groups, WIV is whole inactivated vaccine (WIV) only, Alum/WIV is WIV formulated with Alum, MF59/WIV is WIV formulated with MF59. A: Vero E6-based infectious viral titers at Day 3, B: Vero E6-based infectious viral titers at Day 6, C: RT-PCR-based viral load at Day 3, and D: RT-PCR-based viral load at Day 6. * Significantly different (<italic>P</italic> < 0.01) after correcting for multiple comparisons.</p></caption><graphic content-type="black-white" xlink:href="KHVI_A_1177688_F0002_B"></graphic></fig></p><p>No gross pathology was noted on either day 3 or 6 (data not shown); however, histopathology was noted in all groups on both days. On a severity scale of 0 to 3 (none, mild, moderate, severe), H&E-stained samples from the Alum and MF59 only groups were graded 1 on both days 3 and 6 for mononuclear cell infiltrations, including lymphocytes, macrophages/monocytes, while each vaccine group was grade 2 on both days (<xref rid="t0001" ref-type="table">Table 1</xref>). Lung sections were similarly scored 0 to 3 for eosinophil infiltrations. As shown in <xref ref-type="fig" rid="f0003">Figure 3 (left)</xref>, few eosinophils (MBP<sup>+</sup> brown) were detected in the peribronchiolar space (Alum, day 3) or alveolar wall (MF59, day 3). This level of eosinophilic infiltration was similar to that revealed in infected mice without prior manipulation, and scored as 0. However, moderate levels (scored 2) of eosinophilic infiltration into peribronchiolar or perivascular spaces could be readily observed at day 3 (<xref ref-type="fig" rid="f0003">Fig. 3</xref>, right) and spread to alveoli of mice at day 6 p.i. in each vaccine group (data not shown).
<fig id="f0003" orientation="portrait" position="float"><label>Figure 3.</label><caption><p>Representative photomicrographs of lung tissue 3 days after challenge of previously vaccinated mice with MERS-CoV. Lung sections were stained with an antibody directed specifically against eosinophilic major basic protein as described (3); eosinophils are brown. The vaccine groups (alum only, MF59 only, WIV only, WIV plus Alum and WIV plus MF59) and the eosinophil infiltration severity score (E0 and E2) are noted on the micrograph; E0 is none, E2 is moderate.</p></caption><graphic content-type="color" xlink:href="KHVI_A_1177688_F0003_C"></graphic></fig><table-wrap id="t0001" orientation="portrait" position="float"><label>Table 1.</label><caption><p>Severity of lung histopathology of vaccinated mice after challenge with MERS-CoV.</p></caption><pmc-comment>OASIS TABLE HERE</pmc-comment><table frame="hsides" rules="groups"><colgroup><col width="86.4pt" align="left"></col><col width="86.4pt" align="left"></col><col width="86.4pt" align="left"></col></colgroup><thead><tr><th align="left"> </th><th colspan="2" align="center">Severity score of lung pathology<xref rid="t1fn0001" ref-type="fn"><sup>*</sup></xref><hr></hr></th></tr><tr><th align="left">Vaccination Groups</th><th align="center">Day 3<xref rid="t1fn0002" ref-type="fn"><sup>**</sup></xref></th><th align="center">Day 6</th></tr></thead><tbody><tr><td align="left">Alum only</td><td align="center">1</td><td align="center">1</td></tr><tr><td align="left">MF59 only</td><td align="center">1</td><td align="center">1</td></tr><tr><td align="left">WIV/Alum</td><td align="center">2</td><td align="center">2</td></tr><tr><td align="left">WIV/MF59</td><td align="center">2</td><td align="center">2</td></tr><tr><td align="left">WIV only</td><td align="center">2</td><td align="center">2</td></tr></tbody></table><table-wrap-foot><fn id="t1fn0001"><label>*</label><p>Pathology severity scores (0-3): 0- no pathology, 1- mild, 2- moderate, and 3- severe.</p></fn><fn id="t1fn0002"><label>**</label><p>Day post challenge.</p></fn></table-wrap-foot></table-wrap></p><p>Pulmonary cytokine profiling of vaccinated and challenged mice was performed by using qRT-PCR assays.<xref rid="cit0005" ref-type="bibr"><sup>5</sup></xref> Because of the small number of animals in each test group,<xref rid="cit0003" ref-type="bibr"><sup>3</sup></xref> cytokine assays were performed twice. The day 3 pattern was similar in each test, and there were no significant differences between tests (<xref ref-type="fig" rid="f0004">Fig. 4</xref>). Some cytokine activities were seen in the adjuvant only groups but were not significantly different from those in uninfected animals. However, significant increases were seen for all 3 cytokines tested in the vaccine groups. Notable are the increases of IL-5 and IL-13, cytokines associated with hypersensitivity reactions that include eosinophil infiltrations.<xref rid="cit0010" ref-type="bibr"><sup>10,11</sup></xref> Cytokine levels were lower for the vaccine groups for IL-5 and IL-13 at day 6 and not significantly greater than those for the uninfected; however, IFN-γ was significantly increased for the WIV, WIV/MF59 and MF59 only groups (<italic>P</italic> < 0.01) (data not shown).
<fig id="f0004" orientation="portrait" position="float"><label>Figure 4.</label><caption><p>Mean lung cytokine levels on day 3 after challenge of vaccinated mice with MERS-CoV. Alum and MF59 are adjuvant only groups, WIV is whole inactivated vaccine (WIV) only, Alum/WIV is WIV formulated with Alum, MF59/WIV is WIV formulated with MF59. Test 1 and test 2 are separate day tests of the same lung tissue specimen. Results are mean fold increase over naïve transgenic mice based on ΔCt values of each group in reference to those of the internal mouse GAPDH gene. * Significantly greater than for the naïve mouse group (<italic>P</italic> < 0.01) after correcting for multiple comparisons; ** <italic>P</italic> = 0.026.</p></caption><graphic content-type="black-white" xlink:href="KHVI_A_1177688_F0004_B"></graphic></fig></p><p>This study was conducted to test whether an inactivated MERS-CoV vaccine would induce neutralizing antibody and protection against MERS-CoV infection and yet lead to a hypersensitivity-type lung immunopathologic reaction with eosinophil infiltrations when challenged with infectious virus, as had been seen with SARS-CoV-inactivated vaccines.<xref rid="cit0003" ref-type="bibr"><sup>3</sup></xref> The results suggest that a similar risk exists for inactivated MERS-CoV vaccines.</p><p>The vaccine lot size and requirement for transgenic mice limited the study group sizes. Because of concern for immununogenicity, we included MF59 adjuvant groups since the MF59 adjuvant had been reported to induce superior antibody responses when compared with other adjuvants for a MERS-CoV receptor-binding domain (RBD) protein-based vaccine.<xref rid="cit0012" ref-type="bibr"><sup>12</sup></xref> Serum neutralizing antibody and protection against infection were found in the vaccine alone and both adjuvant groups, but each also exhibited a hypersensitivity-type lung reaction after challenge that included increased pathology with eosinophil infiltrations.</p><p>Immune reactions leading to eosinophil infiltrations are considered hypersensitivity reactions and are TH2-type responses mediated via TH2 cytokines.<xref rid="cit0010" ref-type="bibr"><sup>10</sup></xref> Notable cytokines that promote eosinophil infiltrations are IL-5 and IL-13.<xref rid="cit0013" ref-type="bibr"><sup>13</sup></xref> We found this association in the lungs of vaccinated and challenged animals, providing support for the vaccination-related hypersensitivity concept.</p><p>Support for attributing the immunopathology to a TH2-type immune response has been provided by immunizations with inactivated SARS-CoV vaccines and TH1-type adjuvants. Studies in mice with inactivated SARS-CoV vaccines given with a TH1 adjuvant did not exhibit a similar immunopathologic reaction after virus challenge.<xref rid="cit0014" ref-type="bibr"><sup>14,15</sup></xref></p><p>The finding for MERS-CoV vaccine and the similar findings for SARS-CoV vaccines are reminiscent of those reported in mice given a formalin-inactivated, whole-virus respiratory syncytial virus (RSV) vaccine and challenged with infectious RSV.<xref rid="cit0016" ref-type="bibr"><sup>16-18</sup></xref> Protection against infection occurred despite an increased histopathology. A similar RSV vaccine given to infants had led to increased pulmonary disease severity and 2 deaths.<xref rid="cit0019" ref-type="bibr"><sup>19,20</sup></xref> The component(s) of the vaccine that led to the immunopathology have not been identified, but have been suggested to be viral components as well as contaminants and formalin effects. However, Immunopathology with SARS-CoV vaccines occurred for whole-virus vaccines, subunit vaccines, different inactivation methods, different preparation substrates, and with recombinant surface (S) protein. This experience may indicate that the responsible components(s) for the SARS and MERS-CoV vaccines are viral. Results of studies with vector vaccines point to the nucleoprotein (N) protein as responsible for the immunopathological effects seen and indicate that the S protein might be free of the risk; however, rS protein induced the pathology.<xref rid="cit0003" ref-type="bibr"><sup>3,21,22</sup></xref> Identifying and remedying the specific basis for the immunopathology would facilitate vaccine trials in humans.</p><p>The implication of the current study is that application of an inactivated MERS-CoV vaccine for prevention of MERS in humans may carry a risk for lung immunopathology if subsequently exposed to MERS-CoV. The study also leads us to suggest that the extensive background of preclinical experience with inactivated SARS-CoV vaccines may be applicable to inactivated MERS-CoV vaccines.</p><p>The major limitation of the current study is the small number of animals in the evaluations that reduces the strength of the findings. Nevertheless, the findings seem clear that a risk similar to that of the SARS-CoV vaccine exists for the MERS-CoV vaccine. Additional data supporting the belief that the immunopathology represents a TH2-biased response and that it also occurs for other MERS-CoV vaccines as it did for SARS-CoV vaccines is contemplated in future studies.</p></body><back><sec id="s0002" sec-type="other"><title>Disclosure of potential conflicts of interest</title><p>No potential conflicts of interest were disclosed.</p></sec><sec><title>Acknowledgments</title><p>We thank Dr. Heinz Feldmann, National Institute of Health at Hamilton, Montana, and Dr. Ron A. Fouchier, Erasmus Medical Center at Rotterdam, The Netherlands for the MERS-CoV.</p></sec><sec><title>Funding</title><p>This research was supported in part by a National Institutes of Health Grant, R21AI113206-01 (to C-T.K.T), and pilot grants from the Center for Biodefense and Emerging Infectious Diseases and from the Galveston National Laboratory (Grant Number: 5UC7AI094660-05. 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