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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Mucosal immunisation and immunoprophylaxis as potential strategies for prevention of SARS</title><author><name sortKey="Foxwell, Ar" sort="Foxwell, Ar" uniqKey="Foxwell A" first="Ar" last="Foxwell">Ar Foxwell</name><affiliation><nlm:aff id="aff1">Gadi Research Centre for Medical and Health Sciences, University of Canberra, Canberra, ACT 2601, Australia</nlm:aff></affiliation></author><author><name sortKey="Cripps, Aw" sort="Cripps, Aw" uniqKey="Cripps A" first="Aw" last="Cripps">Aw Cripps</name><affiliation><nlm:aff id="aff2">School of Medicine, Griffith University, Gold Coast Campus, Gold Coast, Queensland, Australia</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">15220029</idno><idno type="pmc">7135173</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135173</idno><idno type="RBID">PMC:7135173</idno><idno type="doi">10.1016/S0140-6736(04)16535-5</idno><date when="2004">2004</date><idno type="wicri:Area/Pmc/Corpus">000A05</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000A05</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Mucosal immunisation and immunoprophylaxis as potential strategies for prevention of SARS</title><author><name sortKey="Foxwell, Ar" sort="Foxwell, Ar" uniqKey="Foxwell A" first="Ar" last="Foxwell">Ar Foxwell</name><affiliation><nlm:aff id="aff1">Gadi Research Centre for Medical and Health Sciences, University of Canberra, Canberra, ACT 2601, Australia</nlm:aff></affiliation></author><author><name sortKey="Cripps, Aw" sort="Cripps, Aw" uniqKey="Cripps A" first="Aw" last="Cripps">Aw Cripps</name><affiliation><nlm:aff id="aff2">School of Medicine, Griffith University, Gold Coast Campus, Gold Coast, Queensland, Australia</nlm:aff></affiliation></author></analytic><series><title level="j">Lancet (London, England)</title><idno type="ISSN">0140-6736</idno><idno type="eISSN">1474-547X</idno><imprint><date when="2004">2004</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Daniel, C" uniqKey="Daniel C">C Daniel</name></author><author><name sortKey="Talbot, Pj" uniqKey="Talbot P">PJ Talbot</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schmidt, Ac" uniqKey="Schmidt A">AC Schmidt</name></author><author><name sortKey="Mcauliffe, Jm" uniqKey="Mcauliffe J">JM McAuliffe</name></author><author><name sortKey="Huang, A" uniqKey="Huang A">A Huang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schmidt, Ac" uniqKey="Schmidt A">AC Schmidt</name></author><author><name sortKey="Mcauliffe, Jm" uniqKey="Mcauliffe J">JM McAuliffe</name></author><author><name sortKey="Murphy, Br" uniqKey="Murphy B">BR Murphy</name></author><author><name sortKey="Collins, Pl" uniqKey="Collins P">PL Collins</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schmidt, Ac" uniqKey="Schmidt A">AC Schmidt</name></author><author><name sortKey="Wenzke, Dr" uniqKey="Wenzke D">DR Wenzke</name></author><author><name sortKey="Mcauliffe, Jm" uniqKey="Mcauliffe J">JM McAuliffe</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Karron, Ra" uniqKey="Karron R">RA Karron</name></author><author><name sortKey="Wright, Pf" uniqKey="Wright P">PF Wright</name></author><author><name sortKey="Hall, Sl" uniqKey="Hall S">SL Hall</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kim, Hw" uniqKey="Kim H">HW Kim</name></author><author><name sortKey="Canchola, Jg" uniqKey="Canchola J">JG Canchola</name></author><author><name sortKey="Brandt, Cd" uniqKey="Brandt C">CD Brandt</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cripps, Aw" uniqKey="Cripps A">AW Cripps</name></author><author><name sortKey="Gleeson, M" uniqKey="Gleeson M">M Gleeson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Clements, Ml" uniqKey="Clements M">ML Clements</name></author><author><name sortKey="Belshe, Rb" uniqKey="Belshe R">RB Belshe</name></author><author><name sortKey="King, J" uniqKey="King J">J King</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Donnelly, Ca" uniqKey="Donnelly C">CA Donnelly</name></author><author><name sortKey="Ghani, Ac" uniqKey="Ghani A">AC Ghani</name></author><author><name sortKey="Leung, Gm" uniqKey="Leung G">GM Leung</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Crowe, Je" uniqKey="Crowe J">JE Crowe</name></author><author><name sortKey="Firestone, Cy" uniqKey="Firestone C">CY Firestone</name></author><author><name sortKey="Murphy, Br" uniqKey="Murphy B">BR Murphy</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="discussion"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Lancet</journal-id><journal-id journal-id-type="iso-abbrev">Lancet</journal-id><journal-title-group><journal-title>Lancet (London, England)</journal-title></journal-title-group><issn pub-type="ppub">0140-6736</issn><issn pub-type="epub">1474-547X</issn><publisher><publisher-name>Elsevier Ltd.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">15220029</article-id><article-id pub-id-type="pmc">7135173</article-id><article-id pub-id-type="publisher-id">S0140-6736(04)16535-5</article-id><article-id pub-id-type="doi">10.1016/S0140-6736(04)16535-5</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Mucosal immunisation and immunoprophylaxis as potential strategies for prevention of SARS</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Foxwell</surname><given-names>AR</given-names></name><email>ruth.foxwell@canberra.edu.au</email><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author"><name><surname>Cripps</surname><given-names>AW</given-names></name><xref rid="aff2" ref-type="aff">b</xref></contrib></contrib-group><aff id="aff1"><label>a</label>Gadi Research Centre for Medical and Health Sciences, University of Canberra, Canberra, ACT 2601, Australia</aff><aff id="aff2"><label>b</label>School of Medicine, Griffith University, Gold Coast Campus, Gold Coast, Queensland, Australia</aff><pub-date pub-type="pmc-release"><day>25</day><month>6</month><year>2004</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="ppub"><day>26</day><month>6</month><year>2004</year></pub-date><pub-date pub-type="epub"><day>25</day><month>6</month><year>2004</year></pub-date><volume>363</volume><issue>9427</issue><fpage>2102</fpage><lpage>2103</lpage><permissions><copyright-statement>Copyright © 2004 Elsevier Ltd. All rights reserved.</copyright-statement><copyright-year>2004</copyright-year><copyright-holder>Elsevier Ltd</copyright-holder><license><license-p>Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.</license-p></license></permissions><related-article related-article-type="article-reference" id="d32e235" ext-link-type="doi" xlink:href="10.1016/S0140-6736(04)16501-X"></related-article><related-article related-article-type="article-reference" id="d32e238" ext-link-type="doi" xlink:href="10.1016/S0140-6736(04)16506-9"></related-article></article-meta></front><body><p id="para10">Severe acute respiratory syndrome (SARS) is a rapid-onset atypical pneumonia that was first identified in epidemic proportions in China in 2002.<xref rid="bib1" ref-type="bibr"><sup>1</sup></xref> WHO recently announced the containment of the latest outbreak, which was centred on the National Institute of Virology in Beijing.<xref rid="bib2" ref-type="bibr"><sup>2</sup></xref></p><p id="para20">In today's <italic>Lancet</italic>, Alexander Bukreyev and colleagues show that a single intranasal immunisation in African green monkeys with the attenuated bovine/human parainfluenza virus type 3 (BHPIV3), into which the envelope spike (S) protein from the SARS coronavirus (SARS-CoV) has been expressed, induced neutralising antibodies to SARS-CoV in serum, and protected against subsequent live-viral challenge with SARS-CoV.</p><p id="para30">This finding is important since it brings together known yet innovative technologies, knowledge, and skills to address prevention of an emerging infectious disease. If applicable generally, the result could represent a major step forward for simplifying mass immunisation in at-risk human populations. On the basis that the S protein of other coronaviruses induced virus-specific immunity and, in some cases, protection against subsequent challenge in animal models,<xref rid="bib3" ref-type="bibr"><sup>3</sup></xref> Bukreyev and colleagues used a well-documented carrier vector, BHPIV,<xref rid="bib3" ref-type="bibr">3</xref>, <xref rid="bib4" ref-type="bibr">4</xref> to create a live-attenuated vaccine that protects monkeys against challenge with SARS-CoV.</p><p id="para40">Several animal viruses display the type of stable host-range restriction that led to the development of the Jennerian approach to live-attenuated vaccines, as used in creating the BHPIV3 vector. This chimeric vector has important potential in inducing protective immune responses against respiratory syncytial virus (A and B) and human parainfluenza virus (type 3) in rhesus monkeys and hamsters.<xref rid="bib5" ref-type="bibr">5</xref>, <xref rid="bib6" ref-type="bibr">6</xref> Human trials show that the live-attenuated bovine parainfluenza virus type 3 (BPIV3) is safe, immunogenic, and stable in infants and children,<xref rid="bib7" ref-type="bibr"><sup>7</sup></xref> and BHPIV3 produces enhanced immunogenicity against disease in rhesus monkeys.<xref rid="bib6" ref-type="bibr"><sup>6</sup></xref> Data are not yet available on the use of the BHPIV3 chimeric vector in human trials.</p><p id="para50">Intranasal live-attenuated viral vectors offer the best possibility of inducing sustainable protective immunity via the mucosal route. In the host-restricted approach to attenuation, it has been seen that: powerful adjuvants are not required;<xref rid="bib6" ref-type="bibr"><sup>6</sup></xref> that both systemic and mucosal immune responses are generated;<xref rid="bib7" ref-type="bibr"><sup>7</sup></xref> and that exacerbation of disease after natural exposure does not seem to occur.<xref rid="bib8" ref-type="bibr"><sup>8</sup></xref> Additionally, mucosal immunisation offers the advantage that mucosal immune mechanisms seem to mature earlier in young children and wane later in elderly people than with systemic immune mechanisms.<xref rid="bib9" ref-type="bibr"><sup>9</sup></xref></p><p id="para60">Despite the promise demonstrated by the Jennerian approach and in particular the BHPIV3/SARS-S intranasal vaccine, we need to know the lag before both mucosal and systemic immune mechanisms are effective, and also the duration of immunity induced. Bukreyev and colleagues only report challenging the monkeys with SARS-CoV at 28 days after immunisation. Whilst the immunisation gave excellent protection from viral shedding at 28 days, the serum concentration of antibody in immunised animals was not greater at 28 days post-challenge than that measured in non-immunised animals. Further studies examining which mucosal immune responses are induced to SARS-CoV and which of these have any role in immune protection need to be done. Dose-response studies for both immunisation and challenge will also be needed before this model can be adopted for human trials.</p><p id="para70">As indicated by Bukreyev and colleagues, the approach they used of a replicating chimeric viral vector with protein inserts from a common human respiratory pathogen might be limited to infants and small children, because of interference from neutralising antibodies developed through natural infection.<xref rid="bib10" ref-type="bibr"><sup>10</sup></xref> Further investigations are warranted to establish a vector construct that would be effective in all age groups, especially because of the increased mortality rate from SARS in elderly people.<xref rid="bib11" ref-type="bibr"><sup>11</sup></xref></p><p id="para80">Possibilities for immuoprophylaxis and treatment of high-risk individuals who have become exposed to SARS-CoV are outlined in a Research letter, also in today's <italic>Lancet</italic>, by Jan ter Meulen and colleagues. These researchers describe preliminary experiments in the ferret, a species that can be naturally infected with SARS-CoV. They found that prophylactic treatment of infected animals with a human monoclonal antibody (directed against the cell-surface spike glycoprotein of SARS-CoV) abrogated viral shedding from the pharynx, and prevented the development of macroscopic lung disease in infected animals. Extrapolation to human beings of a prophylactic treatment that reduced viral shedding and lung lesions would probably reduce transmission and the high morbidity associated with the disease.</p><p id="para90">Such a strategy, in combination with immunisation during a SARS outbreak, would offer potential treatment and prophylactic applications. However, before the monoclonal antibody approach suggested by ter Meulen can be applied to human beings, several further studies are required. Of particular importance are experiments relating to the efficacy of immunoprophylaxis and treatment in the presence of an established infection, appropriate dose-response and safety studies, and, critically, study of the effect of circulating antibody on vaccine efficacy.<xref rid="bib12" ref-type="bibr"><sup>12</sup></xref></p><p id="para100">Bukreyev, ter Meulen, and their colleagues have shown that SARS can be effectively prevented by immunisation of the mucosa of the respiratory tract and immunoprophylaxis in animal models. Whilst further studies are required before these concepts can be applied to human beings, the findings provide exciting strategies for the prevention of disease in target communities and treatment of at-risk individuals.</p></body><back><ref-list id="bibl10"><title>References</title><ref id="bib1"><label>1</label><element-citation publication-type="other" id="reference0005"><person-group person-group-type="author"><collab>World Health Organization</collab></person-group><article-title>Summary table of SARS cases by country, 1 November 2002–7 August 2003. 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