Middle East respiratory syndrome: current status and future prospects for vaccine development
Identifieur interne : 000827 ( Pmc/Corpus ); précédent : 000826; suivant : 000828Middle East respiratory syndrome: current status and future prospects for vaccine development
Auteurs : Lanying Du ; Shibo JiangSource :
- Expert Opinion on Biological Therapy [ 1471-2598 ] ; 2015.
Abstract
The outbreaks of Middle East respiratory syndrome (MERS) previously in Middle East and recently in South Korea have raised serious concerns worldwide, reinforcing the importance of developing effective and safe vaccines against MERS-coronavirus (MERS-CoV). A number of vaccine candidates have been developed on the basis of viral vectors, recombinant proteins, DNAs, nanoparticles, and recombinant MERS-CoV, and some of them have shown efficacy in laboratory animals. However, the paucity of financial support has made it difficult to transfer effective candidates from the preclinical stage to clinical trials. Here, we summarize currently available MERS vaccine candidates and illustrate strategies for future development, with the aim of provoking government agencies and Big Pharma to invest more funds for developing efficacious and safe MERS vaccines.
Url:
DOI: 10.1517/14712598.2015.1092518
PubMed: 26414077
PubMed Central: 4636333
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Middle East respiratory syndrome: current status and future prospects for vaccine development</title><author><name sortKey="Du, Lanying" sort="Du, Lanying" uniqKey="Du L" first="Lanying" last="Du">Lanying Du</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Jiang, Shibo" sort="Jiang, Shibo" uniqKey="Jiang S" first="Shibo" last="Jiang">Shibo Jiang</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26414077</idno><idno type="pmc">4636333</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636333</idno><idno type="RBID">PMC:4636333</idno><idno type="doi">10.1517/14712598.2015.1092518</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000827</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000827</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Middle East respiratory syndrome: current status and future prospects for vaccine development</title><author><name sortKey="Du, Lanying" sort="Du, Lanying" uniqKey="Du L" first="Lanying" last="Du">Lanying Du</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Jiang, Shibo" sort="Jiang, Shibo" uniqKey="Jiang S" first="Shibo" last="Jiang">Shibo Jiang</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author></analytic><series><title level="j">Expert Opinion on Biological Therapy</title><idno type="ISSN">1471-2598</idno><idno type="eISSN">1744-7682</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> The outbreaks of Middle East respiratory syndrome (MERS) previously in Middle East and recently in South Korea have raised serious concerns worldwide, reinforcing the importance of developing effective and safe vaccines against MERS-coronavirus (MERS-CoV). A number of vaccine candidates have been developed on the basis of viral vectors, recombinant proteins, DNAs, nanoparticles, and recombinant MERS-CoV, and some of them have shown efficacy in laboratory animals. However, the paucity of financial support has made it difficult to transfer effective candidates from the preclinical stage to clinical trials. Here, we summarize currently available MERS vaccine candidates and illustrate strategies for future development, with the aim of provoking government agencies and Big Pharma to invest more funds for developing efficacious and safe MERS vaccines.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Zaki, Am" uniqKey="Zaki A">AM Zaki</name></author><author><name sortKey="Van, Bs" uniqKey="Van B">BS Van</name></author><author><name sortKey="Bestebroer, Tm" uniqKey="Bestebroer T">TM Bestebroer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Memish, Za" uniqKey="Memish Z">ZA Memish</name></author><author><name sortKey="Mishra, N" uniqKey="Mishra N">N Mishra</name></author><author><name sortKey="Olival, Kj" uniqKey="Olival K">KJ Olival</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Madani, Ta" uniqKey="Madani T">TA Madani</name></author><author><name sortKey="Azhar, Ei" 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Expert Opin Biol Ther</journal-id><journal-id journal-id-type="iso-abbrev">Expert Opin Biol Ther</journal-id><journal-id journal-id-type="publisher-id">IEBT</journal-id><journal-id journal-id-type="publisher-id">iebt20</journal-id><journal-title-group><journal-title>Expert Opinion on Biological Therapy</journal-title></journal-title-group><issn pub-type="ppub">1471-2598</issn><issn pub-type="epub">1744-7682</issn><publisher><publisher-name>Informa Healthcare</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26414077</article-id><article-id pub-id-type="pmc">4636333</article-id><article-id pub-id-type="doi">10.1517/14712598.2015.1092518</article-id><article-id pub-id-type="publisher-id">1092518</article-id><article-categories><subj-group subj-group-type="heading"><subject>Editorial</subject></subj-group></article-categories><title-group><article-title>Middle East respiratory syndrome: current status and future prospects for vaccine development</article-title><alt-title alt-title-type="running-title">Middle East respiratory syndrome: current status and future prospects for vaccine development</alt-title><alt-title alt-title-type="running-authors">L. Du & S. Jiang</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Du</surname><given-names>Lanying</given-names></name><xref ref-type="corresp" rid="COR0001"></xref><xref ref-type="aff" rid="end-a1"></xref></contrib><contrib contrib-type="author"><name><surname>Jiang</surname><given-names>Shibo</given-names></name><xref ref-type="corresp" rid="COR0001"></xref><xref ref-type="aff" rid="end-a1"></xref><xref ref-type="aff" rid="end-a2"></xref></contrib><aff id="end-a1"><sup>1</sup><institution>Lindsley F. Kimball Research Institute, New York Blood Center</institution>,<addr-line>NY</addr-line>,<country>USA</country><phone>+1 212 570 3459</phone>;<email xlink:href="ldu@nybloodcenter.org">ldu@nybloodcenter.org</email></aff><aff id="end-a2"><sup>2</sup><institution>Fudan University, Shanghai Medical College and Institute of Medical Microbiology, Key Laboratory of Medical Molecular Virology of Ministries of Education and Health</institution>,<addr-line>Shanghai</addr-line>,<country>China</country><phone>+1 212 570 3058</phone>;<email xlink:href="sjiang@nybloodcenter.org">sjiang@nybloodcenter.org</email></aff></contrib-group><author-notes><corresp id="COR0001"><sup>†,</sup>*Authors for correspondence</corresp></author-notes><pub-date pub-type="collection"><year>2015</year></pub-date><pub-date pub-type="epub"><day>28</day><month>9</month><year>2015</year></pub-date><volume>15</volume><issue>11</issue><fpage seq="8">1647</fpage><lpage>1651</lpage><permissions><copyright-statement>© 2015 Taylor & Francis</copyright-statement><copyright-year>2015</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="IEBT_15_1092518.pdf"></self-uri><abstract><p> The outbreaks of Middle East respiratory syndrome (MERS) previously in Middle East and recently in South Korea have raised serious concerns worldwide, reinforcing the importance of developing effective and safe vaccines against MERS-coronavirus (MERS-CoV). A number of vaccine candidates have been developed on the basis of viral vectors, recombinant proteins, DNAs, nanoparticles, and recombinant MERS-CoV, and some of them have shown efficacy in laboratory animals. However, the paucity of financial support has made it difficult to transfer effective candidates from the preclinical stage to clinical trials. Here, we summarize currently available MERS vaccine candidates and illustrate strategies for future development, with the aim of provoking government agencies and Big Pharma to invest more funds for developing efficacious and safe MERS vaccines.</p></abstract><kwd-group kwd-group-type="author"><title>Keywords</title><kwd>Animal models</kwd><kwd>Middle East respiratory syndrome</kwd><kwd>Middle East respiratory syndrome coronavirus</kwd><kwd>receptor-binding domain</kwd><kwd>spike protein</kwd><kwd>vaccines</kwd></kwd-group><counts><fig-count count="0"></fig-count><table-count count="1"></table-count><equation-count count="0"></equation-count><ref-count count="41"></ref-count><page-count count="5"></page-count></counts></article-meta></front><body><sec id="S0001"><label>1. </label><title>Introduction</title><p>Middle East respiratory syndrome (MERS), an emerging infectious disease first identified in June 2012, is caused by the novel MERS-coronavirus (MERS-CoV) <xref rid="CIT0001" ref-type="bibr">[1]</xref>. MERS-CoV, a zoonotic virus, has bats as its natural reservoir and possibly dromedary camels as its intermediate host <xref rid="CIT0002" ref-type="bibr">[2,3]</xref>. MERS-CoV infects humans, especially the elderly, people with diabetes and chronic lung diseases, and immunocompromised persons, causing severe disease with high mortality (∼ 35%). The MERS outbreak has resulted in 1474 laboratory-confirmed cases, including 515 deaths as of August 27, 2015 <xref rid="CIT0004" ref-type="bibr">[4]</xref>. There is still a possibility for MERS-CoV to spread within healthcare facilities, to which a number of cases have been linked <xref rid="CIT0005" ref-type="bibr">[5,6]</xref>. Most MERS cases have been reported from Saudi Arabia, but South Korea is the second largest country with travel-associated MERS cases, which can all be traced back to Saudi Arabia. The continuous spread of MERS-CoV possibly through camel-to-human and human-to-human transmission has raised worldwide concerns, calling for immediate steps to develop effective and safe vaccines.</p><p>The genome of MERS-CoV encodes at least four unique accessory proteins, such as 3, 4a, 4b and 5, two replicase proteins (open reading frame 1a and 1b), and four major structural proteins, including spike (S), envelope (E), nucleocapsid (N), and membrane (M) proteins <xref rid="CIT0007" ref-type="bibr">[7]</xref>. The accessory proteins play nonessential roles in MERS-CoV replication, but they are likely structural proteins or interferon antagonists, modulating <italic>in vivo</italic> replication efficiency and/or pathogenesis, as in the case of SARS-CoV <xref rid="CIT0007" ref-type="bibr">[7-9]</xref>. The other proteins of MERS-CoV maintain different functions in virus replication. The E protein, for example, involves in virulence, and deleting the E-coding gene results in replication-competent and propagation-defective viruses or attenuated viruses <xref rid="CIT0007" ref-type="bibr">[7]</xref>. The S protein is particularly essential in mediating virus binding to cells expressing receptor dipeptidyl peptidase-4 (DPP4) through receptor-binding domain (RBD) in the S1 subunit, whereas the S2 subunit subsequently mediates virus entry via fusion of the virus and target cell membranes <xref rid="CIT0010" ref-type="bibr">[10,11]</xref>. Therefore, these viral structural proteins, particularly S protein, may serve as targets for vaccine development. It is demonstrated that all circulating human MERS-CoV strains represent one single serotype and that virus isolates from other parts of the outbreaks have no differences from EMC2012, the prototype strain, in replication, interferon escape responses and serum neutralization, suggesting that vaccines developed based on the prototype virus strain unlikely affect their success against other virus strains <xref rid="CIT0012" ref-type="bibr">[12,13]</xref>.</p></sec><sec id="S0002"><label>2. </label><title>Current status of MERS vaccines</title><p>No MERS vaccines are available for human use. Vaccines against MERS-CoV thus far developed in the laboratory can be categorized as those based on viral vectors, such as adenovirus (Ad) and Modified Vaccinia virus Ankara (MVA), or those based on recombinant viral proteins, DNAs, nanoparticles, and recombinant virus (<xref rid="T1" ref-type="table">Table 1</xref>).</p><table-wrap id="T1" orientation="portrait" position="float"><label>Table 1.</label><caption><p><bold>MERS vaccines under development.</bold></p></caption><pmc-comment>OASIS TABLE HERE</pmc-comment>
<table frame="hsides" rules="groups"><colgroup><col width="10*" align="left"></col><col width="10*" align="left"></col><col width="10*" align="left"></col><col width="10*" align="left"></col><col width="10*" align="left"></col><col width="10*" align="left"></col></colgroup><thead valign="top"><tr><th align="left"><bold>Vaccine name</bold></th><th align="left"><bold>Vaccine type</bold></th><th align="left"><bold>Viral antigen</bold></th><th align="left"><bold>Animal models</bold></th><th align="left"><bold>Status</bold></th><th align="left"><bold>Ref.</bold></th></tr></thead><tbody valign="top"><tr><td align="left">Ad5-S & Ad41-S</td><td align="left">Viral vector</td><td align="left">Full-length S</td><td align="left">Mice</td><td align="left">Preclinical</td><td align="left"><xref ref-type="bibr" rid="CIT0015">[15]</xref></td></tr><tr><td align="left">Ad5.MERS-S/Ad5.MERS-S1</td><td align="left">Viral vector</td><td align="left">Full-length S/S1</td><td align="left">Mice</td><td align="left">Preclinical</td><td align="left"><xref ref-type="bibr" rid="CIT0014">[14]</xref></td></tr><tr><td align="left">MVA-MERS-S</td><td align="left">Viral vector</td><td align="left">Full-length S</td><td align="left">hDPP4-transduced mice </td><td align="left">Preclinical</td><td align="left"><xref ref-type="bibr" rid="CIT0016">[16]</xref></td></tr><tr><td align="left">S1 – 358 – 588-Fc</td><td align="left">Recombinant protein</td><td align="left">S1-RBD (358 – 588)</td><td align="left">Rabbits</td><td align="left">Preclinical</td><td align="left"><xref ref-type="bibr" rid="CIT0019">[19]</xref></td></tr><tr><td align="left">MERS-CoV rRBD</td><td align="left">Recombinant protein</td><td align="left">S1-RBD (367 – 606)</td><td align="left">Mice</td><td align="left">Preclinical</td><td align="left"><xref ref-type="bibr" rid="CIT0041">[41]</xref></td></tr><tr><td align="left">S-RBD-Fc</td><td align="left">Recombinant protein</td><td align="left">S1-RBD (377 – 662)</td><td align="left">Mice</td><td align="left">Preclinical</td><td align="left"><xref ref-type="bibr" rid="CIT0020">[20]</xref></td></tr><tr><td align="left">S377 – 588-Fc</td><td align="left">Recombinant protein</td><td align="left">S1-RBD (377 – 588)</td><td align="left">Mice, rabbits, hDPP4-mice</td><td align="left">Preclinical</td><td align="left"><xref ref-type="bibr" rid="CIT0021 CIT0023">[21,23]</xref></td></tr><tr><td align="left">MERS </td><td align="left">DNA</td><td align="left">Full-length S</td><td align="left">Mice, camels, NHPs</td><td align="left">Preclinical</td><td align="left"><xref ref-type="bibr" rid="CIT0025">[25]</xref></td></tr><tr><td align="left">S-DNA/S1 protein</td><td align="left">DNA + Recombinant protein</td><td align="left">Full-length S/S1 </td><td align="left">Mice, NHPs</td><td align="left">Preclinical</td><td align="left"><xref ref-type="bibr" rid="CIT0027">[27]</xref></td></tr><tr><td align="left">MERS-S</td><td align="left">Nanoparticles</td><td align="left">Full-length S</td><td align="left">Mice</td><td align="left">Preclinical</td><td align="left"><xref ref-type="bibr" rid="CIT0028">[28]</xref></td></tr><tr><td align="left">rMERS-CoV/rMERS-CoV-ΔE</td><td align="left">Recombinant virus</td><td align="left">MERS-CoV</td><td align="left">Not tested</td><td align="left">Cell culture</td><td align="left"><xref ref-type="bibr" rid="CIT0007 CIT0009">[7,9]</xref></td></tr></tbody></table><table-wrap-foot><fn><p>MERS: Middle East respiratory syndrome; MERS-CoV: Middle East respiratory syndrome coronavirus; NHPs: Non-human primates.</p></fn></table-wrap-foot></table-wrap><p>Most viral vector-based MERS vaccines use the full-length S or S1 protein of MERS-CoV as the coding antigens and exhibit immunogenicity in vaccinated animals. Reports have indicated that recombinant Ad5 vectors, which encode the full-length or S1 extracellular domain, of MERS-CoV S protein induced MERS-CoV S-specific antibody responses in immunized mice, neutralizing MERS-CoV infection <italic>in vitro</italic><xref rid="CIT0014" ref-type="bibr">[14]</xref>. Ad5 or Ad41 vectors expressing full-length S protein of MERS-CoV have elicited MERS-CoV-specific antibody responses, neutralizing antibodies and T-cell responses in immunized mice <xref rid="CIT0015" ref-type="bibr">[15]</xref>. Moreover, a viral vector MVA-based MERS vaccine expressing viral S protein, termed MVA-MERS-S, demonstrated efficacy against MERS-CoV infection in Ad/DPP4-transduced mice <xref rid="CIT0016" ref-type="bibr">[16,17]</xref>. These studies suggest the potential of applying MERS-CoV S protein as a vaccine target. The German Center for Infection Research (DZIF) has supported the Phase I clinical trial of MVA-MERS-S vaccine candidate in humans. About USD $1.66 million was awarded to initiate this trial <xref rid="CIT0018" ref-type="bibr">[18]</xref>.</p><p>In addition to viral vector-based vaccines, vaccines based on the recombinant MERS-CoV S protein, in particular, RBD, have demonstrated efficacy in protecting immunized animals from MERS-CoV infection <xref rid="CIT0019" ref-type="bibr">[19,20]</xref>. Several fragments, including residues 350 – 588, 358 – 588, 367 – 588, 367 – 606, 377 – 588, and 377 – 662, in the RBD of MERS-CoV S are shown to induce MERS-CoV neutralizing antibody responses in mice and/or rabbits <xref rid="CIT0021" ref-type="bibr">[21,22]</xref>. Thus, similar to the RBD of severe acute respiratory syndrome coronavirus (SARS-CoV), the MERS-CoV RBD also contains a critical neutralizing domain (CND) capable of eliciting highly potent neutralizing antibodies and protective immunity against infection from MERS-CoV. Particularly, a fragment containing residues 377 – 588 of MERS-CoV RBD has been identified as a CND able to protect Ad5/hDPP4-transduced and hDPP4-transgenic mice against MERS-CoV. Notably, S377 – 588 is a very effective immunogen, as 1 μg of S377 – 588 protein could induce potent neutralizing antibody responses similar to those raised by high doses, such as 5 and 20 μg, respectively <xref rid="CIT0023" ref-type="bibr">[23,24]</xref>. These reports all confirm that the RBD/CND of MERS-CoV in the S protein is an important target for the development of MERS subunit vaccines.</p><p>DNA vaccines are proven to be effective against MERS-CoV infection. An optimized DNA vaccine encoding full-length S protein of MERS-CoV was able to elicit antigen-specific neutralizing antibodies in mice, camels and rhesus macaques (non-human primates, NHPs), with six of the eight vaccinated macaques showing no radiographic evidence of infiltration after MERS-CoV challenge. Interestingly, potent antigen-specific cellular immune responses were induced in the immunized macaques, suggesting that T cell responses may also play a role in MERS-CoV protection <xref rid="CIT0025" ref-type="bibr">[25]</xref>. Inovio Pharmaceuticals Inc., in collaboration with GeneOne Life Science, will perform a Phase I clinical trial for this DNA-based vaccine <xref rid="CIT0026" ref-type="bibr">[26]</xref>. In addition to the DNA-only strategy, DNA-priming and protein-boosting could be an alternative vaccine approach for MERS-CoV. It is revealed that full-length S DNA priming and S1 subunit protein boosting immunization of mice and NHPs induced robust neutralizing antibody responses against several MERS-CoV strains, protecting NHPs from MERS-CoV challenge <xref rid="CIT0027" ref-type="bibr">[27]</xref>.</p><p>Other potential candidates have been suggested as MERS vaccines. For example, purified MERS-CoV full-length S nanoparticles in combination with appropriate adjuvants could elicit neutralizing antibodies in immunized mice <xref rid="CIT0028" ref-type="bibr">[28]</xref>. Using reverse genetics, recombinant MERS-CoV may efficiently replicate in cell culture of human cell lines with broad tissue tropism, allowing an engineered mutant MERS-CoV lacking the structural E protein to be rescued and propagate in cells expressing the E protein in trans, thus providing a platform to develop live-attenuated, or recombinant, MERS-CoV-based vaccines <xref rid="CIT0007" ref-type="bibr">[7,9]</xref>.</p></sec><sec id="S0003"><label>3. </label><title>Expert opinion</title><p>The induction of neutralizing antibodies is the key to the prevention of MERS-CoV infection, as supported by the fact that the reduction of lung pathogenesis and protection from MERS-CoV infection has been correlated with neutralizing antibody levels in the animal models <xref rid="CIT0023" ref-type="bibr">[23,29]</xref>. In addition, vaccines that enjoy a high safety profile, combined with the ability to induce broad-spectrum immune responses and strong protective neutralizing antibodies, should have top priority for further development.</p><p>Efficacy and protective immunity of MERS candidate vaccines are, of necessity, evaluated in appropriate animal models. Thus, before moving to clinical trials, NHP rhesus macaque and common marmoset models <xref rid="CIT0030" ref-type="bibr">[30,31]</xref> and camel model <xref rid="CIT0032" ref-type="bibr">[32]</xref>, have been established and utilized for such purposes. However, the use of NHP and camel models is financially and facility restrictive for many researchers. Fortunately, recent advancements in establishing small animal models, including Ad5/hDPP4-transduced mouse model <xref rid="CIT0033" ref-type="bibr">[33]</xref> and hDPP4-transgenic mouse models <xref rid="CIT0034" ref-type="bibr">[34]</xref>, have provided a portable and economical platform for assessing the efficacy of MERS candidate vaccines, despite the fact that each of these animal models has its advantages and disadvantages.</p><p>Although very promising, the recombinant MERS-CoV-based vaccines will need to be further characterized in suitable MERS-CoV animal models to confirm their efficacy and safety. Viral vector-based vaccines, on the other hand, may show protective immunity in challenged mouse animals. However, these vaccines might have safety concerns by the presence of pre-existing immunity in humans (in the case of Ad) or the potential to induce harmful immune responses. Thus, safety tests are strongly recommended. Also, this vaccine type might lead to incomplete protection or fail to protect aged groups, as shown in the case of SARS-CoV vaccines <xref rid="CIT0035" ref-type="bibr">[35]</xref>. By comparison, recombinant protein-based subunit vaccines possess the highest safety profile because they utilize full-length spike protein, or its subunit (e.g., S1) or fragment (e.g., RBD) as the antigen. In the presence of suitable adjuvants, this type of vaccine is generally able to induce higher titers of neutralizing antibody responses than those elicited by other vaccine types, and they can be easily injected via different pathways, including intramuscular injection, an adopted route for human vaccines. Importantly, some of these MERS subunit vaccines are shown to be protective against MERS-CoV infection in challenged mouse and/or NHP models <xref rid="CIT0023" ref-type="bibr">[23,27]</xref>, demonstrating their ability for further scale-up and/or human clinical trials.</p><p>Among these recombinant protein-based subunit vaccines, we believe that RBD-based vaccines are more effective and safer than those based on the full-length S protein. RBD contains the CND in the S protein, and most of the highly potent neutralizing antibodies target the RBD <xref rid="CIT0021" ref-type="bibr">[21,36-38]</xref>. Recombinant proteins containing RBD induce strong neutralizing antibody responses and protection in the vaccinated animals against MERS-CoV infection <xref rid="CIT0021" ref-type="bibr">[21,23]</xref>. In contrast, the full-length S protein contains some non-neutralizing immunodominant domains, which may compromise the immunogenicity with the CND in RBD, or even induces virus-enhancing or harmful immune responses, as demonstrated in the S protein of SARS-CoV <xref rid="CIT0039" ref-type="bibr">[39]</xref>. This may be one of the reasons that the development of full-length S protein-based SARS vaccine has been discontinued. One may criticize that the vaccines based on the RBD sequences of the current MERS-CoV strains might be not effective against future emerged MERS-CoV strains with mutations in RBD. This should not be a problem for RBD-based vaccines because RBD contains several conformational neutralizing epitopes, and thus mutation(s) in one epitope may not significantly affect the neutralizing activity of antibodies elicited by other epitopes. For example, the RBD-specific mAb F11 could not neutralize the Bisha1 strain of MERS-CoV, whose RBD contains 509 mutation, but susceptible to neutralization of D12, another MERS-CoV RBD-specific mAb <xref rid="CIT0027" ref-type="bibr">[27]</xref>. Previous studies have demonstrated that RBD of SARS-CoV Tor2 strain, which contains six different conformational neutralizing epitopes, induces antibodies in the vaccinated animals with neutralizing activity against all SARS-CoV strains tested, including those caused by the early SARS outbreaks (e.g., GD03 strain) and late SARS pandemics (e.g., Urbani strain), as well as the SARS-like CoV strain from civets (SZ strain) <xref rid="CIT0040" ref-type="bibr">[40]</xref>. Although some epitopes outside MERS-CoV RBD may have neutralizing activity, such ability is significantly lower than that of the RBD. For example, neutralizing mAbs G2 and G4 target epitopes at MERS-CoV S1 and S2, respectively, both of which are outside the RBD, their neutralizing ability is not as potent as RBD-specific mAbs F11 and D12 <xref rid="CIT0027" ref-type="bibr">[27]</xref>. Nevertheless, these non-RBD neutralizing epitopes, if being clearly identified, could be potentially included in vaccine design to increase the breadth and strength of MERS-CoV vaccines.</p><p>It is common knowledge that the process of vaccine approval is long and that it is further complicated by regulatory restrictions and a shortage of funds. As a case in point, MERS vaccines are urgently needed, yet Big Pharma has consistently refused to invest funds for manufacturing or developing in pre-clinical and clinical studies based on the uncertainty of immediate return on such investments. In addition, adequate financial support from government entities is not guaranteed by the general lack of funds. As noted above, however, some firms in U.S. and DZIF Academy in Germany have taken the first step toward clinical trials of the two MERS vaccines based on DNA and viral vector, respectively. Big Pharma and governments of these countries and other parts of the world should take note of this signal and act accordingly.</p></sec></body><back><sec><title>Declaration of interest</title><p>The authors were funded by NIH grants R21AI109094, R21AI111152 and R01AI098775, as well as intramural funds from the New York Blood Center, grant NYB000348. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. 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Virol</source><year>2015</year>;<volume>89</volume>(<issue>16</issue>):<fpage>8651</fpage>-<lpage>6</lpage><pub-id pub-id-type="pmid">26018172</pub-id></mixed-citation><note><label>• </label><p><bold>This paper demonstrates the protection of MERS-CoV infection by a viral vector-based vaccine.</bold></p></note></ref><ref id="CIT0017"><label>17.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Song</surname><given-names>F</given-names></name>, <name name-style="western"><surname>Fux</surname><given-names>R</given-names></name>, <name name-style="western"><surname>Provacia</surname><given-names>LB</given-names></name>, <etal>et al.</etal></person-group><article-title>Middle East respiratory syndrome coronavirus spike protein delivered by modified vaccinia virus Ankara efficiently induces virus-neutralizing antibodies</article-title>. <source>J Virol</source><year>2013</year>;<volume>87</volume>(<issue>21</issue>):<fpage>11950</fpage>-<lpage>4</lpage><pub-id pub-id-type="pmid">23986586</pub-id></mixed-citation></ref><ref id="CIT0018"><label>18.</label><mixed-citation publication-type="web"><person-group person-group-type="author"><name name-style="western"><surname>Paddock</surname><given-names>C</given-names></name></person-group><article-title>MERS vaccine ’ready for human trials’. Medical News Today</article-title>. <comment>Available from:</comment><uri xlink:href="http://www.medicalnewstoday.com/articles/296023.php">http://www.medicalnewstoday.com/articles/296023.php</uri><comment>[Last accessed 29 June 2015]</comment></mixed-citation></ref><ref id="CIT0019"><label>19.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Mou</surname><given-names>H</given-names></name>, <name name-style="western"><surname>Raj</surname><given-names>VS</given-names></name>, <name name-style="western"><surname>van Kuppeveld</surname><given-names>FJ</given-names></name>, <etal>et al.</etal></person-group><article-title>The receptor binding domain of the new MERS coronavirus maps to a 231-residue region in the spike protein that efficiently elicits neutralizing antibodies</article-title>. <source>J Virol</source><year>2013</year>;<volume>87</volume>(<issue>16</issue>):<fpage>9379</fpage>-<lpage>83</lpage><pub-id pub-id-type="pmid">23785207</pub-id></mixed-citation></ref><ref id="CIT0020"><label>20.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Du</surname><given-names>L</given-names></name>, <name name-style="western"><surname>Zhao</surname><given-names>G</given-names></name>, <name name-style="western"><surname>Kou</surname><given-names>Z</given-names></name>, <etal>et al.</etal></person-group><article-title>Identification of a receptor-binding domain in the S protein of the novel human coronavirus Middle East respiratory syndrome coronavirus as an essential target for vaccine development</article-title>. <source>J Virol</source><year>2013</year>;<volume>87</volume>(<issue>17</issue>):<fpage>9939</fpage>-<lpage>42</lpage><pub-id pub-id-type="pmid">23824801</pub-id></mixed-citation></ref><ref id="CIT0021"><label>21.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Ma</surname><given-names>C</given-names></name>, <name name-style="western"><surname>Wang</surname><given-names>L</given-names></name>, <name name-style="western"><surname>Tao</surname><given-names>X</given-names></name>, <etal>et al.</etal></person-group><article-title>Searching for an ideal vaccine candidate among different MERS coronavirus receptor-binding fragments – the importance of immunofocusing in subunit vaccine design</article-title>. <source>Vaccine</source><year>2014</year>;<volume>32</volume>(<issue>46</issue>):<fpage>6170</fpage>-<lpage>6</lpage><pub-id pub-id-type="pmid">25240756</pub-id></mixed-citation><note><label>•• </label><p><bold>This was one of the papers demonstrating MERS-CoV RBD as an important vaccine target.</bold></p></note></ref><ref id="CIT0022"><label>22.</label><mixed-citation 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name-style="western"><surname>Tao</surname><given-names>X</given-names></name>, <etal>et al.</etal></person-group><article-title>Optimization of antigen dose for a receptor-binding domain-based subunit vaccine against MERS coronavirus</article-title>. <source>Hum Vaccin Immunother</source><year>2015</year>;<volume>11</volume>(<issue>5</issue>):<fpage>1244</fpage>-<lpage>50</lpage><pub-id pub-id-type="pmid">25874632</pub-id></mixed-citation></ref><ref id="CIT0025"><label>25.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Muthumani</surname><given-names>K</given-names></name>, <name name-style="western"><surname>Falzarano</surname><given-names>D</given-names></name>, <name name-style="western"><surname>Reuschel</surname><given-names>EL</given-names></name>, <etal>et al.</etal></person-group><article-title>A synthetic consensus anti-spike protein DNA vaccine induces protective immunity against Middle East 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al.</etal></person-group><article-title>Tailoring subunit vaccine immunity with adjuvant combinations and delivery routes using the Middle East respiratory coronavirus (MERS-CoV) receptor-binding domain as an antigen</article-title>. <source>PLoS One</source><year>2014</year>;<volume>9</volume>(<issue>11</issue>):<fpage>e112602</fpage><pub-id pub-id-type="pmid">25405618</pub-id></mixed-citation></ref></ref-list></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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