A Highly Immunogenic, Protective, and Safe Adenovirus-Based Vaccine Expressing Middle East Respiratory Syndrome Coronavirus S1-CD40L Fusion Protein in a Transgenic Human Dipeptidyl Peptidase 4 Mouse Model
Identifieur interne : 000742 ( Main/Exploration ); précédent : 000741; suivant : 000743A Highly Immunogenic, Protective, and Safe Adenovirus-Based Vaccine Expressing Middle East Respiratory Syndrome Coronavirus S1-CD40L Fusion Protein in a Transgenic Human Dipeptidyl Peptidase 4 Mouse Model
Auteurs : Anwar M. Hashem [Arabie saoudite] ; Abdullah Algaissi ; Anurodh Shankar Agrawal ; Sawsan S. Al-Amri [Arabie saoudite] ; Rowa Y. Alhabbab [Arabie saoudite] ; Sayed S. Sohrab [Arabie saoudite] ; Abdulrahman S. Almasoud [Arabie saoudite] ; Naif Khalaf Alharbi [Arabie saoudite] ; Bi-Hung Peng ; Marsha Russell [Canada] ; Xuguang Li [Canada] ; Chien-Te K. TsengSource :
- The Journal of Infectious Diseases [ 0022-1899 ] ; 2019.
Abstract
Infection control measures have played a major role in limiting human/camel-to-human transmission of Middle East respiratory syndrome coronavirus (MERS-CoV); however, development of effective and safe human or camel vaccines is warranted.
We extended and optimized our previous recombinant adenovirus 5 (rAd5)–based vaccine platform characterized by in vivo amplified and CD40-mediated specific responses to generate MERS-CoV S1 subunit-based vaccine. We generated rAd5 constructs expressing CD40-targeted S1 fusion protein (rAd5-S1/F/CD40L), untargeted S1 (rAd5-S1), and Green Fluorescent Protein (rAd5-GFP), and evaluated their efficacy and safety in human dipeptidyl peptidase 4 transgenic (hDPP4 Tg+) mice.
Immunization of hDPP4 Tg+ mice with a single dose of rAd5-S1/F/CD40L elicited as robust and significant specific immunoglobulin G and neutralizing antibodies as those induced with 2 doses of rAd5-S1. After MERS-CoV challenge, both vaccines conferred complete protection against morbidity and mortality, as evidenced by significantly undetectable/reduced pulmonary viral loads compared to the control group. However, rAd5-S1– but not rAd5-S1/F/CD40L–immunized mice exhibited marked pulmonary perivascular hemorrhage post–MERS-CoV challenge despite the observed protection.
Incorporation of CD40L into rAd5-based MERS-CoV S1 vaccine targeting molecule and molecular adjuvants not only enhances immunogenicity and efficacy but also prevents inadvertent pulmonary pathology after viral challenge, thereby offering a promising strategy to enhance safety and potency of vaccines.
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DOI: 10.1093/infdis/jiz137
PubMed: 30911758
PubMed Central: 7107499
Affiliations:
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Sohrab</name><affiliation wicri:level="1"><nlm:aff id="AF0003"><institution>Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University</institution>, Jeddah,<country country="SA">Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="S Almasoud, Abdulrahman" sort="S Almasoud, Abdulrahman" uniqKey="S Almasoud A" first="Abdulrahman" last="S. Almasoud">Abdulrahman S. 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Tseng</name><affiliation><nlm:aff id="AF0004"><institution>Department of Microbiology and Immunology, University of Texas Medical Branch</institution>, Galveston</nlm:aff><wicri:noCountry code="subfield">Galveston</wicri:noCountry></affiliation><affiliation><nlm:aff id="AF0010"><institution>Center of Biodefense and Emerging Disease, University of Texas Medical Branch</institution>, Galveston</nlm:aff><wicri:noCountry code="subfield">Galveston</wicri:noCountry></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">30911758</idno><idno type="pmc">7107499</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7107499</idno><idno type="RBID">PMC:7107499</idno><idno type="doi">10.1093/infdis/jiz137</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000E34</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000E34</idno><idno type="wicri:Area/Pmc/Curation">000E34</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000E34</idno><idno type="wicri:Area/Pmc/Checkpoint">000434</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000434</idno><idno type="wicri:source">PubMed</idno><idno type="RBID">pubmed:30911758</idno><idno type="wicri:Area/PubMed/Corpus">000596</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000596</idno><idno type="wicri:Area/PubMed/Curation">000596</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000596</idno><idno type="wicri:Area/PubMed/Checkpoint">000707</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000707</idno><idno type="wicri:Area/Ncbi/Merge">002161</idno><idno type="wicri:Area/Ncbi/Curation">002161</idno><idno type="wicri:Area/Ncbi/Checkpoint">002161</idno><idno type="wicri:doubleKey">0022-1899:2019:Hashem A:a:highly:immunogenic</idno><idno type="wicri:Area/Main/Merge">000745</idno><idno type="wicri:Area/Main/Curation">000742</idno><idno type="wicri:Area/Main/Exploration">000742</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A Highly Immunogenic, Protective, and Safe Adenovirus-Based Vaccine Expressing Middle East Respiratory Syndrome Coronavirus S1-CD40L Fusion Protein in a Transgenic Human Dipeptidyl Peptidase 4 Mouse Model</title><author><name sortKey="Hashem, Anwar M" sort="Hashem, Anwar M" uniqKey="Hashem A" first="Anwar M" last="Hashem">Anwar M. Hashem</name><affiliation><nlm:aff id="AF0001"><institution>Department of Medical Microbiology and Parasitology, Faculty of Medicine</institution></nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="AF0002"><institution>Vaccines and Immunotherapy Unit, King Fahd Medical Research Center</institution>,<country country="SA">Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="AF0003"><institution>Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University</institution>, Jeddah,<country country="SA">Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Algaissi, Abdullah" sort="Algaissi, Abdullah" uniqKey="Algaissi A" first="Abdullah" last="Algaissi">Abdullah Algaissi</name><affiliation><nlm:aff id="AF0004"><institution>Department of Microbiology and Immunology, University of Texas Medical Branch</institution>, Galveston</nlm:aff><wicri:noCountry code="subfield">Galveston</wicri:noCountry></affiliation><affiliation><nlm:aff id="AF0005"><institution>Department of Medical Laboratories Technology, College of Applied Medical Sciences, Jazan University</institution></nlm:aff></affiliation></author><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="AF0004"><institution>Department of Microbiology and Immunology, University of Texas Medical Branch</institution>, Galveston</nlm:aff><wicri:noCountry code="subfield">Galveston</wicri:noCountry></affiliation></author><author><name sortKey="Al Amri, Sawsan S" sort="Al Amri, Sawsan S" uniqKey="Al Amri S" first="Sawsan S" last="Al-Amri">Sawsan S. Al-Amri</name><affiliation wicri:level="1"><nlm:aff id="AF0002"><institution>Vaccines and Immunotherapy Unit, King Fahd Medical Research Center</institution>,<country country="SA">Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="AF0003"><institution>Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University</institution>, Jeddah,<country country="SA">Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Alhabbab, Rowa Y" sort="Alhabbab, Rowa Y" uniqKey="Alhabbab R" first="Rowa Y" last="Alhabbab">Rowa Y. Alhabbab</name><affiliation wicri:level="1"><nlm:aff id="AF0002"><institution>Vaccines and Immunotherapy Unit, King Fahd Medical Research Center</institution>,<country country="SA">Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="AF0003"><institution>Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University</institution>, Jeddah,<country country="SA">Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation><nlm:aff id="AF0006"><institution>Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University</institution>, Jeddah</nlm:aff><wicri:noCountry code="subfield">Jeddah</wicri:noCountry></affiliation></author><author><name sortKey="Sohrab, Sayed S" sort="Sohrab, Sayed S" uniqKey="Sohrab S" first="Sayed S" last="Sohrab">Sayed S. Sohrab</name><affiliation wicri:level="1"><nlm:aff id="AF0003"><institution>Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University</institution>, Jeddah,<country country="SA">Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="S Almasoud, Abdulrahman" sort="S Almasoud, Abdulrahman" uniqKey="S Almasoud A" first="Abdulrahman" last="S. Almasoud">Abdulrahman S. Almasoud</name><affiliation wicri:level="1"><nlm:aff id="AF0007"><institution>Department of Infectious Disease Research, King Abdullah International Medical Research Center</institution>, Riyadh,<country country="SA">Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Alharbi, Naif Khalaf" sort="Alharbi, Naif Khalaf" uniqKey="Alharbi N" first="Naif Khalaf" last="Alharbi">Naif Khalaf Alharbi</name><affiliation wicri:level="1"><nlm:aff id="AF0007"><institution>Department of Infectious Disease Research, King Abdullah International Medical Research Center</institution>, Riyadh,<country country="SA">Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></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="AF0008"><institution>Department of Neurosciences, Cell Biology, and Anatomy, University of Texas Medical Branch</institution>, Galveston</nlm:aff><wicri:noCountry code="subfield">Galveston</wicri:noCountry></affiliation></author><author><name sortKey="Russell, Marsha" sort="Russell, Marsha" uniqKey="Russell M" first="Marsha" last="Russell">Marsha Russell</name><affiliation wicri:level="2"><nlm:aff id="AF0009"><institution>Center for Vaccine Evaluation, Biologics and Genetic Therapies Directorate, Health Canada</institution>, Ottawa, Ontario</nlm:aff><country>Canada</country><placeName><region type="province">Ontario</region></placeName><wicri:cityArea>, Ottawa</wicri:cityArea></affiliation></author><author><name sortKey="Li, Xuguang" sort="Li, Xuguang" uniqKey="Li X" first="Xuguang" last="Li">Xuguang Li</name><affiliation wicri:level="2"><nlm:aff id="AF0009"><institution>Center for Vaccine Evaluation, Biologics and Genetic Therapies Directorate, Health Canada</institution>, Ottawa, Ontario</nlm:aff><country>Canada</country><placeName><region type="province">Ontario</region></placeName><wicri:cityArea>, Ottawa</wicri:cityArea></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="AF0004"><institution>Department of Microbiology and Immunology, University of Texas Medical Branch</institution>, Galveston</nlm:aff><wicri:noCountry code="subfield">Galveston</wicri:noCountry></affiliation><affiliation><nlm:aff id="AF0010"><institution>Center of Biodefense and Emerging Disease, University of Texas Medical Branch</institution>, Galveston</nlm:aff><wicri:noCountry code="subfield">Galveston</wicri:noCountry></affiliation></author></analytic><series><title level="j">The Journal of Infectious Diseases</title><idno type="ISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Abstract</title><sec id="s0100"><title>Background</title><p>Infection control measures have played a major role in limiting human/camel-to-human transmission of Middle East respiratory syndrome coronavirus (MERS-CoV); however, development of effective and safe human or camel vaccines is warranted.</p></sec><sec id="s0101"><title>Methods</title><p>We extended and optimized our previous recombinant adenovirus 5 (rAd5)–based vaccine platform characterized by in vivo amplified and CD40-mediated specific responses to generate MERS-CoV S1 subunit-based vaccine. We generated rAd5 constructs expressing CD40-targeted S1 fusion protein (rAd5-S1/F/CD40L), untargeted S1 (rAd5-S1), and Green Fluorescent Protein (rAd5-GFP), and evaluated their efficacy and safety in human dipeptidyl peptidase 4 transgenic (hDPP4 Tg<sup>+</sup>) mice.</p></sec><sec id="s0102"><title>Results</title><p>Immunization of hDPP4 Tg<sup>+</sup> mice with a single dose of rAd5-S1/F/CD40L elicited as robust and significant specific immunoglobulin G and neutralizing antibodies as those induced with 2 doses of rAd5-S1. After MERS-CoV challenge, both vaccines conferred complete protection against morbidity and mortality, as evidenced by significantly undetectable/reduced pulmonary viral loads compared to the control group. However, rAd5-S1– but not rAd5-S1/F/CD40L–immunized mice exhibited marked pulmonary perivascular hemorrhage post–MERS-CoV challenge despite the observed protection.</p></sec><sec id="s0103"><title>Conclusions</title><p>Incorporation of CD40L into rAd5-based MERS-CoV S1 vaccine targeting molecule and molecular adjuvants not only enhances immunogenicity and efficacy but also prevents inadvertent pulmonary pathology after viral challenge, thereby offering a promising strategy to enhance safety and potency of vaccines.</p></sec></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 Boheemen, S" uniqKey="Van Boheemen S">S van Boheemen</name></author><author><name sortKey="Bestebroer, Tm" uniqKey="Bestebroer T">TM Bestebroer</name></author><author><name sortKey="Osterhaus, Ad" uniqKey="Osterhaus A">AD Osterhaus</name></author><author><name sortKey="Fouchier, Ra" 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Tseng</name></noCountry><country name="Arabie saoudite"><noRegion><name sortKey="Hashem, Anwar M" sort="Hashem, Anwar M" uniqKey="Hashem A" first="Anwar M" last="Hashem">Anwar M. Hashem</name></noRegion><name sortKey="Al Amri, Sawsan S" sort="Al Amri, Sawsan S" uniqKey="Al Amri S" first="Sawsan S" last="Al-Amri">Sawsan S. Al-Amri</name><name sortKey="Al Amri, Sawsan S" sort="Al Amri, Sawsan S" uniqKey="Al Amri S" first="Sawsan S" last="Al-Amri">Sawsan S. Al-Amri</name><name sortKey="Alhabbab, Rowa Y" sort="Alhabbab, Rowa Y" uniqKey="Alhabbab R" first="Rowa Y" last="Alhabbab">Rowa Y. Alhabbab</name><name sortKey="Alhabbab, Rowa Y" sort="Alhabbab, Rowa Y" uniqKey="Alhabbab R" first="Rowa Y" last="Alhabbab">Rowa Y. Alhabbab</name><name sortKey="Alharbi, Naif Khalaf" sort="Alharbi, Naif Khalaf" uniqKey="Alharbi N" first="Naif Khalaf" last="Alharbi">Naif Khalaf Alharbi</name><name sortKey="Hashem, Anwar M" sort="Hashem, Anwar M" uniqKey="Hashem A" first="Anwar M" last="Hashem">Anwar M. Hashem</name><name sortKey="S Almasoud, Abdulrahman" sort="S Almasoud, Abdulrahman" uniqKey="S Almasoud A" first="Abdulrahman" last="S. Almasoud">Abdulrahman S. Almasoud</name><name sortKey="Sohrab, Sayed S" sort="Sohrab, Sayed S" uniqKey="Sohrab S" first="Sayed S" last="Sohrab">Sayed S. Sohrab</name></country><country name="Canada"><region name="Ontario"><name sortKey="Russell, Marsha" sort="Russell, Marsha" uniqKey="Russell M" first="Marsha" last="Russell">Marsha Russell</name></region><name sortKey="Li, Xuguang" sort="Li, Xuguang" uniqKey="Li X" first="Xuguang" last="Li">Xuguang Li</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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