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A Highly Immunogenic and Protective Middle East Respiratory Syndrome Coronavirus Vaccine Based on a Recombinant Measles Virus Vaccine Platform.
J Virol. 2015 Nov; 89(22):11654-67.JV

Abstract

In 2012, the first cases of infection with the Middle East respiratory syndrome coronavirus (MERS-CoV) were identified. Since then, more than 1,000 cases of MERS-CoV infection have been confirmed; infection is typically associated with considerable morbidity and, in approximately 30% of cases, mortality. Currently, there is no protective vaccine available. Replication-competent recombinant measles virus (MV) expressing foreign antigens constitutes a promising tool to induce protective immunity against corresponding pathogens. Therefore, we generated MVs expressing the spike glycoprotein of MERS-CoV in its full-length (MERS-S) or a truncated, soluble variant of MERS-S (MERS-solS). The genes encoding MERS-S and MERS-solS were cloned into the vaccine strain MVvac2 genome, and the respective viruses were rescued (MVvac2-CoV-S and MVvac2-CoV-solS). These recombinant MVs were amplified and characterized at passages 3 and 10. The replication of MVvac2-CoV-S in Vero cells turned out to be comparable to that of the control virus MVvac2-GFP (encoding green fluorescent protein), while titers of MVvac2-CoV-solS were impaired approximately 3-fold. The genomic stability and expression of the inserted antigens were confirmed via sequencing of viral cDNA and immunoblot analysis. In vivo, immunization of type I interferon receptor-deficient (IFNAR(-/-))-CD46Ge mice with 2 × 10(5) 50% tissue culture infective doses of MVvac2-CoV-S(H) or MVvac2-CoV-solS(H) in a prime-boost regimen induced robust levels of both MV- and MERS-CoV-neutralizing antibodies. Additionally, induction of specific T cells was demonstrated by T cell proliferation, antigen-specific T cell cytotoxicity, and gamma interferon secretion after stimulation of splenocytes with MERS-CoV-S presented by murine dendritic cells. MERS-CoV challenge experiments indicated the protective capacity of these immune responses in vaccinated mice.

IMPORTANCE

Although MERS-CoV has not yet acquired extensive distribution, being mainly confined to the Arabic and Korean peninsulas, it could adapt to spread more readily among humans and thereby become pandemic. Therefore, the development of a vaccine is mandatory. The integration of antigen-coding genes into recombinant MV resulting in coexpression of MV and foreign antigens can efficiently be achieved. Thus, in combination with the excellent safety profile of the MV vaccine, recombinant MV seems to constitute an ideal vaccine platform. The present study shows that a recombinant MV expressing MERS-S is genetically stable and induces strong humoral and cellular immunity against MERS-CoV in vaccinated mice. Subsequent challenge experiments indicated protection of vaccinated animals, illustrating the potential of MV as a vaccine platform with the potential to target emerging infections, such as MERS-CoV.

Authors+Show Affiliations

Oncolytic Measles Viruses and Vaccine Vectors, Paul-Ehrlich-Institut, Langen, Germany German Center for Infection Research, Langen, Germany.Institut für Virologie, Philipps Universität Marburg, Marburg, Germany German Center for Infection Research, Marburg, Germany.Oncolytic Measles Viruses and Vaccine Vectors, Paul-Ehrlich-Institut, Langen, Germany.Oncolytic Measles Viruses and Vaccine Vectors, Paul-Ehrlich-Institut, Langen, Germany.Oncolytic Measles Viruses and Vaccine Vectors, Paul-Ehrlich-Institut, Langen, Germany.Novel Vaccination Strategies and Early Immune Responses, Paul-Ehrlich-Institut, Langen, Germany.TRON gGmbH, Mainz, Germany.Novel Vaccination Strategies and Early Immune Responses, Paul-Ehrlich-Institut, Langen, Germany.Universitätsmedizin Mainz, Mainz, Germany.Oncolytic Measles Viruses and Vaccine Vectors, Paul-Ehrlich-Institut, Langen, Germany.Institut für Virologie, Philipps Universität Marburg, Marburg, Germany German Center for Infection Research, Marburg, Germany.Institut für Virologie, Philipps Universität Marburg, Marburg, Germany German Center for Infection Research, Marburg, Germany.Institut für Virologie, Philipps Universität Marburg, Marburg, Germany German Center for Infection Research, Marburg, Germany.Oncolytic Measles Viruses and Vaccine Vectors, Paul-Ehrlich-Institut, Langen, Germany.Oncolytic Measles Viruses and Vaccine Vectors, Paul-Ehrlich-Institut, Langen, Germany.Biostatistics, Paul-Ehrlich-Institut, Langen, Germany.Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany German Center for Infection Research, Hannover, Germany.Universities Gieβen and Marburg Lung Center, Department of Internal Medicine II, Section of Infectious Diseases, Giessen, Germany.TRON gGmbH, Mainz, Germany Universitätsmedizin Mainz, Mainz, Germany.Oncolytic Measles Viruses and Vaccine Vectors, Paul-Ehrlich-Institut, Langen, Germany German Center for Infection Research, Langen, Germany.German Center for Infection Research, Langen, Germany Novel Vaccination Strategies and Early Immune Responses, Paul-Ehrlich-Institut, Langen, Germany.Institut für Virologie, Philipps Universität Marburg, Marburg, Germany German Center for Infection Research, Marburg, Germany.Institut für Virologie, Philipps Universität Marburg, Marburg, Germany German Center for Infection Research, Marburg, Germany.Oncolytic Measles Viruses and Vaccine Vectors, Paul-Ehrlich-Institut, Langen, Germany German Center for Infection Research, Langen, Germany Michael.Muehlebach@pei.de.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26355094

Citation

Malczyk, Anna H., et al. "A Highly Immunogenic and Protective Middle East Respiratory Syndrome Coronavirus Vaccine Based On a Recombinant Measles Virus Vaccine Platform." Journal of Virology, vol. 89, no. 22, 2015, pp. 11654-67.
Malczyk AH, Kupke A, Prüfer S, et al. A Highly Immunogenic and Protective Middle East Respiratory Syndrome Coronavirus Vaccine Based on a Recombinant Measles Virus Vaccine Platform. J Virol. 2015;89(22):11654-67.
Malczyk, A. H., Kupke, A., Prüfer, S., Scheuplein, V. A., Hutzler, S., Kreuz, D., Beissert, T., Bauer, S., Hubich-Rau, S., Tondera, C., Eldin, H. S., Schmidt, J., Vergara-Alert, J., Süzer, Y., Seifried, J., Hanschmann, K. M., Kalinke, U., Herold, S., Sahin, U., ... Mühlebach, M. D. (2015). A Highly Immunogenic and Protective Middle East Respiratory Syndrome Coronavirus Vaccine Based on a Recombinant Measles Virus Vaccine Platform. Journal of Virology, 89(22), 11654-67. https://doi.org/10.1128/JVI.01815-15
Malczyk AH, et al. A Highly Immunogenic and Protective Middle East Respiratory Syndrome Coronavirus Vaccine Based On a Recombinant Measles Virus Vaccine Platform. J Virol. 2015;89(22):11654-67. PubMed PMID: 26355094.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A Highly Immunogenic and Protective Middle East Respiratory Syndrome Coronavirus Vaccine Based on a Recombinant Measles Virus Vaccine Platform. AU - Malczyk,Anna H, AU - Kupke,Alexandra, AU - Prüfer,Steffen, AU - Scheuplein,Vivian A, AU - Hutzler,Stefan, AU - Kreuz,Dorothea, AU - Beissert,Tim, AU - Bauer,Stefanie, AU - Hubich-Rau,Stefanie, AU - Tondera,Christiane, AU - Eldin,Hosam Shams, AU - Schmidt,Jörg, AU - Vergara-Alert,Júlia, AU - Süzer,Yasemin, AU - Seifried,Janna, AU - Hanschmann,Kay-Martin, AU - Kalinke,Ulrich, AU - Herold,Susanne, AU - Sahin,Ugur, AU - Cichutek,Klaus, AU - Waibler,Zoe, AU - Eickmann,Markus, AU - Becker,Stephan, AU - Mühlebach,Michael D, Y1 - 2015/09/09/ PY - 2015/07/16/received PY - 2015/09/03/accepted PY - 2015/9/11/entrez PY - 2015/9/12/pubmed PY - 2016/1/30/medline SP - 11654 EP - 67 JF - Journal of virology JO - J Virol VL - 89 IS - 22 N2 - UNLABELLED: In 2012, the first cases of infection with the Middle East respiratory syndrome coronavirus (MERS-CoV) were identified. Since then, more than 1,000 cases of MERS-CoV infection have been confirmed; infection is typically associated with considerable morbidity and, in approximately 30% of cases, mortality. Currently, there is no protective vaccine available. Replication-competent recombinant measles virus (MV) expressing foreign antigens constitutes a promising tool to induce protective immunity against corresponding pathogens. Therefore, we generated MVs expressing the spike glycoprotein of MERS-CoV in its full-length (MERS-S) or a truncated, soluble variant of MERS-S (MERS-solS). The genes encoding MERS-S and MERS-solS were cloned into the vaccine strain MVvac2 genome, and the respective viruses were rescued (MVvac2-CoV-S and MVvac2-CoV-solS). These recombinant MVs were amplified and characterized at passages 3 and 10. The replication of MVvac2-CoV-S in Vero cells turned out to be comparable to that of the control virus MVvac2-GFP (encoding green fluorescent protein), while titers of MVvac2-CoV-solS were impaired approximately 3-fold. The genomic stability and expression of the inserted antigens were confirmed via sequencing of viral cDNA and immunoblot analysis. In vivo, immunization of type I interferon receptor-deficient (IFNAR(-/-))-CD46Ge mice with 2 × 10(5) 50% tissue culture infective doses of MVvac2-CoV-S(H) or MVvac2-CoV-solS(H) in a prime-boost regimen induced robust levels of both MV- and MERS-CoV-neutralizing antibodies. Additionally, induction of specific T cells was demonstrated by T cell proliferation, antigen-specific T cell cytotoxicity, and gamma interferon secretion after stimulation of splenocytes with MERS-CoV-S presented by murine dendritic cells. MERS-CoV challenge experiments indicated the protective capacity of these immune responses in vaccinated mice. IMPORTANCE: Although MERS-CoV has not yet acquired extensive distribution, being mainly confined to the Arabic and Korean peninsulas, it could adapt to spread more readily among humans and thereby become pandemic. Therefore, the development of a vaccine is mandatory. The integration of antigen-coding genes into recombinant MV resulting in coexpression of MV and foreign antigens can efficiently be achieved. Thus, in combination with the excellent safety profile of the MV vaccine, recombinant MV seems to constitute an ideal vaccine platform. The present study shows that a recombinant MV expressing MERS-S is genetically stable and induces strong humoral and cellular immunity against MERS-CoV in vaccinated mice. Subsequent challenge experiments indicated protection of vaccinated animals, illustrating the potential of MV as a vaccine platform with the potential to target emerging infections, such as MERS-CoV. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/26355094/A_Highly_Immunogenic_and_Protective_Middle_East_Respiratory_Syndrome_Coronavirus_Vaccine_Based_on_a_Recombinant_Measles_Virus_Vaccine_Platform_ L2 - http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=26355094 DB - PRIME DP - Unbound Medicine ER -