PMID- 30567978 OWN - NLM STAT- MEDLINE DCOM- 20191119 LR - 20240410 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 93 IP - 6 DP - 2019 Mar 15 TI - A Recombinant Rabies Virus Expressing the Marburg Virus Glycoprotein Is Dependent upon Antibody-Mediated Cellular Cytotoxicity for Protection against Marburg Virus Disease in a Murine Model. LID - 10.1128/JVI.01865-18 [doi] LID - e01865-18 AB - Marburg virus (MARV) is a filovirus related to Ebola virus (EBOV) associated with human hemorrhagic disease. Outbreaks are sporadic and severe, with a reported case mortality rate of upward of 88%. There is currently no antiviral or vaccine available. Given the sporadic nature of outbreaks, vaccines provide the best approach for long-term control of MARV in regions of endemicity. We have developed an inactivated rabies virus-vectored MARV vaccine (FILORAB3) to protect against Marburg virus disease. Immunogenicity studies in our labs have shown that a Th1-biased seroconversion to both rabies virus and MARV glycoproteins (GPs) is beneficial for protection in a preclinical murine model. As such, we adjuvanted FILORAB3 with glucopyranosyl lipid adjuvant (GLA), a Toll-like receptor 4 agonist, in a squalene-in-water emulsion. Across two different BALB/c mouse challenge models, we achieved 92% protection against murine-adapted Marburg virus (ma-MARV). Although our vaccine elicited strong MARV GP antibodies, it did not strongly induce neutralizing antibodies. Through both in vitro and in vivo approaches, we elucidated a critical role for NK cell-dependent antibody-mediated cellular cytotoxicity (ADCC) in vaccine-induced protection. Overall, these findings demonstrate that FILORAB3 is a promising vaccine candidate for Marburg virus disease.IMPORTANCE Marburg virus (MARV) is a virus similar to Ebola virus and also causes a hemorrhagic disease which is highly lethal. In contrast to EBOV, only a few vaccines have been developed against MARV, and researchers do not understand what kind of immune responses are required to protect from MARV. Here we show that antibodies directed against MARV after application of our vaccine protect in an animal system but fail to neutralize the virus in a widely used virus neutralization assay against MARV. This newly discovered activity needs to be considered more when analyzing MARV vaccines or infections. CI - Copyright (c) 2019 American Society for Microbiology. FAU - Keshwara, Rohan AU - Keshwara R AD - Department of Microbiology and Immunology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, USA. FAU - Hagen, Katie R AU - Hagen KR AD - Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Maryland, USA. FAU - Abreu-Mota, Tiago AU - Abreu-Mota T AD - Department of Microbiology and Immunology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, USA. AD - Life and Health Sciences Research Institute (ICVS) School of Medicine, University of Minho, Braga, Portugal. AD - ICVS/3B's, PT Government Associate Laboratory, Braga/Guimaraes, Portugal. FAU - Papaneri, Amy B AU - Papaneri AB AD - Emerging Viral Pathogens Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. FAU - Liu, David AU - Liu D AD - Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Maryland, USA. FAU - Wirblich, Christoph AU - Wirblich C AD - Department of Microbiology and Immunology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, USA. FAU - Johnson, Reed F AU - Johnson RF AD - Emerging Viral Pathogens Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. FAU - Schnell, Matthias J AU - Schnell MJ AUID- ORCID: 0000-0001-9040-9405 AD - Department of Microbiology and Immunology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, USA Matthias.schnell@jefferson.edu. AD - Jefferson Vaccine Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, USA. LA - eng GR - HHSN272200700016I/AI/NIAID NIH HHS/United States GR - R01 AI105204/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20190305 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (Antibodies, Neutralizing) RN - 0 (Antibodies, Viral) RN - 0 (Glycoproteins) RN - 0 (Rabies Vaccines) RN - 0 (Viral Vaccines) SB - IM MH - Animals MH - Antibodies, Neutralizing/*immunology MH - Antibodies, Viral/*immunology MH - Cell Line MH - Chlorocebus aethiops MH - Disease Models, Animal MH - Female MH - Glycoproteins/*immunology MH - HEK293 Cells MH - Humans MH - Marburg Virus Disease/*immunology MH - Marburgvirus/*immunology MH - Mice MH - Mice, Inbred BALB C MH - Mice, Inbred C57BL MH - Rabies/*immunology MH - Rabies Vaccines/immunology MH - Rabies virus/*immunology MH - Vaccination/methods MH - Vero Cells MH - Viral Vaccines/immunology PMC - PMC6401435 OTO - NOTNLM OT - ADCC OT - Marburg virus OT - antibody function OT - filovirus OT - immunization OT - rabies virus OT - vaccine EDAT- 2018/12/21 06:00 MHDA- 2019/11/20 06:00 PMCR- 2019/09/05 CRDT- 2018/12/21 06:00 PHST- 2018/10/19 00:00 [received] PHST- 2018/12/10 00:00 [accepted] PHST- 2018/12/21 06:00 [pubmed] PHST- 2019/11/20 06:00 [medline] PHST- 2018/12/21 06:00 [entrez] PHST- 2019/09/05 00:00 [pmc-release] AID - JVI.01865-18 [pii] AID - 01865-18 [pii] AID - 10.1128/JVI.01865-18 [doi] PST - epublish SO - J Virol. 2019 Mar 5;93(6):e01865-18. doi: 10.1128/JVI.01865-18. Print 2019 Mar 15.