Distinct Immunogenicity and Efficacy of Poxvirus-Based Vaccine Candidates against Ebola Virus Expressing GP and VP40 Proteins.
Zaire and Sudan ebolavirus species cause a severe disease in humans and nonhuman primates (NHPs) characterized by a high mortality rate. There are no licensed therapies or vaccines against Ebola virus disease (EVD), and the recent 2013 to 2016 outbreak in West Africa highlighted the need for EVD-specific medical countermeasures. Here, we generated and characterized head-to-head the immunogenicity and efficacy of five vaccine candidates against Zaire ebolavirus (EBOV) and Sudan ebolavirus (SUDV) based on the highly attenuated poxvirus vector modified vaccinia virus Ankara (MVA) expressing either the virus glycoprotein (GP) or GP together with the virus protein 40 (VP40) forming virus-like particles (VLPs). In a human monocytic cell line, the different MVA vectors (termed MVA-EBOVs and MVA-SUDVs) triggered robust innate immune responses, with production of beta interferon (IFN-β), proinflammatory cytokines, and chemokines. Additionally, several innate immune cells, such as dendritic cells, neutrophils, and natural killer cells, were differentially recruited in the peritoneal cavity of mice inoculated with MVA-EBOVs. After immunization of mice with a homologous prime/boost protocol (MVA/MVA), total IgG antibodies against GP or VP40 from Zaire and Sudan ebolavirus were differentially induced by these vectors, which were mainly of the IgG1 and IgG3 isotypes. Remarkably, an MVA-EBOV construct coexpressing GP and VP40 protected chimeric mice challenged with EBOV to a greater extent than a vector expressing GP alone. These results support the consideration of MVA-EBOVs and MVA-SUDVs expressing GP and VP40 and producing VLPs as best-in-class potential vaccine candidates against EBOV and SUDV.IMPORTANCE EBOV and SUDV cause a severe hemorrhagic fever affecting humans and NHPs. Since their discovery in 1976, they have caused several sporadic epidemics, with the recent outbreak in West Africa from 2013 to 2016 being the largest and most severe, with more than 11,000 deaths being reported. Although some vaccines are in advanced clinical phases, less expensive, safer, and more effective licensed vaccines are desirable. We generated and characterized head-to-head the immunogenicity and efficacy of five novel vaccines against EBOV and SUDV based on the poxvirus MVA expressing GP or GP and VP40. The expression of GP and VP40 leads to the formation of VLPs. These MVA-EBOV and MVA-SUDV recombinants triggered robust innate and humoral immune responses in mice. Furthermore, MVA-EBOV recombinants expressing GP and VP40 induced high protection against EBOV in a mouse challenge model. Thus, MVA expressing GP and VP40 and producing VLPs is a promising vaccine candidate against EBOV and SUDV.
['Lázaro-Frías|Adrián|A|', 'Gómez-Medina|Sergio|S|', 'Sánchez-Sampedro|Lucas|L|', 'Ljungberg|Karl|K|', 'Ustav|Mart|M|', 'Liljeström|Peter|P|', 'Muñoz-Fontela|César|C|', 'Esteban|Mariano|M|', 'García-Arriaza|Juan|J|']
D000818:Animals D000914:Antibodies, Viral D045744:Cell Line, Tumor D018925:Chemokines D002642:Chick Embryo D015023:Democratic Republic of the Congo D003713:Dendritic Cells D046129:Ebola Vaccines D029043:Ebolavirus D006023:Glycoproteins D057809:HEK293 Cells D006367:HeLa Cells D019142:Hemorrhagic Fever, Ebola D006801:Humans D007074:Immunoglobulin G D016899:Interferon-beta D007694:Killer Cells, Natural D051379:Mice D008807:Mice, Inbred BALB C D009504:Neutrophils D013397:Sudan D014611:Vaccination D019444:Vaccines, DNA D014763:Viral Matrix Proteins D014765:Viral Vaccines
immunogenicity Ebola GP VP40 poxvirus MVA mice protection