Successful Topical Respiratory Tract Immunization of Primates against Ebola Virus

Abstract

Ebola virus causes outbreaks of severe viral hemorrhagic fever with high mortality in humans. The virus is highly contagious and can be transmitted by contact and by the aerosol route. These features make Ebola virus a potential weapon for bioterrorism and biological warfare. Therefore, a vaccine that induces both systemic and local immune responses in the respiratory tract would be highly beneficial. We evaluated a common pediatric respiratory pathogen, human parainfluenza virus type 3 (HPIV3), as a vaccine vector against Ebola virus. HPIV3 recombinants expressing the Ebola virus (Zaire species) surface glycoprotein (GP) alone or in combination with the nucleocapsid protein NP or with the cytokine adjuvant granulocyte-macrophage colonystimulating factor were administered by the respiratory route to rhesus monkeys-in which HPIV3 infection is mild and asymptomatic-and were evaluated for immunogenicity and protective efficacy against a highly lethal intraperitoneal challenge with Ebola virus. A single immunization with any construct expressing GP was moderately immunogenic against Ebola virus and protected 88% of the animals against severe hemorrhagic fever and death caused by Ebola virus. Two doses were highly immunogenic, and all of the animals survived challenge and were free of signs of disease and of detectable Ebola virus challenge virus. These data illustrate the feasibility of immunization via the respiratory tract against the hemorrhagic fever caused by Ebola virus. To our knowledge, this is the first study in which topical immunization through respiratory tract achieved prevention of a viral hemorrhagic fever infection in a primate model.

Post-exposure treatments for Ebola and Marburg virus infections

“…Nearly all these vaccines use filovirus glycoprotein (GP) as the protective immunogen. These vaccines completely protected NHPs against lethal disease and are mostly replication-defective or replication-competent viral vectors, including alphavirus replicons 241,242 , human adenoviruses [243][244][245][246][247] , chimpanzee adenoviruses 248 , paramyxoviruses 249,250 , rabies viruses 251,252 and several different strategies with recombinant vesicular stomatitis viruses (rVSVs), including both the prototype rVSV vaccine [253][254][255][256][257] and a newer rVSV vaccine developed for enhanced safety (VesiculoVax) 258 . Virus-like particles [259][260][261] , a biologically contained EBOV lacking viral protein 30 (VP30) 262 , DNA 244 and several combinations of vaccines that include DNA, modified vaccinia Ankara (MVA) and various adenoviruses can also completely protect NHPs from lethal filovirus disease 244,248,263 .…”

How Ebola and Marburg viruses battle the immune system

“…A recent report with a recombinant adenovirus that expresses the ZEBOV glycoprotein, in which the minimal protective dose of 10 10 particles is described as a 'low dose' , affirms that protection is dependent on the vaccine dose 65 , and might explain why repliconbased vaccines given at much lower doses have not been uniformly successful 67 and DNA vaccines have been only partially effective 79 . Live vesicular stomatitis virus (VSV) 64 or parainfluenza virus 80,81 recombinants, which show considerable promise in protecting non-human primates from filoviral infection, presumably generate high amounts of viral glycoprotein antigen in vivo. Herein resides a most familiar challenge of vaccine licensure: the achievement of a suitable balance between vaccine potency and vaccine safety.…”

Recent advances inEbolavirusvaccine development

“…102 Results obtained from vaccinated NHPs with VSV-based vector, parainfluenza virus vector, or VLP-based vector also induced the presence of antigen specific antibodies in all survivors prior to lethal EBOV virus challenge. 118,133,140 While evidence presented to date indicates that each vector platform capable of inducing significant antibody responses is correlated to their efficacy, some subjects found to contain similar ELISA-based IgG levels have resulted in different survival outcomes. In addition, passive transfer of immune component of current vaccine candidates contains either the pathogen of interest in an attenuated or inactivated form, a purified protein subunit of the pathogen, or a delivery mechanism capable of producing the antigenic components of the target pathogen.…”