450. A Single Immunization With Optimized DNA Vaccines Protects Against Lethal Ebola Virus Challenge in Mice and Induces Seroconversion in Non-Human Primates Following a DNA Prime–DNA Boost Approach

Abstract

Ebola is a hemorrhagic fever virus that is responsible for the severe, ongoing outbreak in West Africa, with over 21000 confirmed cases and a mortality rate of >39%. Control of the outbreak has been a considerable challenge as there are no approved vaccines or therapies. Recent reports suggest that the outbreak is more severe than previously thought and investigating alternative immunization approaches would be of great benefit. We generated 3 DNA vector vaccine candidates expressing the Zaire ebolavirus (EBOV) glycoprotein (GP): 2 vaccines designed based on consensus sequences of EBOV GPs (1976-2014) and a 3rd matched construct to a 2014 Guinea strain. Immunogenicity and protection was first evaluated in mice, followed by studies in non-human primates (NHP). BALB/c mice received a single immunization of each DNA vaccine (40mg), delivered by intramuscular injection followed by electroporation (IM-EP). We also co-administered 2 or 3 construct formulations of DNA vaccines as an alternative strategy to broaden efficacy against antigenically distant EBOV strains. All 3 single and all co-formulated vaccines generated strong T cell responses, including GP-specific polyfunctional CD4+ and CD8+ T cells secreting IFNγ, TNFα, and IL2. BALB/c mice (n=10/group) were challenged with a lethal dose of a heterologous mouse-adapted Mayinga 1976 EBOV strain. The two consensus DNA vaccines and 2 and 3 vaccine combinations were 100% protective in mice. The matched vaccine afforded 90% protection. Total GP-specific IgG levels were high in all surviving mice and low in unprotected animals suggesting that titers may correlate with therapeutic efficacy. As all 3 DNA vaccines were immunogenic and no antigen interference was observed, we next investigated immunogenicity of the 3 DNA vaccines in rhesus macaques following a DNA-DNA prime-boost immunization regimen. Macaques (n=5/group) received by IM-EP delivery:1) matched vaccine (4mg), 2) 3-construct formulation administered at a single injection site (2mg/vaccine), 3) 3-construct formulation delivered at separate injection sites (2mg/vaccine), or 4) 3-construct formulation combined with IL12 adjuvant (2mg/vaccine). Each immunization was followed by 3 subsequent DNA boosts at 1 month intervals. All groups had high GP-specific total IgG titers post-1st boost immunization that continued to increase over subsequent boosts and detectable T-cell responses. Overall, these studies demonstrate that a DNA-DNA prime-boost regimen can effectively induce seroconversion in NHPs and further studies will serve to evaluate protective immunogenicity. This approach not only serves as a tool to better understand the immune responses associated with protection against EBOV infection, but also has potential for translation towards human applications.