There is an outbreak of Marburg virus disease (MVD), relative of Ebola virus, currently ongoing in Equatorial Guinea and Tanzania. There have been multiple, deadly outbreaks of MVD in the past with ~88% lethality. There are currently no approved vaccines or therapeutics for MVD and very few in clinical development. In this proposal, we have rationally designed an immunogen based on MARV glycoprotein (GP) by excluding domains known to trigger non-neutralizing antibodies allowing exposure of key neutralizing epitopes capable of generating a strong immune response. Combined with a novel TLR7/8 agonist adjuvant, Alhydroxyquim- II (AhQ-II), that has shown excellent safety and adjuvant activity in millions of people during COVID-19 pandemic, our rationally designed MARV vaccine induces broadly neutralizing antibodies against isolates Angola, CI67, and Musoke strains of MARV as well as the phylogenetically more distant RAVV. Mice immunized with this MARV vaccine with two or three doses compared to unadjuvanted antigen showed robust antigen-specific binding and neutralizing titers against all four MARV strains demonstrated by ELISA and pseudovirus neutralization assays. In the guinea pig model of MARV infection which shows all hallmarks of filovirus disease the vaccine provided 100% protection against lethal challenge with no detectable viremia, suggesting that the vaccine is likely inducing sterilizing immunity. In summary, this subunit vaccine represents a novel, highly efficacious, and safe candidate for protection against MVD. Here, we propose three specific aims to further develop this rationally designed immunogen: Aim1: To produce and generate a pooled stable cell line for the MARV subunit antigen with a cGMP-compliant tag and demonstrate biochemical and immunogenic properties comparable to the Streptavidin-tagged MARV material used in preliminary studies; Aim 2: to determine optimal effective dose and regimen for maximum protection in BSL-4 guinea pig MARV model; Aim 3: to demonstrate immunogenicity in the filovirus Gold Standard non-human primate model. Upon successful completion of this Phase I project we anticipate a Phase II focused on NHP efficacy studies and advanced development activities.
Public Health Relevance Statement: There has been a rise in filovirus outbreaks caused by Marburg virus, a relative of Ebola virus most specifically in July 2022 and March 2023. These filovirus outbreaks threaten human life, the world economy, and the healthcare system, therefore the need for a highly effective and safe vaccine against Marburg Virus Disease (MVD) is paramount. In this proposal, we seek to develop a vaccine against MVD comprised of a Marburg glycoprotein component in combination with a safe and novel adjuvant that has shown excellent safety in millions of people during COVID-19 pandemic. The vaccine induces broadly neutralizing antibodies against multiple strains of MARV and showed 100% protection against lethal challenge in small animals. Therefore, we aim to further develop this subunit vaccine as a highly efficacious and safe candidate for protection against a large Marburg outbreak. Terms:
