Career Development and Training Program
Individual Project CD009
Collaborating Institution: University of Texas Medical Branch (UTMB), Galveston, TX
Principal Investigator: Alexander Freiberg, PhD – UTMB, Galveston, TX
Title of the Project: Development of a Single-round Replicon-based Nipah Virus Vaccine Candidate
- Alan Barrett, PhD – UTMB, Galveston, TX
- Benhur Lee, MD – UCLA Geffen School of Medicine, Los Angeles, CA
Expected Product: Development of a replicon-based NiV vaccine
Description: Nipah (NiV) and Hendra (HeV) viruses are the deadliest human pathogens within the Paramyxoviridae family, which include human and animal pathogens of global biomedical importance. NiV and HeV are zoonotic viruses that can be transmitted directly to humans from their natural reservoirs in fruit bats. NiV and HeV infections cause respiratory and encephalitic disease and NiV’s mortality rate in humans can exceed 70%. Thus, both viruses are the only paramyxoviruses classified as BSL4 pathogens due to their extreme pathogenicity and lack of licensed vaccines or effective therapeutics. Paramyxoviruses are negative-sense RNA viruses that replicate in the cytoplasm. Their matrix structural protein (M) organizes virion assembly at the plasma membrane and mediates viral budding from the cell surface. We found that a proper nucleocytoplasmic trafficking of M is critical for its functional localization to the plasma membrane, and its subsequent ability to mediate viral budding. Thus, the M protein plays a critical role in virion assembly and budding. The goal of this application is to develop a single-round replicon-based NiV as a candidate vaccine, by generating a recombinant virus which lacks the M protein. Using a packaging cell line that expresses the M protein, we will be able to generate infectious single-round replicon NiV. It is hypothesized that this deficient virus will infect cells and synthesize viral proteins other than the M protein in a single round, thus eliciting protective immunity more efficiently than an inactivated or subunit vaccine.
To address this hypothesis, we propose the following two Specific Aims: (1) Generate a replicon that undergoes one round of replication due to lack of the M protein that is essential for budding of NiV, and (2) demonstrate safety, immunogenicity and efficacy of the NIV replicon vaccine candidate.
It is expected that high levels of neutralizing antibodies will be achieved by presenting biologically functional proteins on the surface of this recombinant virus to immune cells. Further, all NiV genes will be synthesized in a replication-defective context and therefore is expected to be more immunogenic than subunit or VLP-based vaccine candidates. Also, if the aims of the proposed project are achieved, it will allow extending the approach to produce efficacious replicon-based vaccine candidates for other paramyxoviruses and NIAID category A-C viruses.