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Enhancing immunogenicity of respiratory syncytial virus vaccine candidates by altering NS1 function
Monday, March 6, 2017: 2:00 PM
Rooms B308-B309 (Georgia World Congress Center, Building B)
Michael N. Teng, PhD,
Rationale:

Development of an efficacious live-attenuated vaccine for respiratory syncytial virus (RSV) has been stymied by the difficulty in inducing long-lived immune responses. One potential mechanism of improving the immunogenicity of live-attenuated RSV is decreasing the ability of RSV to block type I interferon (IFN) production from infected cells. The RSV NS1 protein has been shown to be a potent IFN antagonist and recombinant RSV (rRSV) lacking NS1 is immunogenic and attenuated in animal models.  However, deletion of NS1 results in a RSV that replicates poorly in vitro even in IFN-deficient Vero cells, indicating that NS1 encodes functions required for efficient viral replication. Our goal was to develop recombinant RSV expressing NS1 mutants that no longer antagonize IFN, but support efficient viral replication.

Methods:

We generated a panel of deletion mutant NS1 alleles to identify residues involved in IFN antagonism but not viral replication. These mutants were initially screened for IFN antagonism using a transfection assay then tested in the context of rRSV for IFN antagonism and viral replication.  

Results:

Initial studies with 10 aa deletions identified sequences in the N- and C-termini of NS1 that are essential for IFN antagonism and viral replication. Through an iterative process using progressively smaller deletions, we identified single residues that affected either NS1’s IFN antagonism or replication activities.

Conclusions:

The IFN antagonism and replication effects of RSV NS1 can be segregated by mutagenesis. This should allow for the development of live-attenuated RSV vaccine candidates with enhanced immunogenicity that can replicate efficiently in vitro for vaccine production purposes.