A non-propagating, recombinant vesicular stomatitis virus replicon encoding the F protein of respiratory syncytial virus is immunogenic and protective against RSV challenge in mice.

Session VI: Johnson: Poster Only

Title of Contribution: A non-propagating, recombinant vesicular stomatitis virus replicon encoding the F protein of respiratory syncytial virus is immunogenic and protective against RSV challenge in mice.
Author(s): Erik Johnson, Susan Witko, Vidia Roopchand, Shakuntala Megati, Jennifer Obregon, Deanne Illenberger, Rebecca Nowak, Lisa McNeil, Irene Yurgelonis, Narender Kalyan, Stefan Hamm, Kathrin Jansen and Maninder Sidhu
Affiliation(s): Wyeth Vaccines Research

Abstract:
Respiratory syncytial virus (RSV) is a significant cause of serious lower respiratory tract (LRT) disease, particularly in infant and elderly populations; there is currently no vaccine available against RSV.  We have generated candidate RSV vaccines using a recombinant vesicular stomatitis virus (rVSV) replicon in which the attachment and fusion domains of the VSV glycoprotein (G) have been deleted (rVSV-Gstem), rendering the virus propagation-defective except on cells in which complementing VSV G is provided in trans.  Mice inoculated intramuscularly with rVSV-Gstem replicons encoding the RSV (A2 strain) F protein generated anti-F antibodies (measured by ELISA), anti-RSV neutralizing titers, F-specific interferon-gamma (IFN-γ) producing cells, balanced responses, and were completely protected from both upper and lower respiratory tract infections following intranasal challenge with RSV A2.  F-specific IFN-γ producing lymphocytes were observed in mice primed and boosted with the rVSV-Gstem-RSV-F replicon, but not in mice primed with RSV A2.  Mice immunized with the Gstem-RSV-F replicon were also protected from a heterologous challenge with RSV M37, a human isolate minimally passaged in culture.  Furthermore, equivalent immune responses were generated when the RSV F gene was inserted as either the first or third gene position in the replicon genome relative to the VSV genomic promoter.  In addition, we compared a prime-boost regimen in which the boosting replicon was complemented with either a homologous VSV G or a heterologous G, derived from a different serotype of VSV, as compared to the priming replicon.  While immune responses were slightly higher following the heterologous boost, mice boosted with a homologous glycoprotein were equally protected from LRT infection following RSV A2 challenge, indicating the feasibility of using a homologous replicon as a booster.  It was later observed that a single dose of the Gstem-RSV-F replicon protected mice from RSV A2 challenge.  Finally, we assessed the safety of the Gstem-RSV-F replicon in mice, by comparing it to formalin-inactivated RSV for its ability to circumvent enhanced disease following RSV challenge.  Based on these results, we plan to test rVSV-vectored RSV vaccine candidates in non-human primate studies.