In that study, it was demonstrated that neutralizing antibodies are not required for survival following lethal VEEV challenge. In this same Thiazovivin in vitro report, Paessler et al evaluated the contribution of T cells subsets in the brain in

protecting mice against lethal VEEV challenge and found αβ T cells are required for protection against a lethal VEEV challenge but that γδ T cells are not. This finding was supported by adoptive transfer studies where CD3+ T cells derived from vaccinated wild-type mice were able to restore protective immunity in αβ TCR deficient mice following a lethal VEEV challenge [41]. The findings from these studies are supported by other reports demonstrating T cell immunity as a key component to protection against VEEV infection [42] and [43]. Based on these reports, it is conceivable that T cell responses may be the predominant protective response following vaccination with the fV3526 formulations and that neutralizing antibodies play a secondary role in protection of the host. Dissecting the specific immune responses induced by the fV3526 formulations which are required for protection were beyond of scope of this study but should be investigated upon

down-selection of a fV3526 formulation. In the Epigenetics inhibitor present study, all fV3526 formulations induced an immune response that solidly protected mice against a SC challenge with VEEV TrD. While not statistically different from vaccination with fV3526 formulations, vaccination with C84 did not induce a protective immune response

in all mice as has been previously reported [37]. While this result was unexpected, so were the found findings in similar studies where C84 also failed to solidly protect mice from SC challenge [19] and [44]. One possible explanation for this discrepancy may be a loss of C84 potency. C84 was manufactured nearly 29 years ago and the loss of potency may be due to the prolonged storage. Stability and potency studies were conducted on C84 for several years following manufacture but this testing ended in the late 1990s, and no current potency data on the inactivated vaccine are available. Differences in the protective immune responses induced by the fV3526 formulations were more apparent when mice were challenged by the aerosol route but those differences failed to reach statistical significance. Survival rates in mice vaccinated with the fV3526 formulations following aerosol challenge were also similar to those for C84, however, similar to SC challenge, C84 again failed to induce a protective response in all mice providing additional support to a loss of C84 vaccine potency. In contrast to mice vaccinated with live V3526, mice vaccinated with fV3526 formulations displayed mild clinical signs of disease following aerosol challenge.