In that fV3526 vaccinations did not induce high levels of circulating neutralizing antibodies, it is tempting to speculate that fV3526 did not induce sufficient levels of nasal mucosal IgA antibodies resulting in VEEV infection in the brain. This supposition is supported by the Sotrastaurin cost transient illness
observed in vaccinated mice following aerosol challenge. Further, as a high percentage of mice ultimately recovered, the involvement of a protective immune mechanisms in the brain [41], that can control and eliminate the VEEV, is supported. In the present study, we found IM vaccination with fV3526 + CpG induced a stronger antibody response and afforded a higher level of protection against an aerosol Modulators challenge compared to mice vaccinated SC with the same formulation. This finding is particularly interesting as IM vaccinated mice received 5 times less viral protein than did SC vaccinated mice. It is not clear why fV3526 + CpG administered by the IM route induced a more protective immune response than SC vaccination. Previously, it has been suggested
that IM vaccination can overcome immune compartmentalization and generate robust mucosal T cell responses [46]. In that study, IM vaccination with a recombinant adenovirus BLZ945 purchase resulted in potent, durable and functional CD8+ T lymphocyte responses at multiple mucosal effector sites, including the pulmonary compartment, in both mice and rhesus macaques. Similarly, IM vaccination with an inactivated, whole-virus vaccine for influenza also showed remarkable protection against respiratory challenge [47] further suggesting IM vaccination may play a role in the induction of mucosal immunity. Since the induction of mucosal immunity is believed to be critically important for protection against an aerosolized VEEV infection [38], [45] and [48] it is possible that vaccinating mice IM with the fV3526 + CpG induced a robust mucosal immune response involving T cells that before failed to be induced by SC vaccination. To gain a better understanding of the contribution of IM and SC vaccination in inducing protective immunity, additional studies administering equivalent concentrations by the
SC and IM route are needed. The success of fV3526 will likely be dependent on co-administration with adjuvant. In this study, adjuvants did not significantly increase the immune responses measured following vaccination or increase survival following aerosol challenge as compared to unadjuvanted fV3526. Although the adjuvants did not appear to play a critical role in this study, it is likely that the benefit of these adjuvants will not be realized until more rigorous efficacy studies evaluating onset and duration of protection and dose titration studies to evaluate potency are conducted or immune responses more relevant to protection are more clearly defined. A limited number of studies are reported that use CpG to augment VEEV-specific immune responses.
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