We have developed an experimental recombinant vesicular stomatitis virus (VSV) vectored plague vaccine expressing a secreted form of Yersinia pestis low calcium response protein V (LcrV) from the first position of the VSV genome. This vector, given intramuscularly in a single dose, induced high-level antibody titers to LcrV and gave 90-100% protection against pneumonic plague challenge in mice. This single-dose protection was significantly better than that generated by VSV expressing the non-secreted LcrV protein. Increased protection correlated with increased anti-LcrV antibody and a bias toward IgG2a and away from IgG1 isotypes. We also found that the depletion of CD4+ cells, but not CD8+ cells, at the time of challenge resulted in reduced vaccine protection, indicating a role for cellular immunity in protection.