In this study, we evaluated a live attenuated influenza vaccine (X-31 ca, H3N2) as a fast-acting prophylaxis against both heterologous (A/New Caledonia/99, H1N1) and heterotypic (B/Shangdong/97, influenza B) infection. An immediate and broad-spectrum protection was achieved in the absence of specific antibody responses. Vaccination immediately prior to challenge resulted in the generation of a significant pool of reassortant virus between the vaccine and virulent strains suggesting that the acquisition of attenuating gene(s) from the live vaccine contributes to the attenuation of virulence. Vaccination resulted in an immediate release of the antiviral IFN-alpha response and pro-inflammatory cytokines. In addition, it was determined that agonists for TLR 3 and TLR 7 provided early protection. Thus, our results suggest that innate immune responses and genetic interference may play a role, independently and synergistically, in early protection by live influenza vaccination. The broad-spectrum and immediate protection provided by live attenuated influenza vaccine may offer a prompt measure for minimizing the initial spread of virus and mitigating the impact of unexpected influenza outbreaks.