Most reported vaccination failures among rabies-exposed patients were due to fail to timely co-administer rabies immunoglobulin (RIG). Considering that such protection failure might be caused by low antigen titers in the vaccine, scientists improved antigen titers to 4.0 IU or even higher, yet the failure remained. Therefore, it becomes vital to develop more efficacious vaccine against rabies. In our evaluation of a novel PIKA rabies vaccine, we used multiple animal models (beagles, golden hamsters and Kunming mice) to mimic post-exposure scenarios. All animals were challenged with wild-type rabies virus, followed by vaccination with either rabies vaccines commercially available or PIKA rabies vaccines. As 100% of animals survived after administration of traditional rabies vaccines and rabies immunoglobulin, 80% of animals survived with rabies immunoglobulin alone. Strikingly, animals receiving traditional rabies vaccines alone showed extremely low survival rates, indicating insignificant benefit for exposed animals (p > 0.05, compared to unvaccinated control groups). To the contrary, 40–80% of animals receiving the experimental PIKA rabies vaccines were protected (p < 0.05, compared to unvaccinated control groups). If the above results are fully confirmed, we may conclude that currently as high as 99% of post-exposure patients who are seeking protection against rabies, but only receiving rabies vaccination, could be meaningless.