With mortality rates as high as 95%, Ebola infection occurs largely by direct contact with blood, tissues or skin of patients, and through mucosal exposure [45, 46] . To date, few efforts have been made to focus on the mucosa as the primary sight of exposure to Ebola virus and priming it for participation in the host defense by vaccination [47] . This is surprising given that the pulmonary, nasal and oral immune systems which comprise the mucosal-associated lymphoid tissues (MALT) are responsible for the production of approximately 80% of all immunocytes [48, 49] and mucosal immunity is often the first line of defense against pathogens coming in contact with susceptible hosts. Many studies in rodents indicate that systemic immunization produces strong anti-viral systemic responses while mucosal vaccination can stimulate both the mucosal and systemic immune systems and can confer long-term immunological memory against a given pathogen despite the fact that the magnitude of these responses are often reported to be somewhat reduced [37, 48, 50] . We have found this to be the case in the studies outlined here since the systemic cellular response and neutralizing antibody levels against Ebola Zaire GP were consistently lower following nasal and oral vaccination. Mucosal vaccination did, however, generate significant cellular and antibody responses in the periphery (BAL, MLN or Peyer's patches) and a single intranasal immunization with Ad5-ZGP conferred 100% protection even in the presence of pre-existing immunity.