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A study to evaluate the immunogenicity and protective efficacy of a Venezuelan equine encephalitis virus (VEEV) DNA vaccine in an aerosol model of nonhuman primate infection was performed. Cynomolgus macaques vaccinated with a plasmid expressing the 26S structural genes of VEEV subtype IAB by particle-mediated epidermal delivery (PMED) developed virus-neutralizing antibodies. No serum viremia was detected in two out of three macaques vaccinated with the VEEV DNA after aerosol challenge with homologous virus, while one displayed a low viremia on a single day postchallenge. In contrast, all three macaques vaccinated with empty vector DNA developed a high viremia that persisted for at least 3 days after challenge. In addition, macaques vaccinated with the VEEV DNA had reduced febrile reactions, lymphopenia, and clinical signs of disease postchallenge as compared to negative control macaques. Therefore, although the sample size was small in this pilot study, these results indicate that a VEEV DNA vaccine administered by PMED can at least partially protect nonhuman primates against an aerosol VEEV challenge.

Mice were vaccinated with a recombinant fusion protein, rF1-V, by an intramuscular prime followed by an intranasal boost, to evaluate protection against pneumonic plague. Forty-two days after the intranasal boost, the mice were challenged by aerosol exposure to Yersinia pestis. Survival after exposure depended upon the dose of rF1-V given i.n. with > or = 80% survival in the highest dose groups. Pulmonary and serum antibody titers to V were the best predictors of outcome. For vaccinated mice that succumbed to the infection, death was delayed by 1-2 days compared to sham-inoculated controls. Weight loss early after exposure correlated with outcome. Pathology studies indicated a severe, necrotizing bronchopneumonia in vaccinated mice that succumbed to the infection, compatible with a prolonged disease course, while the lungs of sham-inoculated mice had only mild pneumonia, which is compatible with a more rapid disease course. Immunity in the respiratory tract appears to be critical for protection against primary pneumonia caused by Y. pestis.

Two live, attenuated strains of Venezuelan equine encephalitis virus (VEE), IE1150K and V3526, were administered to macaques to determine if they could elicit protection against an aerosol challenge with virulent VEE virus of the IE variety (VEEV-IE). These viruses were rescued from full-length cDNA clones of 68U201 (VEEV-IE variety) and Trinidad donkey (VEEV-IA/B variety), respectively, and both have a furin cleavage site deletion mutation and a second-site resuscitating mutation. Both vaccines elicited neutralizing antibodies to viruses of the homologous variety but not to viruses of the heterologous variety. Eight weeks after vaccination, the macaques were challenged by aerosol exposure to virulent 68U201. Macaques vaccinated with V3526 were protected as well as macaques inoculated with IE1009, the wild-type infectious clone of 68U201. However, IE1150K failed to significantly protect macaques relative to controls. V3526 has now been shown to protect macaques against both IA/B [Pratt WD, Davis NL, Johnston RE, Smith JF. Genetically engineered, live attenuated vaccines for Venezuelan equine encephalitis: testing in animal models. Vaccine 2003;21(25–26):3854–62] and IE strains of VEE viruses.

Considerable progress has been made over the last decade in developing candidate preventive vaccines that can protect nonhuman primates against Ebola and Marburg viruses. A vaccine based on recombinant vesicular stomatitis virus (VSV) seems to be particularly robust as it can also confer protection when administered as a postexposure treatment. While filoviruses are not thought to be transmitted by aerosol in nature the inhalation route is among the most likely portals of entry in the setting of a bioterrorist event. At present, all candidate filoviral vaccines have been evaluated against parenteral challenges but none have been tested against an aerosol exposure. Here, we evaluated our recombinant VSV-based Zaire ebolavirus (ZEBOV) and Marburg virus (MARV) vaccines against aerosol challenge in cynomolgus macaques. All monkeys vaccinated with a VSV vector expressing the glycoprotein of ZEBOV were completely protected against an aerosol exposure of ZEBOV. Likewise, all monkeys vaccinated with a VSV vector expressing the glycoprotein of MARV were completely protected against an aerosol exposure of MARV. All control animals challenged by the aerosol route with either ZEBOV or MARV succumbed. Interestingly, disease in control animals appeared to progress slower than previously seen in macaques exposed to comparable doses by intramuscular injection.

Vaccines that could protect humans against the highly lethal Marburg and Ebola viruses have eluded scientists for decades. Classical approaches have been generally unsuccessful for Marburg and Ebola viruses and pose enormous safety concerns as well. Modern approaches, in particular those using vector-based approaches have met with success in nonhuman primate models although success against Ebola has been more difficult to achieve than Marburg. Despite these successes, more work remains to be done. For the vector-based vaccines, safety in humans and potency in the face of pre-existing anti-vector immunity may be critical thresholds for licensure. The immunological mechanism(s) by which these vaccines protect has not yet been convincingly determined. Licensure of these vaccines for natural outbreaks may be possible through clinical trials although this will be very difficult; licensure may also be possible by pivotal efficacy studies in animal models with an appropriate challenge. Nevertheless, nonhuman primate studies have shown that protection against Marburg and Ebola is possible and there is hope that one day a vaccine will be licensed for human use.