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Chimpanzee Adenovirus Vector Ebola Vaccine.

2017 03 09

Journal Article

Ledgerwood, J.E.; DeZure, A.D.; Stanley, D.A.; Coates, E.E.; Novik, L.; Enama, M.E.; Berkowitz, N.M.; Hu, Z.; Joshi, G.; Ploquin, A.; Sitar, S.; Gordon, I.J.; Plummer, S.A.; Holman, L.S.A.; Hendel, C.S.; Yamshchikov, G.; Roman, F.; Nicosia, A.; Colloca, S.; Cortese, R.; Bailer, R.T.; Schwartz, R.M.; Roederer, M.; Mascola, J.R.; Koup, R.A.; Sullivan, N.J.; Graham, B.S.

N Engl J Med






Adenoviruses, Simian; Adult; Animals; Antibodies, Neutralizing; Antibodies, Viral; Ebola Vaccines; Ebolavirus; Fever; Genetic Vectors; Glycoproteins; Hemorrhagic Fever, Ebola; Humans; Male; Middle Aged; Pan troglodytes; T-Lymphocytes

BACKGROUND: The unprecedented 2014 epidemic of Ebola virus disease (EVD) prompted an international response to accelerate the availability of a preventive vaccine. A replication-defective recombinant chimpanzee adenovirus type 3-vectored ebolavirus vaccine (cAd3-EBO), encoding the glycoprotein from Zaire and Sudan species, that offers protection in the nonhuman primate model, was rapidly advanced into phase 1 clinical evaluation.METHODS: We conducted a phase 1, dose-escalation, open-label trial of cAd3-EBO. Twenty healthy adults, in sequentially enrolled groups of 10 each, received vaccination intramuscularly in doses of 2×10 particle units or 2×10 particle units. Primary and secondary end points related to safety and immunogenicity were assessed throughout the first 8 weeks after vaccination; in addition, longer-term vaccine durability was assessed at 48 weeks after vaccination.RESULTS: In this small study, no safety concerns were identified; however, transient fever developed within 1 day after vaccination in two participants who had received the 2×10 particle-unit dose. Glycoprotein-specific antibodies were induced in all 20 participants; the titers were of greater magnitude in the group that received the 2×10 particle-unit dose than in the group that received the 2×10 particle-unit dose (geometric mean titer against the Zaire antigen at week 4, 2037 vs. 331; P=0.001). Glycoprotein-specific T-cell responses were more frequent among those who received the 2×10 particle-unit dose than among those who received the 2×10 particle-unit dose, with a CD4 response in 10 of 10 participants versus 3 of 10 participants (P=0.004) and a CD8 response in 7 of 10 participants versus 2 of 10 participants (P=0.07) at week 4. Assessment of the durability of the antibody response showed that titers remained high at week 48, with the highest titers in those who received the 2×10 particle-unit dose.CONCLUSIONS: Reactogenicity and immune responses to cAd3-EBO vaccine were dose-dependent. At the 2×10 particle-unit dose, glycoprotein Zaire-specific antibody responses were in the range reported to be associated with vaccine-induced protective immunity in challenge studies involving nonhuman primates, and responses were sustained to week 48. Phase 2 studies and efficacy trials assessing cAd3-EBO are in progress. (Funded by the Intramural Research Program of the National Institutes of Health; VRC 207 number, NCT02231866 .).

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