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A Monovalent Chimpanzee Adenovirus Ebola Vaccine Boosted with MVA
Katie Ewer1, Tommy Rampling1, Navin Venkatraman1
1From the Jenner Institute and Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford (K.E., T.R., N.V., G.B., D.W., T.L., E.B.I., R.P., C.M.T., N.J.E., G.L., J.J., M.G., A.M., M.W., I.P., N.L., R.R., F.H., C.B., K.S.-D., J.P., E.B., A.J.P., S.J.D., A.L., S.C.G., A.V.S.H.), and Viral Pseudotype Unit, Faculty of Science and Technology, University of Westminster (E.M.B., E.W.), and Virus Reference Department, Public Health Agency (D.S., R.T.), London - all in the United Kingdom; the Institute of Virology, Philipps University Marburg (S.K.F., T.S., N.B., V.K., S.B.), and German Center for Infection Research, Partner Site Giessen-Marburg-Langen (S.B.), Marburg, and Bavarian Nordic, Martinsried (A.V., P.C.) - all in Germany; GlaxoSmithKline Biologicals, Rixensart, Belgium (F.R., I.D.R., W.R.B.); ReiThera, Rome (A.N., L.S., S.C., A.F., S.D.M.), and CEINGE and the Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples (A.N.) - both in Italy; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda (N.J.S., D.A.S., O.T.M., J.E.L., R.M.S., B.S.G., R.A.K.), and the Center for Vaccine Development, University of Maryland School of Medicine, Baltimore (M.M.L.) - both in Maryland; and Keires, Basel, Switzerland (R.C.).
Background:
The West African outbreak of Ebola virus disease that peaked in 2014 has caused more than 11,000 deaths. The development of an effective Ebola vaccine is a priority for control of a future outbreak.
Methods:
In this phase 1 study, we administered a single dose of the chimpanzee adenovirus 3 (ChAd3) vaccine encoding the surface glycoprotein of Zaire ebolavirus (ZEBOV) to 60 healthy adult volunteers in Oxford, United Kingdom. The vaccine was administered in three dose levels--1×10(10) viral particles, 2.5×10(10) viral particles, and 5×10(10) viral particles--with 20 participants in each group. We then assessed the effect of adding a booster dose of a modified vaccinia Ankara (MVA) strain, encoding the same Ebola virus glycoprotein, in 30 of the 60 participants and evaluated a reduced prime-boost interval in another 16 participants. We also compared antibody responses to inactivated whole Ebola virus virions and neutralizing antibody activity with those observed in phase 1 studies of a recombinant vesicular stomatitis virus-based vaccine expressing a ZEBOV glycoprotein (rVSV-ZEBOV) to determine relative potency and assess durability.
Results:
No safety concerns were identified at any of the dose levels studied. Four weeks after immunization with the ChAd3 vaccine, ZEBOV-specific antibody responses were similar to those induced by rVSV-ZEBOV vaccination, with a geometric mean titer of 752 and 921, respectively. ZEBOV neutralization activity was also similar with the two vaccines (geometric mean titer, 14.9 and 22.2, respectively). Boosting with the MVA vector increased virus-specific antibodies by a factor of 12 (geometric mean titer, 9007) and increased glycoprotein-specific CD8+ T cells by a factor of 5. Significant increases in neutralizing antibodies were seen after boosting in all 30 participants (geometric mean titer, 139; P<0.001). Virus-specific antibody responses in participants primed with ChAd3 remained positive 6 months after vaccination (geometric mean titer, 758) but were significantly higher in those who had received the MVA booster (geometric mean titer, 1750; P<0.001).
Conclusions:
The ChAd3 vaccine boosted with MVA elicited B-cell and T-cell immune responses to ZEBOV that were superior to those induced by the ChAd3 vaccine alone. (Funded by the Wellcome Trust and others; ClinicalTrials.gov number, NCT02240875.).
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