Phase 1 Trials of rVSV Ebola Vaccine in Africa and Europe.
Agnandji ST., Huttner A., Zinser ME., Njuguna P., Dahlke C., Fernandes JF., Yerly S., Dayer J-A., Kraehling V., Kasonta R., Adegnika AA., Altfeld M., Auderset F., Bache EB., Biedenkopf N., Borregaard S., Brosnahan JS., Burrow R., Combescure C., Desmeules J., Eickmann M., Fehling SK., Finckh A., Goncalves AR., Grobusch MP., Hooper J., Jambrecina A., Kabwende AL., Kaya G., Kimani D., Lell B., Lemaître B., Lohse AW., Massinga-Loembe M., Matthey A., Mordmüller B., Nolting A., Ogwang C., Ramharter M., Schmidt-Chanasit J., Schmiedel S., Silvera P., Stahl FR., Staines HM., Strecker T., Stubbe HC., Tsofa B., Zaki S., Fast P., Moorthy V., Kaiser L., Krishna S., Becker S., Kieny M-P., Bejon P., Kremsner PG., Addo MM., Siegrist C-A.
BACKGROUND: The replication-competent recombinant vesicular stomatitis virus (rVSV)-based vaccine expressing a Zaire ebolavirus (ZEBOV) glycoprotein was selected for rapid safety and immunogenicity testing before its use in West Africa. METHODS: We performed three open-label, dose-escalation phase 1 trials and one randomized, double-blind, controlled phase 1 trial to assess the safety, side-effect profile, and immunogenicity of rVSV-ZEBOV at various doses in 158 healthy adults in Europe and Africa. All participants were injected with doses of vaccine ranging from 300,000 to 50 million plaque-forming units (PFU) or placebo. RESULTS: No serious vaccine-related adverse events were reported. Mild-to-moderate early-onset reactogenicity was frequent but transient (median, 1 day). Fever was observed in up to 30% of vaccinees. Vaccine viremia was detected within 3 days in 123 of the 130 participants (95%) receiving 3 million PFU or more; rVSV was not detected in saliva or urine. In the second week after injection, arthritis affecting one to four joints developed in 11 of 51 participants (22%) in Geneva, with pain lasting a median of 8 days (interquartile range, 4 to 87); 2 self-limited cases occurred in 60 participants (3%) in Hamburg, Germany, and Kilifi, Kenya. The virus was identified in one synovial-fluid aspirate and in skin vesicles of 2 other vaccinees, showing peripheral viral replication in the second week after immunization. ZEBOV-glycoprotein-specific antibody responses were detected in all the participants, with similar glycoprotein-binding antibody titers but significantly higher neutralizing antibody titers at higher doses. Glycoprotein-binding antibody titers were sustained through 180 days in all participants. CONCLUSIONS: In these studies, rVSV-ZEBOV was reactogenic but immunogenic after a single dose and warrants further evaluation for safety and efficacy. (Funded by the Wellcome Trust and others; ClinicalTrials.gov numbers, NCT02283099, NCT02287480, and NCT02296983; Pan African Clinical Trials Registry number, PACTR201411000919191.).