title: Single-dose vaccine against tick-borne encephalitis.
abstract: Tick-borne encephalitis (TBE) virus is the most important human pathogen transmitted by ticks in Eurasia. Inactivated vaccines are available but require multiple doses and frequent boosters to induce and maintain immunity. Thus far, the goal of developing a safe, live attenuated vaccine effective after a single dose has remained elusive. Here we used a replication-defective (single-cycle) flavivirus platform, RepliVax, to generate a safe, single-dose TBE vaccine. Several RepliVax-TBE candidates attenuated by a deletion in the capsid gene were constructed using different flavivirus backbones containing the envelope genes of TBE virus. RepliVax-TBE based on a West Nile virus backbone (RV-WN/TBE) grew more efficiently in helper cells than candidates based on Langat E5, TBE, and yellow fever 17D backbones, and was found to be highly immunogenic and efficacious in mice. Live chimeric yellow fever 17D/TBE, Dengue 2/TBE, and Langat E5/TBE candidates were also constructed but were found to be underattenuated. RV-WN/TBE was demonstrated to be highly immunogenic in Rhesus macaques after a single dose, inducing a significantly more durable humoral immune response compared with three doses of a licensed, adjuvanted human inactivated vaccine. Its immunogenicity was not significantly affected by preexisting immunity against WN. Immunized monkeys were protected from a stringent surrogate challenge. These results support the identification of a single-cycle TBE vaccine with a superior product profile to existing inactivated vaccines, which could lead to improved vaccine coverage and control of the disease.
authors.affiliation: Sanofi Pasteur, Discovery US, Cambridge, MA 02139, USA.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Rumyantsev
authors.forename: Ana P
authors.initials: AP
authors.lastname: Goncalvez
authors.forename: Maryann
authors.initials: M
authors.lastname: Giel-Moloney
authors.forename: John
authors.initials: J
authors.lastname: Catalan
authors.forename: Yuxi
authors.initials: Y
authors.lastname: Liu
authors.forename: Qing-sheng
authors.initials: QS
authors.lastname: Gao
authors.forename: Jeff
authors.initials: J
authors.lastname: Almond
authors.forename: Harry
authors.initials: H
authors.lastname: Kleanthous
authors.forename: Konstantin V
authors.initials: KV
authors.lastname: Pugachev
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D002460:Cell Line; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D004669:Encephalitis Viruses, Tick-Borne / Q000276:immunology* / Q000502:physiology; D004675:Encephalitis, Tick-Borne / Q000276:immunology* / Q000821:virology; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D008253:Macaca mulatta; D051379:Mice; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome; D014611:Vaccination / Q000379:methods*; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000276:immunology; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000276:immunology; D014709:Vero Cells; D014765:Viral Vaccines / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; D014613:Vaccines, Attenuated; D015164:Vaccines, Inactivated; D014765:Viral Vaccines
keywords: flavivirus vaccine; nonhuman primate; preclinical; prophylaxis