RNA-based adjuvant CV8102 enhances the immunogenicity of a licensed rabies vaccine in a first-in-human trial.

BACKGROUND: We report the first-in-concept human trial of the safety, tolerability and immunogenicity when a novel TLR 7/8/RIG I agonist RNA-based adjuvant, CV8102, was administered alone or mixed with fractional doses of a licensed rabies vaccine (Rabipur®) as model antigen. METHODS: The primary objective was to assess the safety and reactogenicity of various dose levels of CV8102 alone or mixed with Rabipur® in healthy 18-40 year-old male volunteers. A secondary objective was to assess the immune-enhancing potential of bedside-mixes of CV8102 with fractional doses of Rabipur® by measuring induction of rabies virus neutralising titres (VNTs). RESULTS: Fifty-six volunteers received 50-100 µg CV8102 alone (n = 11), bedside-mixed CV8102 and Rabipur® (n = 20), or Rabipur® alone (n = 25; control). When given alone or mixed with Rabipur® CV8102 caused mostly Grade 1 or 2 local or systemic reactogenicity, but no related SAEs. As 100 µg CV8102 was associated with marked CRP increases further dose escalation was stopped. Combining 25-50 µg of CV8102 with fractional doses of Rabipur® significantly improved the kinetics of VNT responses; 50 µg CV8102 also improved the magnitude of VNT responses to 1/10 Rabipur® but caused severe but self-limiting influenza-like symptoms in 2 of 14 subjects. CONCLUSIONS: Doses of 25 and 50 µg CV8102 appeared safe and with an acceptable reactogenicity profile while significantly enhancing the immunogenicity of fractional doses of rabies vaccine. EudraCT No. 2013-004514-18.