mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials

Background: We evaluated safety and immunogenicity of the first mRNA vaccines against potentially pandemic avian H1ON8 and H7N9 influenza viruses. Methods: Two randomized, placebo-controlled, double-blind, phase 1 clinical trials enrolled participants between December 2015 and August 2017 at single centers in Germany (H1ON8) and USA (H7N9). Healthy adults (ages 18-64 years for H1ON8 study; 18-49 years for H7N9 study) participated. Participants received vaccine or placebo in a 2-dose vaccination series 3 weeks apart. H1ON8 intramuscular (IM) dose levels of 25, 50, 75, 100, and 400 a and intradermal dose levels of 25 and 50 mu g were evaluated. H7N9 IM 10-, 25-, and 50-pg dose levels were evaluated; 2-dose series 6 months apart was also evaluated. Primary endpoints were safety (adverse events) and tolerability. Secondary immunogenicity outcomes included humoral (hemagglutination inhibition [HAI], microneutralization [MN] assays) and cell-mediated responses (ELISPOT assay). Results: H10N8 and H7N9 mRNA IM vaccines demonstrated favorable safety and reactogenicity profiles. No vaccine-related serious adverse event was reported. For H1ON8 (N = 201), 100-mu g IM dose induced HAI titers >= 1:40 in 100% and MN titers >= 1:20 in 87.0% of participants. The 25-mu g intradermal dose induced HAI titers >= 1:40 in 64.7% of participants compared to 34.5% of participants receiving the IM dose. For H7N9 (N = 156), IM doses of 10, 25, and 50 mu g achieved HAI titers >= 1:40 in 36.0%, 96.3%, and 89.7% of participants, respectively. MN titers >= 1:20 were achieved by 100% in the 10- and 25-mu g groups and 96.6% in the 50-mu g group. Seroconversion rates were 78.3% (HAI) and 87.0% (MN) for H1ON8 (100 mu g IM) and 96.3% (HAI) and 100% (MN) in H7N9 (50 mu g). Significant cell-mediated responses were not detected in either study. Conclusions: The first mRNA vaccines against H1ON8 and H7N9 influenza viruses were well tolerated and elicited robust humoral immune responses. (C) 2019 The Author(s). Published by Elsevier Ltd.