Preclinical and Clinical Demonstration of Immunogenicity by mRNA Vaccines against H10N8 and H7N9 Influenza Viruses

"Introduction

... In this study, we evaluated the immunogenicity of two LNP-formulated, modified mRNA-based influenza A vaccines encoding the HA [hemagglutinin] of H10N8 (A/Jiangxi-Donghu/346/2013) and H7N9 (A/Anhui/1/2013) in animals and H10N8 HA mRNA in humans from an ongoing trial...

Results

H10N8 and H7N9 HA mRNA Immunogenicity in Mice

... Given this innovative vaccine platform, we examined the biodistribution of the mRNA vaccines for both routes of administration. Male CD-1 mice received 6 μg formulated H10 mRNA either IM [intramuscular] or ID [intradermal]. Following IM administration, the maximum concentration (C_max) of the injection site muscle was 5,680 ng/mL, and the level declined with an estimated t_1/2 of 18.8 hr. Proximal lymph nodes had the second highest concentration at 2,120 ng/mL (t_max of 8 hr with a relatively long t_1/2 of 25.4 hr), suggesting that H10 mRNA distributes from the injection site to systemic circulation through the lymphatic system. The spleen and liver had a mean C_max of 86.9 ng/mL (area under the curve [AUC]_0–264 of 2,270 ng.hr/mL) and 47.2 ng/mL (AUC_0–264 of 276 ng.hr/mL), respectively. In the remaining tissues and plasma, H10 mRNA was found at 100- to 1,000-fold lower levels...

H10 mRNA Immunogenicity and Safety in Humans

To evaluate the safety and immunogenicity of H10 mRNA in humans, a randomized, double-blind, placebo-controlled, dose-escalating phase 1 trial is ongoing (Clinical Trials Identifier NCT03076385). We report here interim results, obtained 43 days post-vaccination of 31 subjects (23 of whom received active H10 at 100 μg IM and eight of whom received placebo)...

The majority of adverse events (AEs) were mild (107/163 events; 66%) or moderate (52/163 events; 32%), using the Center for Biologics Evaluation and Research (CBER) severity scale... Only four events (2.5%), reported by three subjects (13% of exposed subjects), were categorized as severe and included injection site erythema (1.2%), injection site induration (0.6%), and chills/common cold (0.6%)...

First-in-Human Phase 1 Study

... Safety was assessed from solicited (local and systemic reactogenicity events) and unsolicited AEs via scheduled clinic visit (vital signs, laboratory assessments, and physical examinations), subject diaries, and follow-up telephone calls at specific intervals. AEs were defined as any problematic medical occurrence even if seemingly unrelated to treatment and graded by the Toxicity Grading Scale and defined as mild (transient with no normal daily activity limitations), moderate (some normal daily limitations), and severe (unable to perform normal daily activities). Serious AEs were defined as any occurrence of death, a life-threatening situation, hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or any medical event that jeopardizes the subject or requires medical intervention."