A phase I/II clinical trial of intradermal, controllable self-replicating RNA vaccine EXG 5003 against SARS-CoV-2 (preprint)

mRNA vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have played a key role in reducing morbidity and mortality from coronavirus disease 2019 (COVID 19). We conducted a double-blind, placebo-controlled phase I/II trial to evaluate the safety, tolerability, and immunogenicity of EXG 5003, a two-dose, controllable self-replicating RNA vaccine against SARS-CoV-2. EXG 5003 encodes the receptor binding domain (RBD) of SARS-CoV-2 and was administered intradermally without lipid nanoparticles (LNP). The participants were followed for 12 months. Forty healthy participants were enrolled in Cohort 1 (5 g per dose, n = 16; placebo, n = 4) and Cohort 2 (25 g per dose, n = 16; placebo, n = 4). No safety concerns were observed with EXG 5003 administration. SARS-CoV-2 RBD antibody titers and neutralizing antibody titers were not elevated in either cohort. Elicitation of antigen-specific cellular immunity was observed in the EXG 5003 recipients in Cohort 2. At the 12-month follow-up, participants who had received an approved mRNA vaccine (BNT162b2 or mRNA-1273) >1 month after receiving the second dose of EXG 5003 showed higher cellular responses compared to equivalently vaccinated participants in the placebo group. The findings suggest a priming effect by EXG-5003 on the long-term cellular immunity of approved SARS-CoV-2 mRNA vaccines.

Controllable self-replicating RNA vaccine delivered intradermally elicits predominantly cellular immunity (preprint)

Intradermal delivery of self-replicating RNA (srRNA) is a promising vaccine platform. Considering that human skin temperature is around 33{degrees}C, lower than core body temperature of 37{degrees}C, we have developed an srRNA that functions optimally at skin temperature and is inactivated at or above 37{degrees}C as a safety switch. This temperature-controllable srRNA (c-srRNA), when tested as an intradermal vaccine against SARS-CoV-2, functions when injected naked without lipid nanoparticles. Unlike most currently available vaccines, c-srRNA vaccines predominantly elicit cellular immunity with little or no antibody production. Interestingly, c-srRNA-vaccinated mice produced antigen-specific antibodies upon subsequent stimulation with antigen protein. Antigen-specific antibodies were also produced when B-cell stimulation using antigen protein was followed by c-srRNA booster vaccination. Using c-srRNA, we have designed a pan-coronavirus booster vaccine that incorporates both spike receptor binding domains as viral surface proteins and evolutionarily conserved nucleoproteins as viral non-surface proteins, from both SARS-CoV-2 and MERS-CoV. It can thereby potentially immunize against SARS-CoV-2, SARS-CoV, MERS-CoV, and their variants. c-srRNA may provide a route to activate cellular immunity against a wide variety of pathogens.