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

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 µg per dose, n = 16; placebo, n = 4) and Cohort 2 (25 µg 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. ### Competing Interest Statement MiK is a paid consultant to Elixirgen Therapeutics, Inc. TA, HY, MA, MB, PR, ACK, MSHK are employees of Elixirgen Therapeutics, Inc. EL and JK were former employees of Elixirgen Therapeutics, Inc. AA and NW are employees of the National Institute on Aging, National Institutes of Health, and declare no competing interests. YD has served as a consultant for Moderna. TK, TM, TI, HY, ST, AS, HF, MaK declare no competing interest. ### Clinical Trial jRCT2041210013 [NCT04863131][1] ### Funding Statement This clinical trial was entirely supported by Japan Agency for Medical Research and Development (AMED) under Grant Number JP21nf0101631. Elixirgen Therapeutics provided the EXG-5003 vaccine. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The protocol, amendments, and overall oversight were approved by the Central Institutional Review Board for the Fujita Health University Hospitals (F-D-18) (jRCT2041210013, [NCT04863131][1]). The study was conducted in accordance with the Declaration of Helsinki. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04863131&atom=%2Fmedrxiv%2Fearly%2F2023%2F10%2F11%2F2023.10.07.23296699.atom