Tolerability, Safety and Immunogenicity of Intradermal Delivery of a Fractional Dose mRNA -1273 SARS-CoV-2 Vaccine in Healthy Adults as a Dose Sparing Strategy (preprint)

ABSTRACT

Background: There is an urgent need for fair and equitable access to safe and effective vaccines to end the COVID-19 pandemic. Shortages in reagents and vaccines are a major challenge, as well as limited knowledge on dose response relationship with mRNA COVID-19 vaccines. We explored intradermal fractional dose administration of a mRNA SARS-CoV-2/COVID-19 vaccine as a potential dose-sparing strategy. Methods: We conducted a proof-of-concept, dose-escalation, open-label, randomised-controlled vaccine trial (IDSCOVA) in healthy adults aged 18-30 years. To test initial safety, ten participants received 10 µg mRNA-1273 vaccine through intradermal injection at day 1 and 29. Following a favourable safety review, thirty participants were 11 randomised to receive 20 µg mRNA-1273 either intradermally or intramuscularly. The primary endpoint was tolerability and safety. The secondary endpoint was seroconversion and specific IgG concentration against SARS-CoV-2 spike S1 and Receptor Binding Domain (RBD) after the second dose at day 43. We compared results to two historical cohorts of non-hospitalised COVID-19 patients and vaccinated individuals. Findings: Thirty-eight of forty included participants (median age 25 years) completed the study. There were no serious adverse events. Self-reported local adverse reactions after intradermal delivery were mild, both in the 10 µg and the 20 µg group. In the higher dose group, systemic adverse reactions were more common , but still well tolerated. All 38 participants mounted substantially higher IgG-anti-S1 and IgG-anti-RBD concentrations at day 43 than COVID-19 controls. At day 43, anti-S1 (95% CI) was 1,696 (1,309-2,198) BAU/mL for the 10 µg intradermal group, 1,406 (953·5-2,074) BAU/mL for the 20 µg intramuscular group and 2,057 (1,421-2,975) BAU/mL for the 20 µg intradermal group. Anti-S1 was 107·2 (63-182·2) BAU/mL for the convalescent plasma control group and 1,558 (547·8-4,433) BAU/mL for the individuals vaccinated with 100 µg mRNA-1273.Interpretation: Intradermal administration of 10 µg and 20 µg mRNA-1273 vaccine was well tolerated and safe, and resulted in a robust antibody response. Intradermal vaccination has the potential to be deployed for vaccine dose-sparing.Clinical Trial Registration Details registered in the Netherlands Trial Register (NTR) (https//www.trialregister.nl/trial/9275).Funding Information The trial was supported by crowdfunding (Wake Up to Corona).Declaration of Interests All authors declare no competing interests. Ethics Approval Statement The trial was performed in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines developed by the International Harmonisation Task Force. The protocol was approved by the Medical Ethical Committee Leiden, Den Haag, Delft (NL 76702.058.21). All participants provided written informed consent. The vaccine manufacturer was not involved in this trial.