Abstract
Background/Objectives: Messenger RNA (mRNA) vaccines have enabled rapid vaccine development and have become an important platform for pandemic preparedness; however, clinical evaluation of alternative co-transcriptional 5′ cap technologies remains limited. Here, we report the first-in-human safety, tolerability, and immunogenicity of STP2104, a SARS-CoV-2 mRNA vaccine incorporating the novel co-transcriptional 5′ cap analogue SmartCap® SC101. Methods: In this Phase I, multicenter, open-label, dose-escalation study, 30 healthy adults with no known history of SARS-CoV-2 infection received two intramuscular doses of STP2104 at either 25 μg or 50 μg on Days 0 and 28. Safety and tolerability were evaluated, along with humoral and cellular immune responses, including neutralizing antibodies, binding antibodies, and antigen-specific IFN-γ ELISpot responses. All participants completed the planned two-dose vaccination schedule before early study termination. Results: STP2104 demonstrated an acceptable short-term safety and tolerability profile across both dose cohorts, with no treatment-emergent serious adverse events, Grade ≥ 3 treatment-emergent adverse events under the protocol-defined clinical severity criteria, or events leading to study discontinuation. However, one participant experienced a transient Grade 3 platelet-count laboratory abnormality, which was recorded in the Clinical Study Report (CSR) as a Grade 1 thrombocytopenia treatment-emergent adverse event. Neutralizing antibody titers increased following vaccination in both dose cohorts, reaching their post-boost maximum at Day 35 and remaining above baseline at Day 56. Binding-antibody concentrations also increased following vaccination, and antigen-specific IFN-γ ELISpot responses were detected in both dose cohorts. Conclusions: This first-in-human Phase I study shows that SmartCap® SC101 can be incorporated into an mRNA–LNP vaccine construct for clinical evaluation. STP2104 had an acceptable short-term safety and tolerability profile and induced measurable humoral and cellular immune responses. These results support further clinical evaluation of SmartCap® SC101-containing mRNA constructs with updated or alternative antigens.