On 9–10 December 2025, the Coalition for Epidemic Preparedness Innovations (CEPI) and the International Vaccine Institute (IVI) convened a workshop in Seoul under CEPI’s Disease X Program. The primary objective was to identify existing gaps needing to be filled and streamline vaccine development and preparedness for Severe Fever with Thrombocytopenia Syndrome (SFTS). CEPI’s partners and experts discussed a multifaceted agenda, ranging from understanding the evolving epidemiology to the refinement of animal models and immunological assay harmonization. Key outcomes included the refinement of Target Product Profiles (TPPs) specifying use cases for both peacetime and outbreak contexts, alongside a recommendation for a core immunoassay panel aimed at harmonizing evaluation frameworks and mitigating the challenges posed by low SFTS prevalence. Integration of the One Health approach emerged as a critical strategy for SFTS prevention, complemented by proactive regulatory engagement to compress vaccine development timelines. This report summarizes these key insights from the workshop, delineating a strategic framework for delivering safe, effective, and accessible vaccines for SFTS and broader Disease X threats.

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.