Early epidemiologic and genomic insights from Sierra Leone's first mpox cases, 2025.
INTRODUCTION: early characterization of outbreak cases supports rapid decisions. We conducted real-time analysis during the initial outbreak phase in mid-March 2025 of Sierra Leone's first 44 laboratory-confirmed Mpox cases (10th January to 5th March 2025) to generate epidemiologic and genomic intelligence for response. METHODS: we summarized surveillance data and sequenced 18 early cases with Oxford Nanopore. Firth-penalized logistic regression was employed to explore risk factors for severe disease. RESULTS: median age was 27 years (interquartile range 22 to 35); 68.2% were male. Most cases reported no recent international travel (95.5%). All cases presented with rash; fever occurred in 72.7%. Six cases (13.6%) met severe criteria; no deaths occurred (0 of 44; 95% confidence interval 0 to 8.0). Household secondary attack rate was 7.3% during the study window and 8.2% after completion of follow-up. Sequencing identified two co-circulating sub-lineages consistent with A.2.2 and B.1.6 and a strong APOBEC3 pattern (142 of 212 guanine-to-adenine in thymine-cytosine versus 70 of 212 cytosine-to-thymine in guanine-adenine; exact binomial p approximately 8.6x10-7; X2= 24.5, df = 1, p≈ 7.6x10-7). Root-to-tip analysis showed weak temporal signal (R2=0.31; date randomization p= 0.18), so we did not interpret clock estimates. CONCLUSION: real-time analysis during the initial outbreak phase showed community transmission, quantified household spread, documented two sub-lineages with an APOBEC3 signature, and generated severity hypotheses that immediately informed surveillance and vaccine prioritization. Findings require validation in larger cohorts.