Vaccination status has emerged as the single most powerful predictor of severe mpox outcomes in the United States — a finding with direct implications for anyone in a risk-eligible population who has deferred completing the two-dose immunization series. As mpox transitions from acute outbreak to persistent endemic background transmission, understanding who remains vulnerable and why is increasingly urgent.
U.S. surveillance data spanning 2024 into late 2025 captured 2,803 and 2,519 reported infections respectively, with a notable surge in September–October 2025 that doubled the case counts seen during the same window in 2024, though numbers subsequently returned to baseline by December. Most striking was the hospitalization analysis drawn from 860 patients with complete records: after controlling for age group and HIV status, unvaccinated individuals faced 9.73 times the odds of hospitalization compared to fully vaccinated counterparts. Ten clade Ib cases were detected in 2025, up from a single travel-associated case in 2024, signaling gradual importation of a genetically distinct lineage with potential clinical differences. Patient demographics — sex, race and ethnicity, sexual orientation, lesion location, and age — remained largely consistent with prior outbreak years.
The near-10-fold hospitalization differential is one of the largest protective effect sizes yet quantified for mpox vaccination in a real-world surveillance context, and it reinforces mechanistic evidence from earlier immunogenicity studies. That said, the analysis is observational rather than randomized, and unmeasured confounders — including healthcare-seeking behavior, prior immunity from natural infection, or comorbidity burden beyond HIV — could partially influence the effect estimate. The emergence of clade Ib importations merits close attention; this lineage has shown higher transmissibility in some African settings and may behave differently in populations with heterogeneous immunity. For the broader research community, this report also underscores the persistent under-vaccination gap: many at-risk individuals have not completed the two-dose JYNNEOS series years into the outbreak. Overall, this is a confirmatory but practically significant surveillance update — not paradigm-shifting science, but a clear quantitative signal that vaccine series completion meaningfully alters disease trajectory.