Mpox vs Smallpox: transmission, rash, mortality and vaccine compared
Mpox and smallpox are both caused by orthopoxviruses and share a similar rash, but they differ profoundly in severity, transmissibility, and current status. Smallpox was eradicated in 1980 and exists only in two BSL-4 repositories; mpox continues to circulate with clade I and clade IIb strains causing WHO-declared PHEICs.
| Metric | mpox | smallpox |
|---|---|---|
| Pathogen | Monkeypox virus (MPXV) — Poxviridae, Orthopoxvirus | Variola virus (VARV) — Poxviridae, Orthopoxvirus |
| Current status | Endemic in Central/West Africa; 2022-2024 global clade IIb PHEIC; 2024-ongoing clade Ib PHEIC (DRC and neighbours) | Eradicated globally in 1980; no natural cases since 1977; stocks held at CDC (USA) and VECTOR (Russia) under WHO oversight |
| Transmission (R₀) | Clade IIb: ~1.1–2.4 (sexual networks); clade I: ~1.0–1.8 household. Zoonotic re-introduction possible from rodent/primate reservoir. | ~5–7 in unvaccinated populations; spread via respiratory droplets and direct contact with lesions/fluid; no animal reservoir |
| Rash presentation | Face → centrifugal spread; palms and soles common; clade IIb: few/genitoanal lesions; macule → papule → vesicle → pustule → scab; lesions may be in mixed stages | Face → centrifugal spread; uniform deep-seated umbilicated pustules, all lesions at same stage simultaneously; no genitoanal predilection |
| Lymphadenopathy | Prominent — hallmark sign; distinguishes mpox from smallpox and chickenpox | Absent — no lymph node swelling during smallpox |
| Case fatality rate | Clade II: <1% (resource-rich); clade I: 1–10%, higher in children and immunocompromised | ~30% overall; variola major 30%; variola minor (alastrim) ~1%; hemorrhagic/flat forms >90% |
| Incubation period | 5–21 days (typically 6–13 days) | 7–17 days (typically 10–14 days) |
| Vaccine | JYNNEOS (MVA-BN) — 2-dose, approved for mpox and smallpox; ACAM2000 also protective. Pre-1980 smallpox vaccination ~85% cross-protective, now waned. | Smallpox vaccines (ACAM2000, JYNNEOS) are stockpiled; routine vaccination ended globally ~1980 after eradication |
| Treatment | Tecovirimat (TPOXX) approved; brincidofovir/cidofovir for severe cases; most clade II cases self-limiting in 2–4 weeks | Tecovirimat and brincidofovir are stockpiled for emergency use; no approved treatment for natural disease (eradicated) |
| Zoonotic reservoir | Yes — rodents (rope squirrels, dormice, Gambian giant rats) and non-human primates; zoonotic spill-over ongoing | No — humans were the only host; eradication was possible because no animal reservoir existed |
Verdict
Mpox is substantially less dangerous than smallpox: case fatality rates are 10–30× lower and transmissibility is far smaller. The critical practical difference is that smallpox no longer exists naturally — any case today would represent a biosafety incident or deliberate release. Mpox, by contrast, is an ongoing zoonotic public health concern. The JYNNEOS vaccine protects against both, and pre-1980 smallpox vaccination still provides some residual cross-protection against mpox, which partly explains why older adults saw milder disease in the 2022 global outbreak.