Kenneth Glad
More than four decades after smallpox was eradicated, scientists are reassessing the legacy of that public health triumph.
As governments contend with post-Covid fatigue, tighter public health budgets and uneven vaccine uptake, concern is shifting back to older viral families that never fully disappeared.
Recent findings on mpox treatments, paired with warnings from infectious disease experts, suggest the world may be entering a new phase of orthopox risk.
Testing the response
In the summer of 2025, the University of California reported that UC San Francisco had led a major international clinical trial during the 2022 global mpox outbreak. Researchers set out to determine whether tecovirimat, or TPOXX, a drug approved for smallpox, could speed recovery in mpox patients.
The United States recorded more than 20,000 cases and nearly six dozen deaths during that outbreak, according to the university. Although physicians were permitted to prescribe the drug under investigational protocols, clear evidence of benefit was lacking.
Annie Luetkemeyer, MD, who heads UCSF’s Advancing Clinical Trials Globally unit, said the trial showed the medication was safe but did not shorten recovery time. A separate study conducted largely among children in the Democratic Republic of the Congo produced similar results.
The World Health Organization declared mpox a Public Health Emergency of International Concern in 2024 following a surge in cases in Central Africa, a designation that remains in effect.
Since 2022, cases have been reported in dozens of countries beyond historically endemic regions.
A fading shield
Smallpox once killed hundreds of millions of people in the 20th century before a WHO-led eradication campaign ended routine vaccination in 1980. In the United States, routine smallpox immunisation for the general public stopped in 1972, according to the US Centers for Disease Control and Prevention.
That decision reshaped global immunity. Most people under 45 have never received a smallpox vaccine, and the cross-protection it offered against related orthopoxviruses has waned.
Dr Raina MacIntyre, a biosecurity specialist whose research focuses on emerging infectious threats at the University of New South Wales, has argued that this generational shift leaves populations exposed.
According to The Daily Express, she said earlier this month: “Before smallpox was eliminated, people were frequently exposed to the virus and there were mass vaccination campaigns that resulted in a baseline of protection to orthopoxviruses more broadly. But the population of the world, at the moment, are just sitting ducks for any orthopox virus emergence, because we don’t have immunity.”
Her warning reflects a broader academic debate. According to Science Media Centre, Dr Jonas Albarnaz, senior virologist at the Pirbright Institute, noted: “Public health experts predicted before eradication that other orthopoxviruses could ‘occupy’ the niche vacated by variola virus [which caused smallpox], with mpox a prime candidate.”
Growing pressure
Mpox spreads through close physical contact and can cause painful lesions and fever. Madagascar’s Ministry of Public Health said that the country has recorded more than 260 suspected cases and 94 confirmed infections as of mid-January, a marked rise compared with typical annual totals prior to the current outbreak.
A wider regional surge prompted the WHO’s 2024 emergency declaration. Sustained transmission increases the chances of viral recombination, and a hybrid strain combining clade I and clade II variants was identified in the UK last year.
The underlying issue is demographic as much as virological: a largely unvaccinated global population, dense international travel networks and uneven surveillance systems create openings for orthopoxviruses to spread. Containment depends on speed. And speed depends on preparation.
Sources: The Daily Express; Science Media Centre; University of California; U.S. Centers for Disease Control and Prevention.
