Three Critical Knowledge Gaps Remain in New Mpox Outbreak

The World Health Organization's decision to declare mpox a global health emergency for the second time in two years has raised urgent questions—but not the kind that come with ready answers. Scientists studying the new Clade 1b variant find themselves in the uncomfortable position of sounding alarms about a virus whose basic behavior remains poorly understood. What they know is precise enough to worry about. What they don't know is vast enough to keep them awake.

Mpox itself is not new. It is a viral infection that resembles smallpox but circulates primarily in animals across Central and West Africa, where it has remained endemic since humans first encountered it during the global campaign to eradicate smallpox in the 1970s. The virus exists in two main lineages. Clade 1, concentrated in the Democratic Republic of Congo and surrounding regions, carries a fatality rate as high as 10 percent. Clade 2, which circulates in West Africa, kills roughly 1 percent of those it infects. In 2022, a new subvariant of Clade 2—designated Clade 2b—emerged with a troubling characteristic: it spread efficiently through sexual contact. That variant ignited the first global mpox outbreak outside Africa, with Brazil becoming the second-most affected country worldwide. The virus has since faded from headlines but never disappeared from circulation.

Now a new threat has materialized. Clade 1b, a recently identified subvariant of the more lethal Clade 1 lineage, has begun spreading in ways that mirror the 2b pattern. It moves through sexual contact among adults rather than through the household and animal-contact routes that characterize traditional Clade 1 transmission. It has already crossed into four countries bordering the Democratic Republic of Congo—nations that had never recorded mpox cases before. The Democratic Republic of Congo itself is experiencing its largest outbreak on record, with more than 500 deaths. Yet even as the alarm spreads, fundamental questions remain unanswered.

The first uncertainty concerns lethality. The WHO has reported a 3.1 percent fatality rate in the Democratic Republic of Congo, substantially lower than the 10 percent associated with Clade 1a. But the country is simultaneously experiencing outbreaks of both the original Clade 1a and the new 1b variant, and the data do not distinguish between them. Researchers cannot say with confidence whether 1b is genuinely less deadly than 1a or whether other factors—the quality of local healthcare, the age distribution of cases, the underlying health status of infected populations—are skewing the numbers. Rafael Galliez, an infectious disease specialist at the Federal University of Rio de Janeiro, notes that fatality rates for the same virus can vary dramatically depending on the strength of a country's health system. Clade 2 killed far fewer people in Europe than in Africa, even though it was the same virus. Until the data are disaggregated, the true lethality of 1b will remain a shadow.

The second gap concerns transmission and vulnerable populations. Clade 1a has historically infected children in endemic regions through multiple routes. Clade 1b, by contrast, appears to spread primarily through sexual contact and has so far affected predominantly adults. But researchers do not yet know whether this pattern will hold as the virus moves into new territories with different population densities, different sexual networks, and different baseline immunity. They do not know how many infected people are asymptomatic—a critical figure for understanding how far the virus travels undetected. They do not know the basic reproduction number, the epidemiological measure of how many people one infected person typically infects. They do not know which populations will bear the heaviest burden. José Cerbino Neto, an infectious disease specialist at Brazil's National Institute of Infectology, worries that the 1b variant might replicate the 2022 pattern, when Clade 2b spread rapidly through networks of men who have sex with men and people living with HIV. But he emphasizes that the data simply do not exist yet to confirm or refute this concern.

The third uncertainty involves the tools meant to contain the outbreak. Antivirals and vaccines developed for smallpox offer some protection against mpox through cross-reactivity, but their effectiveness against Clade 1b remains untested. Early studies suggest that tecovirimat, one of the primary antivirals, may have limited efficacy. Vaccine effectiveness is similarly opaque. These are not theoretical concerns. They are the difference between a manageable outbreak and a spreading catastrophe. Yet they cannot be answered without time, data, and the kind of detailed surveillance that is difficult to maintain in regions already stretched thin by disease and poverty.

What comes next is a race against uncertainty. The virus has already demonstrated its capacity to cross borders and establish itself in new populations. Scientists are watching to see whether Clade 1b will behave like its Clade 1a ancestor—devastating but geographically contained—or whether it will follow the path of Clade 2b and become a global problem. The answers will determine whether the world faces a contained regional crisis or the beginning of something far larger.