The ancient scourge smallpox was relegated to biowaste bin of history more than 30 years ago, the result of the world's first and only successful disease eradication programs. Since then, however, cases of monkeypox—a serious, although less severe smallpoxlike illness—have substantially increased in central Africa, according to a study published August 30 in Proceedings of the National Academy of Sciences. The authors stress that better surveillance and a thorough assessment of the public health threat posed by this once-rare viral infection are needed.

"I'm concerned about monkeypox," says Don Burke director of the Center for Vaccine Research at the University of Pittsburgh, who wasn't involved in the study. "It isn't going to emerge as pandemic tomorrow, but could at any time start to increase its transmission. It's worrisome. This is the type of warning siren we need to take very seriously."

Although monkeypox was first discovered in laboratory monkeys in 1958, its natural hosts are squirrels and other rodents. People can catch the disease from direct contact with infected animals or humans. Approximately two weeks after exposure an infected person will develop a fever, muscle aches, exhaustion and a rash with raised bumps that last for two to four weeks.

Since its discovery most cases have occurred in western and central Africa, although in 2003 a few cases occurred in the U.S. Midwest after infected animals were imported from Africa. There is no treatment for monkeypox, which is fatal in as many as 10 percent of cases. Because the viruses that cause small and monkeypox are closely related (both belong to the Orthopoxvirus genus), the smallpox vaccine also protects against monkeypox infection.

In the new study University of California, Los Angeles, School of Public Health epidemiologist Anne Rimoin and colleagues surveyed for active human cases of monkeypox between 2006 and 2007 in regions of the Democratic Republic of Congo (DRC) where the virus is known to circulate. They documented 760 active cases (approximately 14 per 10,000 people) of the illness during that period, with more than 90 percent occurring in individuals born after routine smallpox vaccination ceased in 1980. Compared with the World Health Organization's (WHO) estimated incidence of less than one case per 10,000 in the same region between 1981 and 1986, the authors suggest that monkeypox cases have jumped nearly 20-fold in less than 30 years.

"This is no longer a rare, sporadic infection in the rainforests of Africa," Rimoin says, adding that "the disease has become commonplace in areas where people are highly dependent upon hunting squirrels and other rodent species as primary sources of protein."

Rimoin adds that the 2003 monkeypox outbreak in the U.S. showed that the virus is "very capable of spreading to species outside central Africa" and has the ability to infect a variety of rodent species. She notes that the American ground squirrel is highly susceptible to monkeypox.

"Monkeypox has probably occurred for millennia in central Africa, but it's only since the eradication of smallpox that it's been a disease that actually happens in humans," Rimoin says. "The consequence of ceasing smallpox vaccination is the world's population is now sensitive to poxviruses."

Following a 1997 monkeypox outbreak in the DRC, the WHO reported that the virus appeared to be changing its pattern of infection with much higher rates of person-to-person transmission.

"The rise that we're finding is way above and beyond what anyone expected to see," Rimoin says. "It's not linear, it's exponential. That suggests that secondary (person-to-person) transmission is going on."

Burke thinks that Rimoin's figures are credible, but cautions that the two data sets (from the 1980s and the 2000s) were collected by different teams using different methods, making direct comparisons difficult. In the future he would like to see more detailed, standardized studies to determine how transmissible monkeypox is from person to person, what happens to the virus as it infects humans, and whether there is any evidence that the virus is evolving.

Rimoin agrees, and explains that there are two traits that determine the severity of an infectious disease: the virulence of the pathogen and its transmissibility. "At this point, we just don't know," Rimoin says. "This is just a first pass to look at how common monkeypox is." Her team plans to continue its active surveillance of monkeypox and hopes to monitor whether the virus is really changing over time. They also want to quantify how transmissible it is and determine what complications are associated with it.

Nathan Wolfe, director of the San Francisco–based Global Viral Forecasting Initiative and co-author of the study, notes that "the results of this research really point to the benefits of long-term monitoring and this model of creating listening posts" to catch infectious diseases early, before they become pandemics. "I think that increasingly many people in global public health recognize that simply waiting for pandemics to occur is not going to be sufficient. Part of what we need is early detection, control and prevention of pandemics, rather than response."

Although smallpox vaccines protect against monkeypox, Rimoin says that experts do not consider the vaccines suitable for use in populations of people who are highly immunocompromised, as by HIV or severe malnutrition, because being inoculated can cause severe health complications. She suggests that the best solution for preventing further monkeypox proliferation would be behavioral interventions, including isolation of infected patients and the development of better practices for handling animals that are likely to be infected.

"These are exactly the kind of studies that we—the U.S.—and other wealthy countries, should be investing heavily in to prevent epidemics," Burke says. "Although there has been an increase in this, we are far behind the curve in understanding where threats come from, and stopping them before they begin."

"What we're seeing in the Democratic Republic of Congo is a harbinger of things to come," Rimoin warns. "We will see poxviruses emerge more frequently in susceptible populations."

Wolfe took a more cautious tone: "We don't know yet whether [monkeypox] will be important, but this represents a new way of how global disease detection is occurring. In order to catch the most important things, we have to monitor all of the small events."