Researchers develop new diagnostic methods to better detect future monkeypox or smallpox outbreaks

Researchers at the Vaccine and Gene Therapy Institute (VGTI) at Oregon Health & Science University have developed new diagnostic methods to better detect future monkeypox or smallpox outbreaks.

The research also sheds new light on the 2003 monkeypox outbreak in the Midwest - monkeypox is closely related to smallpox. This new information suggests that the 2003 outbreak was larger than the 72 cases reported by the Centers for Disease Control and Prevention (CDC). The research was released online this week by the medical journal Nature Medicine. The study will also appear in the September 2005 print edition of the journal.

"The 2003 outbreak of monkeypox provided some incredibly valuable information about the country's level of preparedness for an infectious disease outbreak that is either naturally occurring or an act of terrorism," said Mark Slifka, Ph.D., lead author and an assistant scientist at the VGTI, an assistant professor of molecular microbiology and immunology in the OHSU School of Medicine and an assistant scientist at the Oregon National Primate Research Center. "Our research demonstrates that the limitations of currently used technology likely allowed monkeypox cases to slip through the system. This problem was further exacerbated by the two-week delay that occurred during the diagnosis of the first monkeypox cases. If the 2003 outbreak had been smallpox instead of monkeypox, the situation could have been much worse because secondary spread of the virus to other victims would likely have occurred before the outbreak was recognized."

To conduct this research, Slifka and colleagues traveled to Wisconsin to test those who had been exposed to monkeypox in 2003. Although 72 potential cases were reported at that time, only about half of the cases have been officially confirmed. Directly following the outbreak, the CDC released a report that focused on 11 of the 72 cases. Of those 11, six cases were confirmed and the remaining five cases remained unconfirmed, until now.

The test the CDC uses to confirm monkeypox cases requires that the virus be directly identified in blood or tissue samples. Because monkeypox virus is eventually cleared by the body, the evidence is quickly wiped out, resulting in a high percentage of unconfirmed cases due to the limited window of opportunity for diagnosis. In comparison, OHSU's research team tested samples using a variety of methods. One such test, called the ELISA test, resulted in very accurate results (95 percent sensitivity, 90 percent specificity.) This high level of accuracy allowed Slifka and colleagues to correctly diagnose previously confirmed cases as well as confirm several probable,suspect cases of monkeypox that had remained unconfirmed for the last two years. Most importantly, Slifka's lab identified and confirmed three new cases of monkeypox that had previously gone undetected by the CDC.

The ELISA test is based on a Slifka lab research finding that specific genes found in the monkeypox virus are recognized by antibodies produced by the human immune system. By testing for this unique immune response, which remains detectable for years, researchers can accurately determine if the patient has been infected with the virus.

"While this research primarily focused on monkeypox, this same technology could also be used to better detect a smallpox outbreak," said Slifka. "This is an active area of further investigation."

The test even works in cases where infection may not be obvious. For instance, three of eight subjects who had previous smallpox vaccinations failed to show any outward signs of viral infection and had no noticeable disease symptoms. The researchers found this particularly interesting because this virulent strain of monkeypox virus resulted in numerous hospitalizations. In one case that has been previously reported, a child remained in a coma for 12 days.

Due to similarities between the monkeypox and smallpox viruses, the smallpox vaccine likely kept these inoculated people from becoming seriously ill. The researchers believe these people were fully protected against monkeypox because smallpox vaccination can provide cross-protective immunity against this virus.

"In our study, we found one subject who had fully protective immunity that was maintained for 48 years after a single smallpox vaccination," said Slifka. "In a previous study, we predicted that about 50 percent of previously vaccinated people would maintain fully protective immunity against virulent poxvirus infections, and these findings are totally in line with what we expected. What this means is that there are more than 100 million people in the U.S. that have partial or even fully protective immunity that is maintained after childhood vaccinations - an important point to consider if we were ever to be deliberately attacked with smallpox or other dangerous poxviruses as weapons of bioterrorism".