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Monkeypox Spurs Test Development, Though Scope of Outbreak Remains Unclear

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NEW YORK – With more than 1,000 global cases of monkeypox reported since early May, the World Health Organization has shone a light on the need for expanded diagnostic and prevalence testing to combat the growing outbreak.

At a meeting to discuss research and development priorities last week, experts outlined approaches to diagnostic testing for the zoonotic virus, emphasizing in particular a need for more point-of-care and serology testing.

Separately, the US Centers for Disease Control and Prevention said in a media briefing on Friday that the Laboratory Response Network (LRN) will carry out US testing going forward.

The global outbreak was first detected in the UK in early May, followed about two weeks later by cases in Spain, Portugal, and the US. It has now expanded to include a total of 1,073 confirmed cases in 39 countries.

Monkeypox is in the family of orthopox viruses, and most molecular tests are general for all non-smallpox orthopoxes. Overall, there are 66 public health labs and eight Department of Defense labs that can perform orthopox PCR testing in the US among the 110 total LRN labs.

In 2018, the US Food and Drug Administration issued a 510(k) clearance to the CDC for an assay to detect all non-smallpox orthopox viruses. The test is limited for use in LRN labs, according to the authorization letter, and was developed in part to combat potential bioterrorism threats.

Raj Panjabi, leader of the White House pandemic preparedness office, said during the CDC presentation that, to date, more than 120 orthopox PCR tests have been performed across the country, and that the LRN has the capacity to test more than 1,000 samples per day.

"What we are working on now is to ensure that testing capacity is used," Panjabi said.

"We are asking individuals with symptoms … to go to their healthcare providers, and we are asking healthcare providers across the country to send more tests in if there is any clinical suspicion of monkeypox."

Consequently, "We should expect, if this is working, that there will be more cases and more tests in the coming days," Panjabi said on Friday.

The circulating strain in the current outbreak is the West African clade, which typically produces milder symptoms than another predominant strain, dubbed the Congo Basin clade, experts presenting during the WHO conference noted.

According to a Morbidity and Mortality Weekly Report published by the CDC on Friday, the first two US cases in the current outbreak sought treatment on May 4 after recent international travel. A man in Massachusetts sought care four times before news coverage of the outbreak in the UK led his clinicians to request monkeypox testing on May 17, the CDC's incidence response coordinator Jennifer McQuiston said on Friday.

His orthopox virus PCR came back positive that same day from the Massachusetts Department of Public Health LRN lab, and the CDC confirmed monkeypox virus the following day, she said. The next day, the West African clade was identified using sequencing, and the CDC initiated an emergency response.

Melissa Miller, director of the clinical microbiology lab at the University of North Carolina, Chapel Hill Health Center, noted in an email that, at this point, the LRN orthopox test should be sufficient given the follow-up confirmatory testing and sequencing offered by the CDC.

However, the presence of a more significant stealth outbreak here is "absolutely a possibility," she said, particularly given recent reports that two strains may be circulating in the US, suggesting two separate introductions. "That, coupled with what is likely undertesting [due in part to] providers not thinking about monkeypox, may contribute to such a scenario," Miller said.

Current tests

Dan Bausch, director of emerging threats and global health security at Switzerland-based diagnostics evaluator FIND, said in a presentation at the WHO event that as recently as a few weeks ago none of these new commercial tests for monkeypox had been available.

As of last Wednesday, there were 30 tests in FIND's curated list of available assays. Less than a week later, the list totals 40 tests.

Among these 40 tests, there are a total of 33 molecular assays for monkeypox. With the exception of two near point-of-care tests, all are lab-based.

The FIND list also includes seven immunoassays: Two of which are lab-based, one is for near-point-of-care use, and four are true point-of-care tests.

These tests are manufactured by 31 different firms, 18 based in China, five each based in Germany and the US, and one each from the UK, Japan, and Russia.

The molecular diagnostic tests include one from Altona Diagnostics and three from Roche and its subsidiary TIB Molbiol: an orthopox test and a monkeypox specific test, as well as an assay that combines these two. There is also a molecular test in development from collaborators Becton Dickinson and CerTest Biotec that has not yet appeared in the FIND list. 

Among the 40 assays, 19 tests have the CE-IVD mark — including 18 molecular tests and one immunoassay —while the remainder have unknown regulatory status, according to FIND. Bausch said in his presentation at the WHO event that it is unknown whether any of these tests are actually available for purchase.

Furthermore, "We have a large number of biotech companies coming in, saying, 'We have the tools to diagnose monkeypox,' and we definitely encourage that," Bausch said.

"But, we also want to recognize that just this year in [the Democratic Republic of Congo] there were already more than 1,200 cases and 15 deaths, and no one in the last 20 or 30 years has been proposing diagnostic assays to address this problem in Africa," he said. Diseases endemic to low- and middle-income countries need to be addressed with diagnostic testing sooner, he concluded, not just when they get to high-income countries.

For now, Bausch also said an orthopox PCR test should be sufficient — except in rare cases of people who have workplace exposures to more zoonotic viruses — because clinical presentation plus an orthopox-positive test would lead to a confident monkeypox diagnosis.

Nevertheless, "We need validation of all of the tools," Bausch said. "Until we have the right tools, we can't understand what is going on with this virus," he said. In particular, there is a need for validated serology tests to determine seroprevalence and epizoology tools to characterize the zoonotic reservoirs of monkeypox, he said.

Testing and research priorities

Much remains unknown about the current monkeypox outbreak.

According to the CDC MMWR, the identification of monkeypox clusters in countries that do not have endemic disease and involve patients who had not traveled to monkeypox-endemic areas suggests the outbreak is being fueled by person-to-person community spread.

Arnaud Fontanet, a researcher at Institut Pasteur, noted at the WHO conference that there are also 47 new mutations in the West African clade virus causing the current outbreak compared to the genome of the virus during a 2017 outbreak in Nigeria. This indicates the virus may have been circulating in new hosts over the past four years, he said.

"That new host could be either a new animal or sustained human-to-human transmission," he said. If the latter turns out to be the case, "we have to be much more energetic in the way we stop the circulation of this virus," Fontanet added.

Dimie Ogoina, a researcher at Niger Delta University in Nigeria, said at the WHO meeting that the virus had previously been more predominant among children who were exposed to infected animals in rainforest regions. Now, most cases in the current outbreak are among young adults in urban centers and particularly among men who have sex with men in the current outbreak.

Knowing whether this changing scope is related to travel or to a new host animal reservoir — such as rodents, domestic animals, or pets — is critical, he said.

Ogoina also noted that monkeypox rashes are typically painful, oozing sores, that are hard to miss. Since almost all cases in the current outbreak have come from sexual contact, he suggested researchers need to investigate potential asymptomatic transmission, possibly in seminal fluid or vaginal secretions.

In Nigeria, there is also underreporting, he said, and there is only one national reference lab that can make the diagnosis. "It is important to decentralize" testing, Ogoina said.

Using serosurveillance to determine the scope of infection is also challenging at this time because current immunoassays can't distinguish between recent monkeypox infection and prior smallpox vaccination, so new tests could be very helpful. 

Gianfranco Spiteri, a sexually transmitted infections expert at the European CDC, said at the WHO conference that serology will be critical to distinguish whether this is a new outbreak or one that had been flying under the radar in nonendemic countries for some time.

Another research priority, according to Isabel Oliver of the UK Health Security Agency, is to determine whether skin-to-skin contact as a mode of transmission changes the incubation period or enables asymptomatic transmission. Strengthening diagnostics will also be critical to surveillance going forward, Oliver said.

Numerous experts at the WHO meeting highlighted a need for point-of-care testing for the current outbreak, particularly because the relatively mild rashes could potentially be mistaken for other sexually transmitted infections, such as herpes.

Oliver also said her agency is investigating the potential to use wastewater testing to reveal the scope of the monkeypox outbreak there.

One of the first monkeypox outbreaks occurred in the 1960s among animals at a zoo in the Netherlands. It is believed to have become endemic in parts of Africa, with sporadic outbreaks over the years and a likely non-primate animal vector, such as a rodent, that acts as a viral reservoir.

A US outbreak in 2003 infected 71 people across six Midwestern states and was ultimately traced to prairie dogs that had been infected in a pet warehouse after being co-housed with Gambian pouched rats. The CDC subsequently banned the import of pet rodents from Africa.

WHO experts said more research is needed to determine whether there is an animal vector now established in Europe.

And in the US, McQuiston said it is "too early to know whether monkeypox can become endemic." But, she added, "It is important to keep in mind that monkeypox has been endemic in several countries for decades."