Mpox Clade I Raises Concerns in Africa, But U.S. Risk Remains Low, Experts Say

As concerns grow about a more severe variant of mpox spreading in Africa, infectious disease experts are cautiously optimistic that this strain may not spread as widely in the United States or cause as severe health impacts. The potential threat to the U.S. from this mpox subtype, known as clade I, could be minimized due to several factors, including immunity from previous vaccination and infection during the 2022 outbreak of a different variant, lack of viral circulation in wild animals, and better healthcare access and living standards.

On Wednesday, the World Health Organization (WHO) reinstated mpox as a public health emergency of international concern due to a large outbreak of clade I in the Democratic Republic of Congo (DRC), which has spread to other African nations. Sweden reported the first case of clade I outside Africa on Thursday.

“It was only a matter of time before we saw this extend beyond the African continent,” said Dr. Boghuma Titanji, an infectious disease specialist at Emory University.

On Friday, Dr. Pamela Rendi-Wagner, director of the European Centre for Disease Prevention and Control, announced that the agency had raised the risk level of clade I to the general European population from “very low” to “low,” citing the close connections between Europe and Africa. “We must be prepared for more imported clade I cases,” she added.

The Centers for Disease Control and Prevention (CDC) confirmed on Friday that no cases of clade I have been reported in the U.S. so far.

Clade I is generally considered more transmissible and severe than clade II, the variant responsible for the global mpox outbreak that peaked in August 2022, which had a death rate of 0.2%. People with weakened immune systems, particularly those with untreated, advanced HIV, have been most at risk of severe disease, hospitalization, and death from clade II. The U.S. continues to see low-level transmission of clade II.

Anne Rimoin, an epidemiologist at the University of California, Los Angeles, and a leading mpox expert, emphasized the importance of context when comparing how mpox might behave in Western countries versus Africa. “I think we have to be very, very cautious about saying that this is more dangerous,” she said of clade I. “The data on the severity, associated mortality — all of that is scant. There are a lot of questions about whether or not the perceived severity might have more to do with the population that it’s spreading in, their immune system, the route of transmission, the infectious dose.”

On Thursday, the National Institutes of Health (NIH) reported that the antiviral TPOXX did not reduce clade I symptom duration in a DRC clinical trial. However, only 1.7% of participants died, compared to the typical clade I death rate of 3.6% or higher in the DRC. NIH experts credited better medical care provided to study participants for the lower death rate.

Epidemiologist Dr. Jennifer McQuiston, the lead for the CDC’s mpox clade I response, expressed hope that high-quality healthcare in the U.S. could help minimize deaths from the disease. Dr. Dan Barouch, a virologist at Harvard Medical School, acknowledged the possibility of clade I cases in the U.S. but stated, “The absolute risk in the U.S. is currently low, although we need to remain vigilant.”

The CDC first alerted doctors and healthcare providers in December to be on the lookout for clade I, updating the advisory on August 7. When U.S. clinics order testing for potential mpox cases, some testing centers can directly screen for the clade type, while others send samples to the CDC for analysis. All positive results must be reported to the CDC. Additionally, numerous sites across the country monitor wastewater for signs of the virus in local populations.

“We are more worried about clade I than we are about clade II,” McQuiston said, highlighting the CDC’s continued domestic vigilance.

The CDC recently reported that receiving both doses of the Jynneos vaccine appears to reduce the risk of mpox. The vaccine is expected to protect against both clades. Throughout the clade II outbreak, which is now at low levels, mpox has primarily spread through sexual contact between men. The CDC continues to urge men with multiple male partners to receive both doses of the Jynneos vaccine. However, only about one in four of those considered at high risk in the U.S. have been fully vaccinated.

In the DRC outbreak, clade I has spread significantly through sexual transmission among both gay men and female sex workers. Children have been particularly affected, accounting for two-thirds of the roughly 20,000 suspected cases and three-quarters of the 975 suspected deaths in the DRC since January 2023, according to the CDC.

There is speculation that recent mutations in the virus may have increased its transmissibility. Rimoin suggested that close physical contact, whether sexual or nonsexual household contact, likely remains necessary for transmission. In the DRC, people often live in much more cramped conditions compared to the U.S.

“We don’t hear reports of people getting it at the market,” McQuiston noted, adding that household spread might be occurring in the DRC due to family members caring for the sick without adequate protection and limited ability to isolate those who are infected.

The vaccine remains scarce in the DRC, while in the U.S., where supply is sufficient, household contacts of infected people can seek the vaccine prophylactically. In rural DRC, people also likely contract mpox from an unknown wild animal host, possibly a rodent. No animals in the U.S. are believed to carry the virus.

Dr. Jeffrey Klausner, an infectious disease expert at the University of Southern California, pointed out that differences in sexual behavior between gay men and heterosexuals in the U.S. might limit the spread of mpox among the broader American population. Unlike the general heterosexual population, gay and bisexual men include a smaller group whose behaviors could sustain an mpox outbreak outside of Africa, Klausner explained in a commentary published in The Lancet Microbe on August 7.

Klausner also argued that infectious disease researchers may have underestimated the rate of natural immunity from previous infections. For now, he believes that a combination of natural and vaccine-induced immunity is sufficient among those engaging in high-risk sexual behavior to largely prevent a substantial outbreak.

However, research suggests that natural immunity from the 2022 outbreak may wane over time, and mpox may mutate to evade these defenses. Additionally, the extent to which immunity from clade II will protect against clade I is still unknown, according to Dr. Chloe Orkin, an infectious disease expert at Queen Mary University of London.

Emory’s Titanji added a note of caution, saying of clade I, “I don’t want people to get into a complacency and think that we cannot see this in a heterosexual network” in the U.S.