In 2022, the unprecedented large-scale outbreak of monkeypox once again drew the world’s attention to this highly threatening virus to humans.
Just recently (August 14, 2024), the World Health Organization (WHO) announced that the monkeypox outbreak has once again constituted a “Public Health Emergency of International Concern”. This is the second time since 2022 that WHO has declared the monkeypox outbreak to be a “Public Health Emergency of International Concern”.
According to data from the Africa Centers for Disease Control and Prevention on August 9, this year, 13 African countries have reported 17,541 cases of monkeypox, with 517 deaths, of which the Democratic Republic of Congo alone reported 16,789 cases of monkeypox and 511 deaths.
After the WHO alarm was raised, on August 15, China’s General Administration of Customs issued a notice on preventing the spread of the monkeypox epidemic into our country.
Such strict prevention is because there is currently no specific anti-monkeypox virus drug in China for this aggressive viral infection. Internationally, the monkeypox candidate drug Tecovirimat, which was previously thought to be effective against monkeypox infection, was also recently declared to have no significant efficacy…

01

What is Monkeypox?

Monkeypox is caused by the monkeypox virus (Mpox virus, MPXV) and is clinically characterized mainly by fever, rash, and lymph node enlargement. Before 2022, the disease was thought to be mainly prevalent in Central and West Africa.
The monkeypox virus was first discovered in 1958. At that time, two outbreaks of a disease similar to pox occurred in monkey colonies raised for research, hence the initial name “monkeypox.” However, the source of the virus is still unknown. Scientists have suspected that African rodents and non-human primates (such as monkeys) may carry the virus and infect humans.
The monkeypox virus belongs to the genus Orthopoxvirus of the family Poxviridae and is one of the four orthopoxviruses that cause diseases in humans, the other three being the smallpox virus, the vaccinia virus, and the cowpox virus. It mainly enters the human body through mucous membranes and broken skin. It is mainly transmitted through direct contact with the patient’s skin lesions or mucous membranes, and can also be transmitted through contact with items contaminated by the virus, long-term close inhalation of the patient’s respiratory droplets, contact with the respiratory secretions, exudates, blood, and other body fluids of infected animals, or infection through bites or scratches from infected animals.
In 1970, the first case of human monkeypox was recorded in what is now the Democratic Republic of Congo. In 2022, monkeypox spread to various parts of the world. Before that, cases of monkeypox in other places were rare and usually related to travel or the import of animals from areas where monkeypox is endemic.
Currently, there are two types of monkeypox virus, “Clade I” and “Clade II”. Patients infected with the Clade I strain have a higher mortality rate and are mainly spread in Central Africa. In contrast, patients infected with the Clade II monkeypox virus have a survival rate of over 99.9% and were mainly spread in West Africa in the past. It is worth mentioning that the large-scale outbreak of monkeypox in 2022 was mainly caused by “Clade II”.
When the monkeypox epidemic spread widely in 2022, our country issued the “Diagnosis and Treatment Guidelines for Monkeypox (2022 Edition)”. The guidelines pointed out that there are currently no specific anti-monkeypox virus drugs in the country, mainly symptomatic support and treatment of complications.
In fact, there are very few drugs available for the treatment of monkeypox infections worldwide. However, there are currently monkeypox vaccines approved and on the market globally.
On July 13, 2018, the FDA approved the first drug for the treatment of smallpox – TPOXX (tecovirimat). Two years later, the FDA approved another smallpox treatment drug, Tembexa (brincidofovir). As mentioned earlier, the smallpox virus and the monkeypox virus belong to the same genus, so these two drugs are also considered to be treatable for monkeypox infections, but the monkeypox indications for these two drugs have not yet been approved by the FDA.
To verify the safety and efficacy of the first smallpox treatment drug tecovirimat in the monkeypox-infected population, the National Institutes of Health (NIH) is conducting relevant research. But on August 15, 2024, the NIH official website disclosed: tecovirimat is safe, but did not show significant therapeutic efficacy in “Clade I” monkeypox virus-infected patients.

02

The most promising drug proves ineffective

Although tecovirimat was approved for the treatment of smallpox, in fact, this drug did not undergo clinical trials in the patient population before it was marketed, like other drugs.

The reason for this is related to the particularity of the disease smallpox. Smallpox was once one of the infectious diseases that seriously endangered people in the world, but humans have found ways to deal with this disease with wisdom. In 1980, WHO officially announced that the smallpox virus had been eradicated (smallpox no longer exists naturally). The only remaining virus samples are in high-security laboratories in the United States and Russia, used for research purposes.

Considering ethical issues, tecovirimat was only verified for efficacy in relevant animal models and its safety was assessed in 359 healthy human volunteers without smallpox infection. These animal models use animal models of related orthopoxviruses, especially non-human primates infected with monkeypox virus and rabbits infected with rabbitpox virus. But animals are animals after all, and the infection situation is not similar to humans.

Unlike smallpox, even before the outbreak in 2022, monkeypox still occurred naturally in some parts of Africa. Therefore, the safety and efficacy of tecovirimat in the treatment of monkeypox need to be verified by real clinical trials.

For this reason, before the outbreak of the monkeypox epidemic in 2022, NIH had already planned (formally started in October 2022) to conduct experiments in the Democratic Republic of Congo to evaluate the safety and efficacy of tecovirimat in treating monkeypox. After the large-scale outbreak in 2022, considering the differences in infection and virus clades, NIH developed another trial based on the infected population in the United States.

The data announced this time comes from the part of the experiment conducted in the Democratic Republic of Congo (where the number of cases infected with the Clade I strain is increasing). Preliminary analysis results show that there is no significant difference in lesion healing time between the tecovirimat group and the placebo group, that is, tecovirimat did not show significant efficacy for patients infected with the Clade I monkeypox virus strain in the Democratic Republic of Congo. But on the bright side, due to good care received by patients in both groups during the trial, the mortality rate was only 1.7%, lower than the mortality rate reported in previous cases in the Democratic Republic of Congo (3.6% or higher).

“These findings are disappointing, but they provide us with necessary information and strengthen the need to identify other treatment candidates for monkeypox, while we will continue to study the use of tecovirimat in other monkeypox populations,” said Jeanne Marrazzo, director of NIAID.

03

Domestic vaccines are on the way

Two large-scale monkeypox infections have reminded countries to be vigilant against this highly threatening virus.

The monkeypox vaccines recommended by the US Centers for Disease Control and Prevention (CDC) are:

1. JYNNEOS: Approved by the FDA in September 2019 for the prevention of smallpox and monkeypox in adults aged 18 and over who are determined to be at high risk of smallpox or monkeypox infection.
2. ACAM2000: Approved for smallpox immunization, and can be used for the prevention of monkeypox under the Emergency Use Authorization (EUA) agreement. It has more known side effects and contraindications compared to JYNNEOS.

At present, the development of monkeypox vaccines in China is also accelerating. On February 16, 2024, the official website of the China CDC Weekly published a review report titled “The Current Status and Progress of Monkeypox Vaccine Development,” revealing the latest progress in the development of monkeypox vaccines in China. The review mentioned: The domestically developed monkeypox mRNA vaccine is about to enter clinical trials.

【Editor’s note】The above content (~7500 words) is a quick translation of a Chinese article （2024-08-17）by DrugTimes team. To read the original article, please click here. All comments are warmly welcome. Many thanks!