Publications

Background and Epidemiology

The first case of human monkeypox was detected in 1970 in the Democratic Republic of Congo.¹ Monkeypox virus is a member of the Orthopoxvirus genus in the family Poxviridae. The virus is related to smallpox with a similar but less severe clinical presentation.² Two distinct clades of monkeypox have been identified: the West African clade, which is associated with milder clinical presentation and a case fatality ratio closer to 1%, and the Congo Basin (Central African) clade, which has been historically associated with greater human-to-human transmission and higher morbidity with a case fatality ratio as high as 10%.^1-4

Monkeypox is considered a zoonotic disease with transmission primarily occurring from animals, such as rodents and primates, to humans. However, limited sustained human-to-human transmission has been observed with up to 6 generations of human-to-human transmission being previously identified. Transmission of the virus can occur through contact with bodily fluids, wounds on the skin or internal mucosal surfaces, respiratory droplets, or contaminated objects. Consumption of inadequately cooked meat or other products from infected animals may also pose increased risks of infection.²

Through 2021, 15 countries on 4 continents have reported confirmed human monkeypox cases. The majority of cases are identified in countries where monkeypox is endemic, such as Nigeria, Central African Republic (CAR), Cameroon, and Democratic Republic of Congo (DRC). The DRC has reported cases this year.⁵ Until this year, imported cases have been reported in the United States, the United Kingdom, Israel, Benin, South Sudan, Singapore.⁶ In recent years, monkeypox has been reevaluated as an emerging public health threat as the frequency and geographic distribution of cases has increased, particularly in West Africa, where contact between susceptible populations and infected animals has increased due to factors such as deforestation and insecurity.⁴

Clinical Characteristics and Diagnosis

The incubation period for monkeypox can range from 5–21 days but usually falls within 7–14 days. Clinical presentation of monkeypox can be similar to chickenpox, caused by varicella-zoster virus.⁷ Symptoms usually begin within 5 days of infection with fever and chills, headache, muscle aches, back pain, fatigue, and swollen lymph nodes (lymphadenopathy), the latter symptom differentiating monkeypox from smallpox and chickenpox. About 1­–3 days, sometimes longer, after the initial onset of symptoms, a rash or lesions can appear, usually beginning on the face and spreading throughout the body, often to the extremities rather than the trunk. Notably, monkeypox lesions can appear on the palms of the hands and soles of the feet (75% of cases). Most individuals with monkeypox experience rash with 1 to >100 skin lesions, but some do not experience these lesions.²

In most patients, symptoms of monkeypox are usually self-limiting and spontaneously resolve within 14-21 days. However, symptoms can be severe and require medical care.² During a 2003 monkeypox outbreak in the US during which most patients appeared to contract the disease through direct or indirect contact with infected animals, 19 of 75 patients for which data were available were hospitalized. Of those, 2 developed severe disease, including a child with monkeypox-associated encephalitis. The case-fatality rate of monkeypox in Africa ranges from 1% to 10%, with the highest risk of death among children and cases caused by the Congo Basin (Central African) clade.⁸

Due to the similarity in clinical symptoms between monkeypox and chickenpox, healthcare providers often face difficulties in diagnosing cases based on clinical symptoms alone.⁹ Additionally, cross-protective antiviral immunity among adults who received childhood smallpox vaccination may lead to mild or no recognizable disease symptoms.¹⁰ Therefore, asymptomatic monkeypox infection and undetected circulation can occur.¹¹

Diagnosis often is made presumptively based on clinical presentation and disease progression. The preferred laboratory test is polymerase chain reaction (PCR) detection of viral DNA, with the best specimens being skin, fluid, or crusts collected directly from skin lesions, or biopsy when possible. PCR blood serum tests are not recommended. Additionally, antigen and antibody detection methods are not recommended due to the serological cross-reactivity among orthopoxviruses and the potential for false positive results among people recently or previously vaccinated against smallpox.²

Prevention and Treatment

Currently, there are no proven treatments specifically for monkeypox. Instead, cases of monkeypox can be treated with medical countermeasures designed for the closely related smallpox virus. There are currently 3 smallpox vaccines that could be used in the US, 2 of which are licensed for smallpox and the other could be used for smallpox under an investigational new drug (IND) protocol. The two licensed vaccines for smallpox are JYNNEOS^TM (also known as Imvamune or Imvanex) and ACAM2000®, of which JYNNEOS^TM is also licensed for monkeypox.

The JYNNEOS^TM vaccine is an attenuated live virus vaccine that is replication-deficient. It is administered subcutaneously in 2 doses, given 4 weeks apart.¹² Pre-exposure prophylaxis to monkeypox can be conferred by the smallpox vaccine JYNNEOS^TM. Data from Africa suggests that the JYNNEOS^TM vaccine is at least 85% effective in preventing monkeypox. This conclusion is supported by studies assessing the immunogenicity of this vaccine in humans and efficacy data from animal challenge studies.¹³ Additionally, the JYNNEOS^TM vaccine is considered to be a potential post-exposure prophylactic to minimize potential development and severity of disease. For post-exposure prophylaxis, the US CDC recommends that the first dose of the vaccine be given within 4 days from the date of exposure to prevent disease onset. If given between 4–14 days after the date of exposure, vaccination may reduce the symptoms of disease but may not prevent disease.¹⁴

The ACAM2000® vaccine is a replication competent live vaccinia virus vaccine that historically has been given to individuals with high-risk of exposure to poxviruses, such as laboratory staff working with variola virus, smallpox, and monkeypox, and is available for use as post-exposure prophylaxis for monkeypox under an expanded access IND protocol (in 2021, the US CDC Advisory Committee on Immunization Practices recommended the JYNNEOS^TM vaccine be used for personnel at high risk of occupational exposure instead of ACAM2000®).¹⁵ The vaccinia virus in this vaccine can be transmitted to contacts of the immunized individual. ACAM2000® is given as a single dose via the multiple puncture technique for percutaneous administration.¹² The vaccination schedule for post-exposure prophylaxis with ACAM2000® is the same as for the first dose of the JYNNEOS^TM vaccine.

The third smallpox vaccine in the US Strategic National Stockpile for smallpox is the Aventis Pasteur Smallpox Vaccine (APSV). It is a replication-competent vaccinia virus vaccine that could be used under an IND or emergency use authorization (EUA). This vaccine would only be used for smallpox if the licensed vaccines are unavailable or contraindicated.¹² It is unclear if this vaccine could be used for monkeypox.¹⁴ Other vaccines for monkeypox are in development, including VACΔ6 and LC16.¹⁵

The antivirals cidofovir and brincidofovir could be used to treat monkeypox, though there is insufficient data on their effectiveness for monkeypox treatment in humans. However, animal studies have demonstrated effectiveness against monkeypox in certain mammalian species.¹⁶ Brincidofovir and cidofovir work by inhibiting the viral DNA polymerase and have been used to treat other viral infections with varying levels of success.^17,18 Tecovirimat (ST-246) is another antiviral that could be used for monkeypox, though there is no data on its effectiveness in humans. Studies using tecovirimat in animal species have demonstrated its effectiveness in treating a variety of poxvirus-caused infections. Tecovirimat is included in the US Strategic National Stockpile but would need to be used under an IND.¹⁶ Tecovirimat is an inhibitor of the viral envelope protein p37 that blocks the ability of virus particles to be released from infected cells.¹⁹

Another potential treatment for monkeypox is vaccinia immune globulin (VIG). However, use of VIG for monkeypox or smallpox has not been tested in humans and there is no data on effectiveness against either virus. VIG for monkeypox treatment would need to be conducted under an IND. However, research is ongoing to develop new immune globulin-based treatments for poxviruses. CDC and their partners have developed 4 new monoclonal antibody mixes that appear to be effective against intracellular and enveloped virion forms of variola and monkeypox viruses in animals.¹⁵

Situation as of May 18, 2022

Recent cases in the United Kingdom (9 confirmed),²⁰ Spain (23 suspected), and Portugal (5 confirmed, 15 suspected)²¹ have renewed concern regarding the threat of monkeypox. While contact tracing is still underway, it is suspected that some cases may have occurred through community transmission. Additionally, it has been noted that an unusual number of the new cases have arisen among gay, bisexual, or other men who has sex with men (MSM).^3,22,23