2023 Volume 5 Issue 1 Pages 13-22
Human monkeypox (hMPX) is a smallpox-like disease caused by the monkeypox virus (MPXV) that belongs to the genus of Orthopoxvirus, in the family of Poxviridae. The natural hosts of MPXV are species of rodents, which are found in habitats in Central and Western Africa. Sporadic cases of patients with hMPX have been identified in central Africa since the discovery of the first cases in the early 1970s in the Democratic Republic of the Congo (DRC) and Western African countries. Since May 2022 (and up to the end of October 2022), more than 75,000 patients with hMPX have been reported, mainly in European and American countries. In the current outbreak, MPXV is transmitted from human to human, through close sexual contact, especially among men who have sex with men (MSM). Safe and effective third-generation smallpox vaccines, namely, LC16m8 and modified vaccinia virus Ankara (MVA), are effective in protecting vaccinees from hMPX. It is highly possible that immediate vaccination of close contacts with MVA or LC16m8, before disease onset, may be effective in reducing the severity of hMPX if infected. A proper vaccination program would reduce the scale of the current hMPX outbreak. Furthermore, hMPX in endemic areas should be prevented through mass vaccination programs with third-generation vaccines for those living in these regions. Notably, the current hMPX outbreak is mainly associated with community-specific MSM circumstances. Special consideration should be given to patients with hMPX, who must be protected from societal discrimination.
Human monkeypox (hMPX), a smallpox-like disease caused by infection with the monkeypox virus (MPXV), is endemic to Central and Western Africa. A large and global outbreak of hMPX has arisen since May 2022, due to the introduction of MPXV to the gay community. More than 75,000 patients have been diagnosed with hMPX, mainly in European and American countries, as of the end of October 2022. Third-generation smallpox vaccines, such as modified vaccinia virus-Ankara (MVA) and LC16m8, are effective. These vaccines should be offered to people at risk of MPXV infection.
Unexpectedly, large-scale outbreaks of emerging viral infections caused by viruses spilled over from nonhuman mammals to humans have occurred in the last 20 years. The cases of such outbreaks include severe acute respiratory syndrome (SARS) in 2002–2003 , Middle East respiratory syndrome (MERS) discovered in the Middle East in 2012 , ebolavirus disease (EVD) in Western Africa in 2014–2015 , and the currently circulating coronavirus disease-2019 (COVID-19) that originated in Wuhan, China and spread to other regions of the world since late 2019 , followed by the recent outbreak of the human monkeypox (hMPX), an infectious disease in humans caused by the infection with monkeypox virus (MPXV), since May 2022 . SARS, MERS, and COVID-19 are caused by SARS-coronavirus-1 (SARS-CoV-1), MERS coronavirus (MERS-CoV), and SARS-coronavirus-2 (SARS-CoV-2), respectively. SARS-CoV-1, SARS-CoV-2, and ebolavirus are viruses of the bat species. The natural host of MERS-CoV is a dromedary, which inhabits the Middle East and Northern Africa. Human MPX is a smallpox-like disease caused by MPXV, which belongs to the genus of Orthopoxvirus, in the family of Poxviridae (Fig. 1A and 1B
The skin lesions of the patients with variola and hMPX are shown (A, B). The skin lesions of a nonhuman primate infected experimentally with MPXV Zr-599 (Congo Basin clade of the MPXV) is also shown (C). Differentiation of the hMPX-associated skin lesions from those of the other orthopoxvirus infections including variola is difficult without virologic tests. (A) and (B) are made available by Dr. Takeshi Kurata, National Institute of Infectious Diseases, Tokyo, Japan, and Professor Jean-Jacques Muyembe Tamfum, Institut National de Recherche Biomédicale, Kinshasa, DRC, respectively. hMPX: human monkeypox; MPXV: monkeypox virus.
Human patients diagnosed with hMPX for the first time in history were discovered in the Democratic Republic of the Congo (DRC) in 1970 [7,8,9,10]. Since its discovery, sporadic outbreaks of hMPX have occurred in Central Africa, especially in the DRC. Human MPX cases have also been reported in Western African countries including Nigeria. Furthermore, hMPX cases have also arisen in non-endemic regions, such as the United Kingdom (UK), the United States of America (USA), and Singapore [11,12,13,14]. In 2003, there was a relatively large-scale outbreak of hMPX in the USA, in which more than 70 patients had laboratory-confirmed, clinically and epidemiologically suspected hMPX . The 2003 multistate outbreak of hMPX in the USA was caused by MPXV introduced to the USA by the shipment of some species of rodents from Ghana, Africa. In this 2003 hMPX outbreak in the USA, human-to-human had not been reported. The number of patients with hMPX in the non-endemic regions had been quite limited. This suggests that the risk of human-to-human infection is limited.
A very large outbreak of hMPX has occurred mainly in countries/regions of Europe and the American continent, including the USA and Canada. Moreover, hMPX has also been identified in other regions of the world, including Africa, the Middle East, Asia, and Oceanian countries, although the number of cases has been fewer than those in Europe and the American continent.
This review article focused on the hMPX outbreak that started in Europe in May 2022. The following aspects were described and discussed: the nature and characteristics of MPXV, clinical presentations of patients with hMPX, mechanisms of human MPXV infection and the current large-scale outbreak of hMPX, preventive measures to combat and control the current outbreak, and ethical issues.
There are two genetically distinct clades of MPXV, namely, the West African and the Congo Basin clades [16, 17] (Table 1). The case fatality rate of patients with hMPX caused by the Congo Basin clade was higher than that of patients with the West African clade. The higher virulence of the Congo Basin clade than that of the West African clade is supported by animal studies in the prairie dog and nonhuman primate models [16, 18]. In the hMPX outbreak that occurred in the Central African Republic, two of 10 patients with hMPX, infected with MPXV of the Congo Basin clade, died . In the hMPX outbreak that occurred in the USA in 2003, 71 cases of hMPX were caused by the West African clade . In the USA outbreak, none of the patients died, and human-to-human transmission was not reported. In contrast, 19,273 suspected hMPX cases and 292 deaths from the disease were reported in the DRC from 2000 to 2015, with a case fatality rate of 1.52% . This evidence suggests a difference in virulence between the Congo Basin and West African clades of MPXV. However, 5 of 40 retrospectively identified patients with hMPX were infected with West African clade and hospitalized between September 2017 to September 2018 were fatal cases . This suggests that there may be fatal cases among patients infected with the West African clade.
MPXV: monkeypox virus; hMPX: human monkeypox; DRC: Democratic Republic of the Congo.
A laboratory diagnostic test to identify patients with suspected hMPX aims to detect the pathogen from materials collected from maculovesicular lesions, the oral cavity, blood and other types of bodily fluids, using methods, such as virus isolation, polymerase chain reaction (PCR), real-time quantitative PCR, and isothermal loop-mediated amplification (LAMP) [22,23,24,25]. If cytopathic effects appear in the cells inoculated with the specimens, an identification process is required. A quantitative real-time PCR designed to specifically detect MPXV genome and differentiate the West African and Congo Basin clades was developed . The target was the A-type inclusion body (ATI) gene of the MPXV, because there is a specific nucleotide sequence in the ATI gene that differs between the Congo Basin and West African clades. Similarly, a LAMP assay was also developed to detect MPXV and specifically differentiate the Congo Basin clade from the West African clade . In the LAMP assay, the primers are designed to detect 1) both clades of the MPXV (COM-LAMP), 2) only the Congo Basin clade (C-LAMP), and 3) only the West African clade (W-LAMP). The target genes are the nucleotide sequences of the ATI gene shared by both the Congo Basin and West African clades, namely, the Congo Basin MPXV-specific D14L gene , and the West African MPXV-specific partial ATI gene . Quantitative real-time PCR to detect the MPXV gene an specifically differentiate the Congo Basin and West African clades of MPXV by targeting another gene has also been developed . In Japan, the standard laboratory test for the diagnosis of hMPX is recommended by the National Institute of Infectious Diseases, Tokyo, Japan (NIID, https://www.niid.go.jp/niid/images/lab-manual/monkeypox20220805.pdf, accessed on 30th October 2022).
Immune responses of the neutralizing antibodies to MPXV induced in infected patients can be detected using neutralization antibody detection assay. The IgG and IgM antibodies induced to MPXV can also be detected with enzyme-linked immunosorbent assay (ELISA) and immunofluorescent assay (IFA), in which MPXV antigens are used. However, any types of antibody to MPXV are cross-reactive with the other orthopoxviruses, such as the variola virus and the vaccinia virus. Therefore, once a significant increase in the antibody titer to MPXV or other orthopoxviruses is demonstrated between the acute and convalescent phases, it would be possible to diagnose hMPX based on the clinical presentations and epidemiological information.
Symptoms of fever, lymphadenopathy, respiratory symptoms, such as throat pain and cough, and purulent fluid-filled skin papulovesicular lesions generally appear after an incubation period of 7–21 days (Fig. 1B). Most patients with hMPX experience hMPX-associated symptoms between 10–12 days post-infection. Lymphadenopathy, such as swollen lymph nodes, usually occurs in approximately 90% of patients.
Human-to-human infections usually occur through close contact between humans. Nosocomial infections, in which medical care providers are infected from patients with hMPX, especially in the absence of stringent infection control, have also been reported [13, 19, 26].
Papulovesicular lesions usually appear on the extremities and peripheral areas first, and then, progressively spread to the central areas. In the global 2022 outbreak, the mode of human-to-human infections is through close sexual contact, and thus, skin lesions tend to appear in the genital and anal areas in approximately half of the patients. Furthermore, there are patients with mild cases of hMPX who presented with only several papulovesicular lesions, probably because the outbreak was caused by the West African clade.
The clinical course and symptoms of nonhuman primates that were experimentally infected with MPXV have been reported [16, 27, 28]. The symptoms included loss of appetite, decreased food consumption, and decreased activity. Papulovesicular rashes appeared from days 7–9 after MPXV-inoculation (Fig. 1C). The general condition deteriorated and activity decreased from days 7–11 after MPXV-inoculation. In severe and fatal cases, body temperature tended to drop continuously. The incubation time for nonhuman primates is approximately 10 days after experimental virus inoculation.
The first case of hMPX was discovered in an 8-month-old infant who had not been vaccinated against smallpox in the DRC, and who suffered from a smallpox-like disease in the village of Bokenda in Basankusu Province . MPXV was isolated from the infant’s skin lesion.
Since the discovery of hMPX in the DRC, relatively large and sporadic outbreaks of hMPX have occurred. Since smallpox vaccination programs have ceased, the number of hMPX cases has increased over time, although the transmission capacity was not sufficiently high to maintain the spread of the outbreak.
In 2005, a relatively small-scale outbreak of hMPX, in which 18 patients were confirmed in total, was identified in the Unity State in Sudan . Specimens obtained from one patient were tested for virus isolation and other orthopoxvirus-associated virologic assays. The results revealed that the causative agent was the Congo Basin clade. The Congo Basin clade -associated outbreaks have been reported not only in the DRC and Sudan, but also in neighboring counties, Gabon, and the Central African Republic [19, 29,30,31,32,33,34,35].
The first case of hMPX caused by the West African clade was identified in Liberia, Sierra Leone, and Nigeria, in 1970 . In 1991, hMPX was reported in a child, in Cameroon . Recently, the scale of hMPX outbreaks in Nigeria has escalated. Although the exact mechanism contributing to the increase in the number of hMPX cases diagnosed in Nigeria is unknown, the increased accessibility to diagnostic tests, increased awareness of hMPX in the community, and an increased number of unvaccinated populations may have contributed to larger hMPX outbreaks.
A relatively large outbreak of hMPX, in which hMPX patients were reported from multiple US states including Missouri, Kansas, Ohio, and others, occurred in 2003. [15, 37]. At the time, more than 70 patients were diagnosed with or suspected of having hMPX, although MPXV does not circulate in nature in the USA. It was later revealed that patients with hMPX in that outbreak were infected with MPXV through close contact with prairie dogs infected with the MPXV, including being bitten by the sick prairie dogs. All sick prairie dogs were raised by a breeder in Texas, and shipped to pet shops in multiple states in the USA, before showing symptoms. It was likely that the prairie dogs were infected with MPXV from some species of rodents, such as African dormice and Gambian giant rats imported from Ghana. During the outbreak, there were no documented cases of human-to-human transmission. The 2003 USA MPX outbreak was caused by the West African clade. Furthermore, that outbreak was the largest in history until the global 2022 hMPX outbreak (Fig. 2).
The epidemiological curve of patients with hMPX in the USA (A). The number of hMPX cases started to increase since May 2022, reached a peak in August, and decreased from September 2022. The MVA vaccination program was started in May 2022. Approximately 1 million people have received at least the first dose of the MVA (B). (A) and (B) are based on the number of hMPX cases and the people who received MVA vaccines reported by the US CDC. (https://www.cdc.gov/poxvirus/monkeypox/response/2022/index.html, accessed on 1st November 2022). hMPX: human monkeypox; MVA: modified vaccinia virus-Ankara; CDC: Centers for Disease Control and Prevetion.
Imported cases of hMPX have been reported in Europe, the USA, and Singapore [11,12,13,14, 38]. Most imported cases were from Nigeria, and the main causative virus was the West African clade of the MPXV.
Human MPX cases occurred mainly in Europe in the very early phase of the 2022 outbreak, and then, the infection spread to Europe, Australia, the USA, Canada, and other countries, including Japan. More than 75,000 cases of hMPX have been diagnosed at of the end of October 2022. Approximately 95% of the patients with hMPX were male. Patients, who disclosed their sexual orientation, were the persons of gay, bisesual, and men who have sex with men (MSM). These findings indicate that MPXV is mainly circulating in the gay, bisexual, and MSM community populations in the current outbreak.
The epidemiological curve has been published by the US Center for Disease Control and Prevention (CDC, https://www.cdc.gov/poxvirus/monkeypox/response/2022/index.html), European CDC (https://www.who.int/europe/emergencies/situations/monkeypox/situation-reports), and WHO (https://www.who.int/emergencies/situations/monkeypox-oubreak-2022). The numbers of new cases in the EU countries and the USA reached their highest in July and August 2022, respectively, and has since decreased thereafter. The current outbreak was caused by the introduction of a single MPXV from an unidentified index patient with hMPX, who may have been infected with the virus in Nigeria. The phylogenetic tree of the MPXV genome sequence associated with the global 2022 hMPX-outbreak-related MPXV is shown in Fig. 3 . The mechanisms leading to the largest hMPX outbreak, with more than 75,000 patients, are as follows. 1) MPXV was introduced into the gay, bisexual, and MSM communities. To maintain a steady spread of MPXV in these communities, the number of sexual partners per person may have been high. 2) The outbreak was caused by the West African clade, which is less virulent than the Congo Basin clade. Individuals infected with MPXV showed very mild or minimal symptoms. This may have led to the continuation of sexual close contact with partners, and unconsciously passing on the MPXV infection. 3) An increase in international travel may be another factor for the multi-country and international spread of hMPX. These factors have led to an extraordinarily large MPXV spread in terms of the number of patients and geography.
Phylogenetic analysis of the MPXV viral genome sequences associated with the 2022 worldwide outbreak. This figure is identical to Fig. 1 in a research article published previously  and reproduced under a Creative Commons Attribution 4.0 International License. The phylogeny was analyzed using the 2022 hMPX outbreak-related MPXV genome sequences publicly released on 20 May 2022 by Portugal, as well as those released in the National Center for Biotechnology Information (NCBI) before 27 May 2022 with 15 sequences in total. Clade 1 in figure (a) is the Congo Basin clade of the MPXV, while Clade 2 and Clade 3 (a) are the West African clade of the MPXV. The MPXV sequences associated with the 2022 outbreak are clustered into the B1 lineage in Clade 3 (b). The authors of the referenced article stated that the 2022 global hMPX outbreak was most likely of a single origin . MPXV: monkeypox virus; hMPX: human monkeypox.
Smallpox vaccines are effective against MPX in nonhuman primates [27, 40]. First-generation smallpox vaccines might be effective against hMPX. However, first-generation smallpox vaccines have severe side effects including death, at a relatively higher incidence. Therefore, first-generation smallpox vaccines should not be used for hMPX at current circumstances.
Two types of highly attenuated smallpox vaccines, with minimal side effects, have been developed (Table 2). These include the MVA and LC16m8 vaccines, which are derived from the vaccinia virus Ankara and the vaccinia virus Lister, respectively.
MVA: modified vaccinia virus-Ankara.
MVA has been developed by the procedures of multiple ( >500) passages of vaccinia virus-Ankara in primary chicken cells. The development procedures made MVA replicate well only in primary chicken cells, but not in other cells; i.e. MVA has the characteristics of cell selectivity. When MVA was developed, variola eradication was in its final stage. Therefore, the efficacy of MVA in preventing variola infection in humans has not been evaluated. It was reported that two inoculations of nonhuman primates with MVA prevented the monkeys from MPX . MVA has been stockpiled in some countries, such as Canada and the USA, as well as some EU countries, in case of a possible outbreak of variola by an intentional release of the infectious variola virus as bioterrorism.
LC16m8 has been developed through multiple passages (36 times) of vaccinia virus Lister in primary rabbit kidney cells at a lower temperature of 30°C. LC16m8 has the characteristic of cell selectivity, which enables the LC16m8 to replicate well in primary rabbit kidney cells, but not in other cells, such as Vero cells. Furthermore, LC16m8 is temperature-sensitive, as it cannot replicate well at 41°C in the primary rabbit kidney cells, whereas Lister replicates well at this higher temperature . LC16m8 has very low neurovirulence compared to Lister. In a clinical trial, more than 100,000 children were immunized with LC16m8, and no severe side effects, including fatality, were reported in this trial. Thus, LC16m8 is considered safe. The efficacy of LC16m8 against smallpox has not been evaluated because smallpox was nearly eradicated from the globe when LC16m8 was developed. Therefore, the efficacy of LC16m8 was evaluated for the protection of monkeys from lethal MPXV infections . The monkeys immunized with LC16m8 at 5 weeks, 6 months, and 12 months before lethal MPXV inoculation showed no MPXV-associated symptoms except for an ulcerative skin lesion at the MPXV inoculation site [27, 28]. Furthermore, vaccination of nonhuman primates just 3 and 7 days before MPXV inoculation induced a relatively strong protective efficacy . Monkeys infected with MPXV followed by a post-exposure vaccination of LC16m8 also showed less severe MPXV disease than the non-vaccinated controls, suggesting the efficacy of post-exposure vaccination in reducing MPX severity.
LC16m8 has been produced regularly and stockpiled in Japan as the preparedness for a possible event of bioterrorism, in which the variola virus would be used. Thus, it is rational that LC16m8 should be used against hMPX in high-risk populations in Japan.
Antiviral agents against the variola virus have been developed by pharmaceutical companies. One of the drugs against variola is ST-246 (Ticovirimat, SIGA Technologies), which inhibits the replication of a wide spectrum of orthopoxviruses, including the variola virus and MPXV . ST-246 inhibits viral replication by targeting the activity of the viral p37 protein, a 37 KDa peripheral membrane protein encoded by the F13L gene . Orothopoxviruses, including MPXV, have three forms: the intracellular mature virion (IMV), intracellular enveloped virion (IEV), and extracellular enveloped virion (EEV). EEV plays an important role in the replication and dissemination of orthopoxviruses, including MPXV in vivo. Therefore, the viral p37 protein is closely associated with the virulence of MPXV and its pathophysiology in patients with hMPX . The F13L-p37 protein is an EEV-associated membrane protein, as are the B5R, A34R, A36R, A56R, and A33R membrane proteins . ST-246 shows its therapeutic efficacy through the mechanism of action of inhibiting the activity of p37, resulting in the reduced production of EEV in vivo.
The use of ST-246 has been approved for patients with hMPX in some EU countries and the USA. Human MPX-associated symptoms generally appear after the incubation period following exposure. According to a study on MPXV infection in nonhuman primates, the viremia level of MPXV-infected nonhuman primates peaked when symptoms first appeared . Antiviral agents induce efficacy by inhibiting MPXV replication. Therefore, the efficacy of the drugs would be limited if the patients were administered the drugs after the disease onset. ST-246 should be administered as soon as possible after disease onset [43, 45,46,47,48]. Furthermore, the use of ST-246 in close contacts of patients with hMPX, before disease onset, may be efficacious in reducing the severity of hMPX if they become infected.
The most effective preventive measure is vaccination of individuals at risk of MPXV infection. The governments of the USA and some EU countries have made available the MVA to people at risk. Approximately one million people have already received at least the first dose of the MVA vaccination as of the end of October 2022, while a second vaccination of MVA is required for completion of the vaccination. Individuals at risk should be advised about vaccination. Once a person is diagnosed with hMPX, it would be ideal to recommend that their close contacts be vaccinated as soon as possible.
Adequate advice to the community, an appropriate diagnostic system establishment, and an appropriate vaccination program for people at risk may make it possible to eliminate the global 2022 hMPX outbreak.
People living in an environment in which MPXV is present and who have a lifestyle that exposures them to MPXV are at risk of being infected with MPXV. After the cessation of the smallpox vaccination program in the late 1970s, sporadic outbreaks of hMPX have continued to occur in MPXV-circulating areas. The incidence of hMPX may be reduced if vaccination programs against hMPX using third-generation smallpox vaccines are initiated properly and regularly. The case fatality rate of patients treated with hMPX in the DRC is relatively high. The fatal cases of hMPX in endemic areas can also be minimized by mass vaccination for at-risk individuals. Controlling hMPX outbreaks in the endemic areas may also help with controlling hMPX in the non-endemic areas, by reducing the number of imported cases of hMPX.
In the current outbreak of hMPX, people at high risk of MPXV infection, including the gay, bisexual, and MSM communities should not be discriminated against in society. People with infectious diseases, including hMPX, should be treated equally as those who are free from the disease.
We live in an environment in which emerging viral infections do occur. It is expected that there will be unexpected events, such as large-scale outbreaks of emerging viral infections in the future, as in the case of the 2022 global hMPX outbreak and the COVID-19 pandemic.
Vaccines are powerful tools against emerging viral infections. Most emerging viral infectious diseases, including hMPX, are zoonotic infectious diseases, indicating that these viral infections are unlikely to be eradicated. The preparation of vaccines against infectious diseases is, therefore, necessary.
Highly attenuated smallpox vaccines, such as the MVA and LC16m8, have been developed and licensed for use against smallpox. Vaccination programs for people at risk of hMPX should be advised to be vaccinated with the LC16m8 vaccine in Japan, although the number of patients with hMPX is quite limited.
During the global 2022 outbreak, the elimination of hMPX in non-endemic regions is possible. To achieve this, the following programs are necessary: access to diagnostic tests for people suspected of having hMPX, proper treatment of infected patients including the use of antiviral agents against hMPX, and vaccination opportunities not only for people at risk of the hMPX as a pre-exposure vaccination but also for close contacts of patients with hMPX as a post-exposure vaccination.
Finally, the human rights of patients with hMPX should be protected. Although in the global 2022 outbreak, patients with hMPX have mostly been from the gay, bisexual, and MSM communities, they should never be discriminated against. This highlights the importance of human rights protection. In this current global outbreak of hMPX, elimination is the aim. This may be possible in society, if all the patients with hMPX are respected and their human rights are protected.
We have experienced a quite large and global outbreak of hMPX in 2022. The mechanism of having such large hMPX outbreak was that MPXV acted as a pathogen of sexually transmitted diseases in a gay, bisexual, and MSM community. The smallpox vaccines, which are classified to the third-generation smallpox vaccines (MVA and LC16m8), have been stockpiled for a possible bioterrorism, in which infectious variola virus was used. Furthermore, antiviral drug, ST-246 (Tecovirimat) has been developed against variola in a variola-associated bioterrorism. Although these vaccines and the drug have not been developed and stockpiled for patients with hMPX, it is quite fortunate that these vaccines and the drug are effective not only against variola but also MPXV infections. Because MPXV is a zoonotic virus and is circulating in nature in central and western Africa, the eradication of hMPX is impossible, but an elimination of hMPX in the current outbreak is possible. A proper vaccination program against hMPX in the hMPX-endemic areas is recommended using the third-generation smallpox vaccines, MVA and LC16m8. Finally, human rights of patients with hMPX should be protected, although the disease has spread in a specific community of gay, bisexual, and MSM.
This author does not have any conflict of interest associated with this manuscript. This author served as an observer for the Advisory Committee for Variola Virus Research established by the WHO since 2010.
This author thanks all the staff involved in the research on MPXV infection and LC18m8 at the National Institute of Infectious Diseases. Some data described in this review article were obtained from experiments conducted with financial support from the Ministry of Health, Labour, and Welfare of Japan.