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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 12  |  Issue : 5  |  Page : 211-216

Monkeypox virus infection – Evolution, molecular biology, epidemiology, clinical features and management aspects


Department of Pediatrics, Institute of Child Health, Sir Ganga Ram Hospital, New Delhi, India

Date of Submission08-Sep-2022
Date of Decision09-Oct-2022
Date of Acceptance11-Oct-2022
Date of Web Publication31-Oct-2022

Correspondence Address:
Dinesh Kaul
Department of Pediatrics, Institute of Child Health, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi - 110 060
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cmrp.cmrp_98_22

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  Abstract 


Monkeypox virus (MPXV) infection has lately emerged as a new public health problem across 100 countries. Surging cases of MPXV infection in non-endemic countries prompted the World Health Organization to declare it a public health emergency in July 2022. The virological and clinical resemblance to eradicated smallpox disease has generated new scientific interest. This DNA orthopoxvirus primarily harbouring in squirrels, rats and non-human primates has led to infection in the human population. A recent surge of cases has been seen across 16 countries, with a clustering of cases in bisexual/homosexual men. The virus spreads through close contact with infected individuals with prodromal symptoms of fever and myalgia. A rash appears after 1–3 days of fever. There is presence of vesicular rash over the face, hands, feet and genital areas, and associated lymphadenopathy. Although no specific antiviral drugs directed against MPXV are available, tecovirimat developed against smallpox infection can be used and is effective. A synthetic analogue drug of cidofovir, i.e., brincidofovir has been evaluated for MPX patients in United Kingdom. A preventive strategy in close contacts may be offered through smallpox vaccines such as ACAM2000 and JYNNEOS. Epidemiological data from Africa suggest that smallpox vaccines provide 85% efficacy in preventing MPXV cases. Vaccinia immunoglobulin intravenous (VIGIV) has been used in immunocompromised patients with T-cell defects as prophylaxis where the use of vaccines is contraindicated. VIGIV can be used as a treatment modality for smallpox or non-variola infections like monkeypox in an outbreak, although the efficacy data are lacking.

Keywords: Monkeypox, orthopoxvirus, public health emergency, smallpox


How to cite this article:
Kaul D, Yadav K, Bansal A. Monkeypox virus infection – Evolution, molecular biology, epidemiology, clinical features and management aspects. Curr Med Res Pract 2022;12:211-6

How to cite this URL:
Kaul D, Yadav K, Bansal A. Monkeypox virus infection – Evolution, molecular biology, epidemiology, clinical features and management aspects. Curr Med Res Pract [serial online] 2022 [cited 2022 Nov 27];12:211-6. Available from: http://www.cmrpjournal.org/text.asp?2022/12/5/211/359947




  Introduction Top


Monkeypox (MPX) infection has emerged as a new public health concern following reporting of cases across 100 countries from May 2022 onwards. Earlier, before April 2022, cases were exclusively reported from seven endemic countries of East or Central Africa.

The World Health Organization (WHO) has already declared MPX as a public health emergency of international concern (PHEIC) on 23rd July, 2022 in the backdrop of the surge of confirmed cases across all five major continents of the world.[1] Recent pandemics of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection (2020), Ebola virus infection (EBOV, 2019), Zika virus infection (2016), EBOV (2014) and H1N1 influenza infection (2009) have been other diseases where the WHO declared them as PHEIC.

The scare of MPX cases being reported has alerted and reminded the public health authorities about an eradicated disease, i.e., smallpox (variola), which resembles MPX in some virological, clinical and therapeutic aspects.[2]

All the countries have discontinued the routine vaccination against smallpox by 1982, as the WHO had declared global disease eradication in 1980. There is a large population in the age group of 0–42 years, i.e., those who were born after 1980–1982 are susceptible to smallpox or MPX infection.


  Molecular Biology Of The Monkeypox Virus Top


MPX virus (MPXV) is a 200–250 nm double-stranded DNA (dsDNA) virus, (genus: Orthopoxvirus) belonging to the poxvirus family of viruses (Poxviridae). Other viruses like MPXV are the variola, vaccinia and cowpox groups of viruses. The viruses are brick-to-oval dumbbell-shaped enveloped viruses with inner nucleocapsid core containing dsDNA genome (200 kb long) and enzymes required for viral entry, uncoating and replication. The outer envelope has the antigenic epitopes for viral entry into the host cell [Figure 1].
Figure 1: Electron micrograph image depicting monkeypox virus particles, isolated from a clinical sample (thin section from human skin) from the 2003 prairie dog outbreak. On the left are mature oval-shaped virus particles, and on the right are immature crescents and spherical particles of immature virions. Adapted from CDC, Credit: Cynthia S Goldsmith, Russell Regnery (2003) https://phil.cdc.gov/Details.aspx?pid = 22664

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Before the present surge of infection, the circulating clades of viruses were of two types (Western and Central African clades), originating from the Democratic Republic of the Congo (DRC, previously Zaire) in the African subcontinent. The Central African clade (Congo Basin) has been historically responsible for severe disease and mortality and may be more transmissible.

A comprehensive analysis of genomic variability of MPXV among humans (60 samples) has been conducted by Kugelman et al. in 2 years from 2005 to 2007. A combination of factors such as genomic destabilisation and polymorphism was responsible for the evolution of MPXV strains in one of the districts of DRC. The authors identified four lineages (A, B, C and D) of the MPXV clades from the isolated samples. Various epidemiological and viral factors have been attributed to the infection in the regional population.[3]

In a brief communication presented recently by Isidro et al. have identified the phylogenetic characterisation of the 2022 muti-country outbreak of MPXV infection. They have characterised the viral genome sequence with shotgun metagenomic analysis. They believe that this outbreak is due to MPXV infection due to clade 3 and the outbreak has a single origin. The virus had adapted to humans with certain adaptations in ongoing microevolution. There is also a role of host mutation APOBEC3 in viral evolution according to the authors.[4]


  Natural Host Of Monkeypox Virus Top


It may be uncertain to define who is the original natural host for these viruses. They have been identified in various wild animals such as squirrels, Gambian rats and non-human primates like African black macaques. Before the 1970s, no human cases had been identified.

They were first identified in Congolese monkeys which had been exported to Copenhagen from Singapore (1958). Some of these cynomolgus macaques (20%–30%) developed non-fatal smallpox-like lesions during their captivity.[5] The lesions erupted from 51 to 62 days after their arrival. However, none of the macaques died.

Subsequently, MPXV infections have been reported from various animal research laboratories in Philadelphia (MSD 1959), Washington (Walter Reed Army Institute of Research 1962) and Zoological Garden (Rotterdam 1964).[6]

Animal hosts, which act as reservoirs of MPXV, include a wide range of rodents and non-human primates.[7]


  Human Infection With Monkeypox Virus Top


In 1970, the first few cases of infection in humans were reported in various regions of DRC, Liberia and Sierra Leone. All six patients were unvaccinated against smallpox and were initially diagnosed with smallpox infections. Most of the victims were infants and children. Only one adult had exposure to handling monkey meat. The exact causal effect relationship with monkeys or handling monkey skin/hides or meat could not be established in these initial cases.[5]

Subsequently, cases have been reported from tropical rainforests in various African countries after 1980 when global eradication of smallpox had been achieved and smallpox vaccination was stopped.

An outbreak of MPXV infection occurred in 1996–1997 in DRC with a lower-case fatality rate (3%) and a high attack rate. About 500 suspected and 300 confirmed cases were reported with a concurrent outbreak of varicella infection, which possibly accelerated the transmission of cases.[7]

In countries outside Africa, the first outbreak occurred in the USA (2003). The culprits were the pet prairie dogs, who were kept with Gambian pouched rats and dormice. This led to various (70) MPXV cases in the USA.

However, recent cases after May 2022 have been reported across different countries in Europe, America and Asia.


  Epidemiology Of Monkeypox Virus Infection Top


There have been about 69,244 confirmed cases of MPXV reported globally to date (4 October 2022) from the start of January 2022. Most of the cases (68,536) have been reported in 100 countries outside of the African subcontinent, seven countries have reported about 706 cases of MPX in this year. Most of the cases have been reported from Portugal, Spain, Belgium, the Netherlands, Germany, France, Italy, Switzerland, USA, UK, Canada and Peru.[8] The cases reported from endemic countries such as DRC (190), Ghana (91), Malta (33) and Central African Republic of the Congo (9) are far less or could be under-reported by the health authorities.

A recent analysis of data across 16 countries has reported a surge in cases, especially in bisexual or homosexual men (98% of the 528 cases). This explains the prolonged skin-to-skin or mucosal contact with the lesions in the infected individuals. About 41% of the infected individuals have human immunodeficiency virus (HIV) coinfection. The transmission was attributed to sexual activity in 95% of the cases.[9] There is no clear evidence to suggest that the virus can be directly transmitted through seminal fluid or vaginal secretions, however, vertical transmission and foetal deaths have been reported.[10] The transmission of the MPXV infection through the respiratory droplet or aerosol route or through fomites is possible but it is less likely to occur as well in the smallpox virus or SARS-CoV-2 infection.

Clinical manifestations

The average incubation period usually is from 6 to 13 days; however, it may range from 5 to 21 days. The infective period may initially start with non-specific viral fever-like prodromal symptoms followed by the appearance of rash or skin eruptions within 1–3 days of fever.[11]

The clinical features of the MPXV infection may be like smallpox. Adults may present with systemic manifestations such as a history of fever, malaise, body aches, headache and presence of lymphadenopathy on physical examination. This is followed by the development of a vesicular rash over the face, hands and feet. The lesions may resemble variola-like skin lesions, with lesser number of skin lesions (<10 lesions). The vesicular lesions may occur over the oral, perioral areas (70%) and anogenital areas (30%). The rashes may also develop over the conjunctiva (20%) and cornea. The rash changes its texture from macular to papular, vesicular and finally crust formation, which finally dries and falls off.[9] The above mentioned study may reflect a biased picture as most of the patients had a history of sexual contact and 98% were gay or bisexual men.[9]

MPX is not primarily transmitted through genital secretions like in cases of HIV infection, genital herpes simplex, syphilis or gonorrhoea. However, it may be transmitted through intimate sexual contact with the lesions and personal contact with shared bedding/clothing.[11]

Differential diagnosis

In the community setup or when there is no history of close heterosexual or homosexual contact with sexual partners, a close differential may be chickenpox, varicella zoster, disseminated herpes, molluscum contagiosum and disseminated fungal infection. A history of occupational exposure to poxviruses may be taken.

In people with exposure to multiple sexual partners presenting with ulcerative genital or anogenital lesions, various sexually transmitted diseases such as syphilis, gonorrhoea/disseminated gonococcal infections, lymphogranuloma venereum, disseminated herpes and chlamydial infection need to be considered.

Diagnostic methods

In the post-smallpox eradication scenario, the common clinical differential illnesses manifesting as rash should be considered. Varicella infection, primary or secondary syphilis, bacterial impetigo-like lesions and drug rash should be considered. Lymphadenopathy is a significant sign in the early prodromal phase, before the development of skin or genital lesions, which is unlikely a feature of smallpox or varicella (chickenpox) infection.

The skin vesicular lesions and oral or genital ulcers may be cultured for viral cultures if possible. The samples may be sent to designated referral laboratories (labs). However, the tissue material or vesicular fluid may be sent for molecular amplification methods for MPXV or varicella. Most of the designated virology referral labs will have facilities for polymerase chain reactions for amplification of the MPXV microbial DNA. The samples should be refrigerated and transported on ice at the earliest. The role of transport media for placement of skin crusts, swabs or biopsy tissue is not recommended for MPXV according to the WHO guidelines. It is also important to provide patient demographic information such as the type of sample, when collected, date of onset of fever, rash and the current status of rash.[11]

Another method of detection of orthopoxvirus can be by immunohistochemical or electron microscopy testing. A confirmed case of the infection by being detected by isolation of MPXV in cultures from clinical specimens.[12]

Serodiagnosis based on antigen or antibody detection is not helpful as the antibodies are cross-reactive with other pox viruses and are not recommended. Detection of anti-orthopoxvirus immunoglobulin M antibody from 4 to 56 days after the onset of rash may be possible.[11]

Management guidelines

MPXV infection unlike other poxvirus infections like smallpox or vaccinia is not very contagious or transmissible. It is advisable to manage moderate-to-severe illness patients in isolation wards with personal protective equipment kits to be worn by health-care individuals. The guidelines provided by local or country-specific occupational safety and health should be adhered to strictly. People who have mild symptoms and do not require hospitalisation should follow policy guidelines for isolation and prevention.[13]

Therapeutic modalities for treatment

Interim guidelines have been issued by the Centers for Disease Control and Prevention (CDC) for the treatment of MPX cases. Mild cases without any risk factors as diabetes and hypertension may be treated symptomatically at home (in isolation). However, patients with severe disease (e.g., haemorrhagic disease, confluent skin/mucosal lesions, sepsis, encephalitis, immunocompromised individuals, leukaemia, lymphoma, post-bone marrow transplantation and solid organ transplant patients, severe gastroenteritis with nausea/vomiting, children <8 years, pregnant women and moderate–severe immunosuppression) require hospitalisation on a priority basis.

There are no specific approved antiviral agents directed against MPXV infection available at present. Various antiviral agents and immunoglobulins which have been developed for smallpox viral infection may prove to be effective. However, data regarding clinical trials for tecovirimat (TPOXX) and vaccinia immune globulin intravenous (VIGIV) is not available in context of MPXV infection.


  Tecovirimat (TPOXX, ST-246) Top


This antiviral agent has been developed during the smallpox infection era and post-eradication phase. This US Food and Drug Administration (FDA) approved drug (2018) is available across different countries under various names. This agent is effective against various poxviruses as proved by animal experiments and human clinical trials. It can be used on compassionate grounds in people infected with non-variola orthopoxvirus infections including MPX. TPOXX may shorten the duration of illness and viral shedding.[14] This targets the gene that produces a major envelope protein (p37) of the poxviruses.

TPOXX is available in oral (capsule 200 mg) and IV formulation (200 mg/20 mL vial). IV TPOXX should not be administered to patients with severe renal impairment (creatinine clearance <30–49 mL/min). The oral formulation of TPOXX is an option for this population. The safety of this drug is not available in pregnancy, lactation and children <2 years of age. They may still receive the drug if considered appropriate after assessment of the risk/benefit model. The dosage for adults and children has been approved for smallpox infection which may be extrapolated to MPXV infection.

Dosage for adults and children (oral formulation)

The recommended dose for individuals over 120 kg is 600 mg thrice daily for 14 days, 600 mg twice daily for 14 days for 40–120 kg, children 25–40 kg: 400 mg twice daily for 14 days and children 13–25 kg: 200 mg twice daily for 14 days.[15]


  Brincidofovir (TEMBEXA) Top


A synthetic analogue of an antiviral drug (cidofovir used for the treatment of cytomegalovirus (CMV) infection in immunocompromised people) has been developed as a therapeutic agent for poxvirus infections. This is a US FDA-approved drug for the treatment of smallpox infection. This drug has been evaluated in animal models measuring survival in variola or non-variola orthopoxvirus infections. The safety of brincidofovir has also been tested in bone marrow transplant patients for non-variola indications.[16] This has also been evaluated in a group of MPX patients treated in the UK from 2018 to 2019, and brincidofovir did not have a clinical benefit if initiated after 7 days of the onset of the rash. It is also immature to speculate that given early in the disease would have a different outcome.

Cidofovir is another antiviral drug used for the treatment of CMV retinitis and disseminated CMV infection in transplant recipients. It is effective in vitro and animal studies against orthopoxviruses, however, it has not been approved for the treatment of orthopoxviruses including MPX.[17] It may be used in case of an outbreak if stockpiled cidofovir is available according to the CDC guidelines.

Vaccinia immune globulin intravenous

This immunoglobulin preparation is primarily indicated in patients who had adverse reactions following vaccinia vaccination (eczema vaccinatum, progressive or severe generalised vaccinia in certain skin conditions).[18] However, this may be used for treatment in patients who are suffering from smallpox or non-variola infections like MPX in an outbreak. The efficacy data in support of VIGIV is lacking for MPX infections. VIGIV has been approved by the US FDA in 2005 for vaccinia-related complications.

VIGIV may also be used prophylactically in persons with severe immunodeficiency (especially with T-cell dysfunction), where the routine use of live attenuated smallpox vaccine is contraindicated and there is an obvious history of MPXV exposure.

Dosage

The recommended dose is 6000 units/kg IV infusion as a single dose (formulation 50,000 units/15 ml vial). A higher dose of 9000 units/kg to 24,000 units/kg may be considered if the patient does not clinically respond to the initial dose. The most common adverse events following administration of VIGIV are headache, nausea, dizziness and rigors (seen in >10% of recipients).

Preventive strategies

In the community, the best preventive strategy happens to be a vaccination against MPX. Smallpox vaccination will protect against the development of MPX. At this time, if may be prudent to revive and enhance the production of smallpox vaccines. Various vaccine manufacturers in India are trying to collaborate with the government to start indigenous smallpox vaccines (live attenuated and DNA recombinant). The vaccines can be administered to exposed persons and people with high-risk behaviour. The WHO has issued interim guidance (14th June, 2022) for the judicious use of limited vaccine supply and advised against mass vaccination.[19]

Some simple rules like avoidance of skin-to-skin contact with people who have a suspicious rash may be MPX. Do not touch the rash or scabs of a person with MPX. Do not kiss, cuddle or have intimate contact with persons with suspected MPX. Avoid sharing personal items such as towels, bedding or clothing. Wash hands often with soap and water or uses an alcohol-based sanitizer before eating food, using of washroom, etc. Avoid contact with animals (dead and alive) like rodents or other non-human primates which may harbour and spread the virus.

Role of vaccines

Currently, there are two vaccines available in USA and Europe which may be given before exposure. This may be offered to high-risk behaviour individuals or to persons exposed to the orthopoxviruses in the laboratory or experimental animals.

The two vaccines which are approved in the USA are ACAM2000 and JYNNEOS (marketed as Imvamune in Canada or Imvanex in European Union). Both vaccines are attenuated vaccines which are given by intradermal and subcutaneous routes, respectively.

The former is a live attenuated vaccinia virus preparation that is injected into the skin surface by a special applicator and the viral multiplication occurs at the site. It may accidentally spread to other body areas. However, the latter has been developed from a non-replicating recombinant vaccinia virus vaccine, i.e., (Modified Vaccinia Ankara). JYNNEOS is given in a two-dose schedule, 1 month apart from the subcutaneous route. It generates good humoral and cellular immune responses to various orthopoxviruses. The protection offered by a two-dose vaccine is effective following 2 weeks after the second dose. JYNNEOS may be offered in patients who are severely immunocompromised or likely to develop disseminated vaccinia infection following the administration of the former vaccine.[20]

Intradermal injection of JYNNEOS may be a reasonable option to provide a lesser dose of the vaccine to a greater number of individuals in a public health setting. However, there is no data available from clinical trials evaluating the efficacy of this vaccine against MPX through subcutaneous or intradermal route. The safety of JYNNEOS given subcutaneously has been studied in HIV-infected people with CD4 counts of 200 cells/μL or higher. In this context, intradermal dosing may safe and immunogenic in the vulnerable population.[21]

Epidemiological data from Africa suggests that smallpox vaccines provide 85% efficacy in preventing MPX cases. This has been proved by a recently concluded clinical vaccine immunogenicity study with JYNNEOS. At present, it seems that the latter is a safe vaccine advocated for pre-exposure prophylaxis in military personnel and high-risk occupation. This may be given 4–5 days before the anticipated exposure. However, if it is given 4–14 days following the exposure, it may reduce the symptoms and ameliorate the disease process, but the infection cannot be prevented altogether.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
World Health Organization, Monkeypox. Questions & Answers. Available from: https://www.who.int. [Last accessed on 2022 Aug 04].  Back to cited text no. 1
    
2.
Breman JG, Henderson DA. Diagnosis and management of smallpox. N Engl J Med 2002;346:1300-8.  Back to cited text no. 2
    
3.
Kugelman JR, Johnston SC, Mulembakani PM, Kisalu N, Lee MS, Koroleva G, et al. Genomic variability of monkeypox virus among humans, democratic Republic of the Congo. Emerg Infect Dis 2014;20:232-9.  Back to cited text no. 3
    
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Isidro J, Borges V, Pinto M, Sobral D, Santos JD, Nunes A, et al. Phylogenomic characterization and signs of microevolution in the 2022 multi-country outbreak of monkeypox virus. Nat Med 2022;28:1569-72.  Back to cited text no. 4
    
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Arita I, Henderson DA. Smallpox and monkeypox in non-human primates. Bull World Health Organ 1968;39:277-83.  Back to cited text no. 5
    
6.
Cho CT, Wenner HA. Monkeypox virus. Bacteriol Rev 1973;37:1-18.  Back to cited text no. 6
    
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World Health Organization. Monkeypox. Available from: https://www.who.int. [Last accessed on 2022 Aug 04].  Back to cited text no. 7
    
8.
Centers for Disease Control and Prevention. Monkeypox. Global Map and Case Count; 2022. Available from: https://www.cdc.gov. [Last accessed on 2022 Sep 04].  Back to cited text no. 8
    
9.
Thornhill JP, Barkati S, Walmsley S, Rockstroh J, Antinori A, Harrison LB, et al. Monkeypox virus infection in humans across 16 countries – April-June 2022. N Engl J Med 2022;387:679-91.  Back to cited text no. 9
    
10.
Mbala PK, Huggins JW, Riu-Rovira T, Ahuka SM, Mulembakani P, Rimoin AW, et al. Maternal and fetal outcomes among pregnant women with human monkeypox infection in the democratic republic of Congo. J Infect Dis 2017;216:824-8.  Back to cited text no. 10
    
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World Health Organization. Monkeypox, Key Facts. Available from: https://www.who.int. [Last accessed on 2022 Aug 04].  Back to cited text no. 11
    
12.
Centers for Disease Control and Prevention. Case definition. Available from: https://www.cdc.gov. Updated 22 July 2022. [Last accessed on 2022 Aug 04].  Back to cited text no. 12
    
13.
Centers for Disease Control and Prevention. Isolation and Infection Control at Home for Monkeypox. Available from: https://www.cdc.gov. [Last accessed on 2022 Aug 05].  Back to cited text no. 13
    
14.
Adler H, Gould S, Hine P, Snell LB, Wong W, Houlihan CF, et al. Clinical features and management of human monkeypox: A retrospective observational study in the UK. Lancet Infect Dis 2022;22:1153-62.  Back to cited text no. 14
    
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Mayo Clinic. Tecovirimat (Oral Route). Available from: https://www.mayoclinic.org. [Last accessed on 2022 Aug 05].  Back to cited text no. 15
    
16.
Centers for Disease Control and Prevention. Brincidofovir. Treatment of Smallpox. https://www.cdc.gov. [Last accessed on 2022 Aug 04].  Back to cited text no. 16
    
17.
Centers for Disease Control and Prevention. Interim clinical guidance for the treatment of Monkeypox. Medical countermeasures available for the treatment. Cidofovir. Available from: https://www.cdc.gov/poxvirus/monkeypox/clinicians/treatment.html#anchor_1655488333148. [Last accessed on 2022 Aug 07].  Back to cited text no. 17
    
18.
Highlights of Prescribing Information for Vaccinia Immune Globulin Intravenous (Human), Sterile Solution. Package Insert for CNJ-016, initial U.S. FD approval; 2005. [Last accessed on 2022 Aug 07].  Back to cited text no. 18
    
19.
WHO. Vaccines and Immunization for Monkeypox. Interim Guidance. Available from: https://www.who.int/news/item/14-06-2022-vaccines-and-immunization-for-monkeypox-interim-guidance-14-june-2022. [Last accessed on 2022 Aug 07].  Back to cited text no. 19
    
20.
JYNNEOS vaccine protocol for monkeypox/IZ program, updated July 26, 2020. Available from: https://www.cdc.gov/pxvirus/monkeypox/considerations-for-monkeypox-vaccination.html. [Last accessed on 2022 Aug 07].  Back to cited text no. 20
    
21.
Brooks JT, Marks P, Goldstein RH, Walensky RP. Intradermal vaccination for monkeypox – Benefits for individual and public health. N Engl J Med 2022;387:1151-3.  Back to cited text no. 21
    


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