Monkeypox (Mpox) virus was first observed in cynomolgus monkeys kept for research in Denmark in 1958,1 and Mpox in humans was first determined in Central Africa in 1970 with clinical similarities and different epidemiology to smallpox.2 Throughout history, the Mpox virus has caused several outbreaks, the most recent of which occurred in endemic and nonendemic regions around the world in 2022.3, 4 Mpox virus, with a double-stranded DNA genome, belongs to the Poxviridae family, the Chordopoxvirinae subfamily, and the genus Orthopoxvirus (OPXV).5 Two genetically different Mpox viral strains (clades) have been discovered, one in Central Africa and the other in West Africa. Compared to the Central African clade, the West African clade has milder disease. Consequently, West Africans have a lower mortality rate. According to available evidence, the current Mpox spread can be referred to the West African clade.6 This zoonotic pathogen has a diverse host range, providing virus dissemination in wild animals for a long time while sporadically spilling over into human populations.5 Person-to-person transmission can occur through direct contact with respiratory droplets, sores, scabs, and body fluids and indirect contact by sharing contaminated fomites such as bedding or clothing.7, 8 Prior to the current outbreak, the majority of cases had histories of animal exposure. Nonetheless, during the 2022 outbreak, skin-to-skin contact accounted for the majority of cases. Intriguingly, the majority of them reported sexual contact, most frequently with men who have sex with men and bisexual men.9 Mpox clinical manifestations include typical features such as fever, headaches, lymphadenopathy, and flulike symptoms, followed by the development of a characteristic rash. However, in the 2022 outbreak, atypical symptoms such as characteristic rash limited to the genital, perigenital, and perianal areas with different developmental stages were observed. It is important to consider patients as infectious from the beginning of the prodrome or rash until the scabs fall off.8, 9 The preferred diagnostic test for identifying a person with suspected active Mpox infection is to examine samples taken from a skin lesion using molecular tests such as polymerase chain reaction.8, 10 To effectively treat Mpox, it is necessary to develop medications with specific viral targets.6 Antiviral medications for Mpox treatment have not yet received official approval.11 Considering the number of reported Mpox mortalities and the severity of Mpox in some patients, immunocompromised individuals, and pregnant women, the study of antiviral therapies should continue to be an option.11 This review attempts to summarize the preventive approaches and current applicable treatment options against Mpox infection. There are currently no specific approved vaccines against the Mpox virus. Immunization with the smallpox vaccine appears to be effective against Mpox virus due to cross-protective immunity between OPXV and viruses of the same genus.5, 12-14 Based on studies conducted in the late 1980s, prior smallpox vaccination with vaccinia virus (VACV) provided approximately 85% protection against Mpox.15, 16 The US national monkeypox vaccination strategy considered two vaccines for Mpox disease prevention during the outbreak: ACAM2000 (second-generation smallpox vaccines) and Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN) (third-generation smallpox vaccines).17-19 ACAM2000 is a live VACV (a “pox”-type virus) that was approved by the US Food and Drug Administration (FDA) in August 2007 for active immunization against smallpox disease in people who are considered to be at high risk for smallpox.17, 20, 21 However, ACAM2000 can use for non-variola OPXV infections (e.g., Mpox) in people aged 1 year and older who have been determined to be at high risk for infection in the event of an outbreak to prevent Mpox.17, 20 Since ACAM2000 contains replication-competent VACV, recipients have reported serious adverse events, such as heart problems (myocarditis and/or pericarditis), progressive vaccinia, and eczema vaccinatum.22-26 It is also important to note that the VACV can also be transmitted from a vaccinated recipient to an unvaccinated person through close contact with the inoculation site. As a result, significant attention to the vaccination site will be required to prevent the virus from spreading.27 ACAM2000 is administered as a single dose percutaneously (scarification) with a 2-pronged (bifurcated) needle and 0.0025-mL droplet of reconstituted vaccine, and should not be injected by other routes such as subcutaneous, intramuscular, intravenous, and intradermal.28-30 The duration of ACAM2000 vaccine immunity is unknown, but peak immunity is expected 4 weeks after vaccination. However, in the United States, the Advisory Committee on Immunization Practices provides a recommendation for revaccination of laboratory and health care personnel who are at risk of ongoing occupational exposure to Mpox virus and replication-competent VACV with a booster dose every 3 years or at least every 10 years, respectively.31 The clinical efficacy of ACAM2000 against Mpox is unknown; however, a study conducted in the Democratic Republic of the Congo revealed that Dryvax, the first-generation smallpox vaccine, protected 1555 vaccinated contacts of 338 patients against Mpox.16 The most important contraindications for ACAM200 vaccine are a history of a severe allergic reaction (e.g., anaphylaxis) following a previous dose of vaccine, major cardiac risk factors, immunosuppression, acquired immune deficiency disorders, atopic dermatitis, pregnancy or breastfeeding, and infants aged less than 1 year.17, 28, 31, 32 MVA-BN, also known as JYNNEOS, is a live vaccine that was approved by the FDA in September 2019.28, 32, 33 It is indicated for prevention of both Mpox and smallpox in adults aged 18 years and older who are at high risk for smallpox or Mpox infection and administered subcutaneously in two doses 28 days (4 weeks) apart.6, 28 MVA-BN vaccines do not cause lesions at the injection site, thereby eliminating the risk of autoinoculation and systemic transmission.33 Although MVA-BN vaccines have some common local (pain at injection site, redness, pruritus, and discoloration) and systemic (fatigue, headache, myalgia, nausea, chills, and fever) side effects, there is no risk of severe adverse effects such as myopericarditis.28 The effectiveness of the MVA-BN vaccines in preventing Mpox is 85%. Its effectiveness and safety in relation to pregnant or breastfeeding women, however, are still up for discussion.33, 34 Compared to ACAM2000, MVA-BN vaccine is more acceptable for active immunization against Mpox due to its higher mean neutralizing antibody titer, high levels of acceptability throughout pregnancy, breastfeeding, and infancy, limited side effects, and lower cost.28, 33, 35 Across 43 U.S. jurisdictions, among males aged 18–49 years eligible for MVA-BN vaccination, Mpox incidence was 10 and 7 times higher among unvaccinated males compared to fully vaccinated and first-dose recipients, respectively.36 In addition, MVA-BN was found to be safe and immunogenic in individuals infected with HIV, with no serious adverse events reported.37 Further studies are needed to clarify the durability of MVA-BN protection; however, evidence supports its protection against Mpox, and all eligible people are recommended to complete the two-dose vaccination series.28, 35 In addition, comparing demographic and clinical characteristics of patients with Mpox who received one dose of MVA-BN vaccine 14 days or more before illness onset with unvaccinated patients with Mpox revealed that symptoms including fever, headache, malaise, and chills were significantly lower among vaccinated patients than unvaccinated patients.38 To achieve the most effective protection against Mpox, all eligible individuals should receive the two-dose vaccination series. One dose of the MVA-BN vaccine may reduce the severity of the disease and hospitalization in patients who become infected after vaccination.38 Although MVA-BN vaccine is contraindicated for people who have atopic dermatitis or have had a severe allergic reaction to a previous dose, there are no contraindications to using it in an emergency situation.28, 30 Preexposure prophylaxis is defined as vaccination prior to Mpox virus exposure.39 The most effective way to contain an Mpox outbreak is to provide preexposure prophylaxis to people who are at high risk of exposure, with a focus on men who have sex with men and health workers who are at high risk of occupational exposure.33, 39 Postexposure Prophylaxis (PEP) is defined as vaccination after known exposure to the Mpox virus within 4 days.20 The best time to initiating vaccination is within 4 days of exposure to prevent disease onset; however, vaccination can be considered between 4 and 14 days after exposure can improve disease prognosis but will not prevent Mpox.17, 33 Ring vaccination, also known as a form of PEP, is an effective method for breaking the Mpox transmission chain, consisting of the vaccination of a ring of individuals surrounding an infected individual.33, 40 PEP is not necessary for individuals who take all reasonable safety precautions and wear personal protective equipment (PPE), as their risk of contracting the disease is not increased.33 Expanded PEP (PEP++) is advised for those with a high risk factor for Mpox infection. This method can be used in regions where a high number of Mpox cases correlate with a high transmission rate.17, 20 Mpox is generally a self-limited disease, and the majority of patients with intact immune systems can be managed with supportive care and symptomatic treatment. There is no specific treatment for Mpox, and antiviral medications for Mpox are still awaiting final approval.11, 20 Patients who are immunocompromised, such as those with HIV infection; those with malignancies; posttransplant patients; those with autoimmune diseases; children; patients with severe medical conditions such as hemorrhagic disease, fusion lesions, sepsis, or encephalitis; those who need a hospital stay; and women who are pregnant or breastfeeding should all be considered for treatment.20 Studies are also being done to determine the efficacy of some treatments that were previously used to manage patients with smallpox.11 Medical options from the Strategic National Stockpile, such as tecovirimat, brincidofovir, cidofovir, and vaccinia immune globulin, are available for the treatment of Mpox. The current treatment options for Mpox infection are summarized in Table S1. Tecovirimat is an antiviral agent that is FDA approved for treating human smallpox caused by the variola virus in adults and children weighing 13 kg or greater; however, the FDA has not authorized its use for other OPXV infections, such as Mpox.41 Tecovirimat use is allowed under the nonresearch Expanded Access Investigational New Drug protocol (also known as “compassionate use”) for the primary or early empiric treatment of nonvariola OPXV infections, including Mpox, in adults and children of all ages.17, 20 This antiviral agent does not prevent the virus replication by interacting with the DNA polymerase enzyme. Indeed, tecovirimat has an antiviral effect by targeting the genes that code for the p37 protein (V061 in cowpox and F13L in vaccinia); this protein, which is conserved among OPXV, is important in the production of extracellular enveloped viruses (EVs) (Figure 1).42 EVs, which cause the viral agent transmission by creating conditions in viral infections, also play a role in the viral agent transmission in the bloodstream to distant tissues in OPXV infections. As a result, it is reasonable to assume that tecovirimat may inhibit VACV transmission by EVs to distant tissues. In addition, other effects of this drug have been reported, such as preventing viral proteins from interacting with cells and preventing cell-to-cell transmission, which ultimately prevents the transition of viral intracellular particles to extracellular particles that can cause independent infection.43, 44 In humans, the efficacy of tecovirimat against Mpox has not been determined. In contrast, many studies in animal models of OPXV infection (nonhuman primates and rabbits infected with Mpox virus and rabbitpox virus) have shown survival rates in tecovirimat-treated individuals compared to a placebo-treated group.45, 46 Tecovirimat has also been used in several case reports as part of a drug regimen for the treatment of vaccinia infection,25, 47 disseminated and ocular cowpox infections,48-50 and as prophylaxis in a patient with acute myelogenous leukemia on chemotherapy to prevent the development of progressive vaccinia infection.51 Tecovirimat is currently being tested in two clinical trials for the treatment of human Mpox infection by the National Institute of Allergy and Infectious Diseases,11 which started a randomized, placebo-controlled, double-blinded trial in the United States in September 2022 to evaluate the safety and efficacy of tecovirimat for the treatment of human Mpox disease.11 As part of the Study of Tecovirimat for Human Monkeypox Virus (STOMP) trial, participants receiving tecovirimat will be compared with those taking placebo to determine whether all lesions heal faster.52 Notably, SIGA Technologies, Inc. announced an Expanded Access Protocol (EAP) in July 2021 for the use of tecovirimat to prevent Mpox infection in the Central African Republic.42, 53 Tecovirimat is available through the Strategic National Stockpile in oral and intravenous formulations. Pain, swelling, erythema, and extravasation at the infusion site, and headache were the most frequently reported adverse reactions with the intravenous formulation, while abdominal pain, nausea, and vomiting were most reported with the oral formulation. When coadministered with repaglinide, blood glucose and hypoglycemic symptoms should be monitored.20 Tecovirimat resistance is an important issue of concern, as it has a relatively low resistance barrier. Substitutions in the viral p37 protein with a particular amino acid can bring considerable reductions in tecovirimat antiviral activity. Although naturally occurring tecovirimat-resistant OPXV has not yet been identified, tecovirimat resistance may develop as a result of drug selection and suboptimal dosing.11, 20, 43 Brincidofovir is an antiviral agent that the FDA approved for the treatment of human smallpox disease in adults and pediatric patients, including neonates, on June 4, 2021.20 Brincidofovir, as a cidofovir nucleotide analog, exhibits antiviral effects by inhibiting DNA polymerase and has important inhibitory effects in the template strand in double-stranded DNA viruses such as adenoviruses, herpesviruses, and poxviruses with a lower half-maximal effective concentration, less nephrotoxicity, oral administration, and easier absorption by cells compared to cidofovir.11, 20, 54 Brincidofovir is a prodrug metabolized by hydrolysis of the phosphodiester bond to form cidofovir, which is subsequently phosphorylated to cidofovir diphosphate as an active metabolite when orally administered (Figure 1). Cidofovir diphosphate inhibits orthopoxvirus DNA polymerase-mediated viral DNA synthesis. Since brincidofovir's efficacy has been studied in animal models of OPXV infection (rabbits infected with rabbitpox virus and mice infected with ectromelia virus), further studies are needed to support the dose and regimen of 200 mg once a week for two doses for treatment of human smallpox disease is necessary.20, 54 The most common adverse reactions are gastrointestinal effects (abdominal pain, diarrhea, nausea, and vomiting) and hepatotoxicity (elevations in hepatic transaminases and bilirubin). Thus, liver function tests (at baseline and during therapy as clinically appropriate), and pregnancy testing prior to initiation should be monitored in individuals of childbearing potential.20, 55, 56 Cidofovir is an antiviral agent that was approved by the FDA in 1996 for the treatment of cytomegalovirus (CMV) retinitis infection in patients with AIDS and is commercially available in the form of injection.57 Cidofovir has broad antiviral activity against herpes viruses, adenovirus, and OPXV by blocking viral DNA synthesis through competitive inhibition of DNA polymerase. Its efficacy against OPXV is supported by in vitro and animal studies.11, 17, 20 The antiviral effect of this drug is dependent on two phosphorylation steps that occur in the cytoplasm, and its diphosphorylated form prevents the replication of different viruses with a higher affinity to viral DNA polymerases than host cell polymerases. For example, the binding affinity of cidofovir diphosphate (CDVpp) for human CMV DNA polymerase has been shown to be 6.6 μM, which is approximately 8–80-fold higher than that of human DNA polymerases. CDVpp inhibits E9L DNA polymerase activity of VACV in several ways, including providing a poor substrate for DNA synthesis by CDVpp compared to deoxycytidine triphosphate (dCTP), preventing the chain's elongation by incorporating CDVpp in the primer strand, retention in DNA, and resistance to removal by DNA polymerase's 3′-to-5′ proofreading activity (Figure 1). Although its effectiveness against OPXV has been shown in in vitro and animal studies, data on its effectiveness in the treatment of Mpox in humans are lacking, and its use in the current outbreak may be considered under an appropriate regulatory mechanism.20, 11, 55 Cidofovir is administered only by intravenous infusion and not as a direct intraocular injection. To reduce the probability of nephrotoxicity, each cidofovir infusion must be accompanied by intravenous hydration with normal saline and the administration of probenecid. Cidofovir is contraindicated if preexisting renal impairment (i.e., serum creatinine greater than 1.5 mg/dL, creatinine clearance 55 mL/min, or urine protein 100 mg/dL [2+ proteinuria]) develops. As a result, renal function (serum creatinine and urine protein) must be monitored 48 h before each dose of cidofovir, and dose adjustments must be made if renal function changes.20, 58-60 In general, brincidofovir, a prodrug of cidofovir, has a better safety profile than cidofovir, with no reports of serious renal toxicity or other adverse events in the treatment of CMV and Mpox infection when compared to cidofovir.61, 62 Vaccinia immune globulin intravenous (VIGV), derived from pooled human plasma of people immunized with the smallpox vaccine, was licensed by the FDA in 2005 to provide passive immunity for individuals with complications of vaccinia vaccination, including eczema vaccinatum, progressive vaccinia, severe generalized vaccinia, vaccinia infections in patients with skin conditions, and aberrant infections caused by VACV (except in cases of isolated keratitis). However, VIGIV is not recommended for inadvertent inoculation that is not severe, mild or limited generalized vaccinia, nonspecific rashes, erythema multiforme, Stevens–Johnson syndrome, and postvaccinial encephalitis or encephalomyelitis. Although several studies have been reported the administration of VIGIV in combination with other antivirals to treat OPXV infections,24, 47, 51 evidence of its effectiveness against Mpox and smallpox is widely lacking, and treatment with vaccinia immune globulin should be done under an Investigational New Drug application.20 The exact mechanism of the VIGIV is unknown, but due to the fact that it is administered through intravenous infusion, it can be distributed in large quantities in different parts of the body and circulate in the blood for a long time. In addition, because the majority of its contents are immunoglobulin G and a small part contains immunoglobulin A, it has the ability to neutralize extracellular viruses and inhibit their spread to prevent infecting other and distant tissues. As a result, it protects tissues from widespread viral infection and activates complement (Figure 1).24 In the event of an outbreak, the Centers for Disease Control and Prevention has an expanded access Investigational New Drug protocol that allows VIGIV to treat Mpox. The use of VIGIV may be considered in severe conditions where the production of a powerful antibody response may be impaired.11 This agent is available in an intravenous formulation and should be injected at a dose of 6000 units/kg as soon as severe vaccine-related symptoms and complications appear. The severity of the symptoms and treatment response determine the need for repeated doses. Because of the maltose component in some VIGIV dosage forms, it may develop falsely elevated glucose readings; therefore, only glucose-specific testing systems should be used to test or monitor blood glucose levels in patients treated with VIGIV.55 There are currently no fully approved preventive and therapeutic lines for Mpox infections; however, some options are suggested. Some antiviral medications can inhibit viral replication, while others can affect other stages of the Mpox life cycle, such as viral protein assembly and release. Furthermore, preventive strategies such as the use of specific anti-Mpox vaccines through the approval of current multiple platforms may be a promising candidate to stop the virus's spread and circulating. These agents’ risks and benefits are likely to change over time, influencing decision making during the Mpox outbreak. Meanwhile, continuing education for health care professionals, public health officials, and the general public about the ongoing nature of the threat of reemerging diseases is required. The authors thank Dr. Simin Dashti-Khavidaki (Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran) for critical reading of the manuscript. The authors have no conflicts of interest to declare. No funding was received for this study. Tecovirimat: TPOXX or ST-246; brincidofovir: Tembexa or CMX001; cidofovir: Vistide. Data are available upon reasonable request. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.