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Oral Tecovirimat for the Treatment of Smallpox
Abstract
Background
Smallpox was declared eradicated in 1980, but variola virus (VARV), which causes smallpox, still exists. There is no known effective treatment for smallpox; therefore, tecovirimat is being developed as an oral smallpox therapy. Because clinical trials in a context of natural disease are not possible, an alternative developmental path to evaluate efficacy and safety was needed.
Methods
We investigated the efficacy of tecovirimat in nonhuman primate (monkeypox) and rabbit (rabbitpox) models in accordance with the Food and Drug Administration (FDA) Animal Efficacy Rule, which was interpreted for smallpox therapeutics by an expert advisory committee. We also conducted a placebo-controlled pharmacokinetic and safety trial involving 449 adult volunteers.
Results
The minimum dose of tecovirimat required in order to achieve more than 90% survival in the monkeypox model was 10 mg per kilogram of body weight for 14 days, and a dose of 40 mg per kilogram for 14 days was similarly efficacious in the rabbitpox model. Although the effective dose per kilogram was higher in rabbits, exposure was lower, with a mean steady-state maximum, minimum, and average (mean) concentration (Cmax, Cmin, and Cavg, respectively) of 374, 25, and 138 ng per milliliter, respectively, in rabbits and 1444, 169, and 598 ng per milliliter in nonhuman primates, as well as an area under the concentration–time curve over 24 hours (AUC0-24hr) of 3318 ng×hours per milliliter in rabbits and 14,352 ng×hours per milliliter in nonhuman primates. These findings suggested that the nonhuman primate was the more conservative model for the estimation of the required drug exposure in humans. A dose of 600 mg twice daily for 14 days was selected for testing in humans and provided exposures in excess of those in nonhuman primates (mean steady-state Cmax, Cmin, and Cavg of 2209, 690, and 1270 ng per milliliter and AUC0-24hr of 30,632 ng×hours per milliliter). No pattern of troubling adverse events was observed.
Conclusions
On the basis of its efficacy in two animal models and pharmacokinetic and safety data in humans, tecovirimat is being advanced as a therapy for smallpox in accordance with the FDA Animal Rule. (Funded by the National Institutes of Health and the Biomedical Advanced Research and Development Authority; ClinicalTrials.gov number, NCT02474589.)
FREE QUICK TAKE VIDEO SUMMARY
An Antiviral Therapy for Symptomatic Smallpox Infection
02:03
... Possible side effects of monkeypox include pneumonia, subsequent bacterial infections, encephalitis, and sight-threatening keratitis.The United States has approved the use of two orally ingestible drugs, tecovirimat and brincidofovir, to treat smallpox in the event of a bioterrorism attack, despite the fact that there are currently no licenced therapies for human monkeypox. [10][11][12] Although both treatments have demonstrated effectiveness in animal models against several orthopoxviruses, no human efficacy studies have been conducted on either (including monkeypox). ...
... In this case, it will be determined under what conditions the epidemic equilibrium is asymptotically stable. The following is the Jacobian matrix for the endemic equilibrium * : Here, (6,4) = τ, a (6,5) = ρ h , a (6,6) = −µ h , a (7,7) = −(µ r + δ r ), a (7,9) = −β r1 S r N r , a (8,7) = δ r , a (8,8) = −(µ r + α 3 ), a (8,9) = β r1 S r N r , a (9,8) = α 3 , a (9,9) = −(µ r + d r + ρ r ), a (10,9) = ρ r , a (10,10) = −µ r . ...
... In this case, it will be determined under what conditions the epidemic equilibrium is asymptotically stable. The following is the Jacobian matrix for the endemic equilibrium * : Here, (6,4) = τ, a (6,5) = ρ h , a (6,6) = −µ h , a (7,7) = −(µ r + δ r ), a (7,9) = −β r1 S r N r , a (8,7) = δ r , a (8,8) = −(µ r + α 3 ), a (8,9) = β r1 S r N r , a (9,8) = α 3 , a (9,9) = −(µ r + d r + ρ r ), a (10,9) = ρ r , a (10,10) = −µ r . ...
... [11] because it is not possible to study naturally occurring smallpox, and because experimental variola infection of humans would be unethical. Therefore, efficacy data supporting the approval of oral tecovirimat for smallpox were based on nonclinical data from rabbits and cynomolgus monkeys [31]. ...
... The clinical pharmacology of tecovirimat, described previously [31], was conducted under USFDA's Animal Rule, in which animal studies are used to inform the selection of the effective human dose by establishing drug exposures that are safe and efficacious in animals. Tecovirimat efficacy has been extensively evaluated in the nonhuman primate (NHP) and rabbit lethal challenge models for prediction of efficacy in human smallpox [16,29,31]. ...
... The clinical pharmacology of tecovirimat, described previously [31], was conducted under USFDA's Animal Rule, in which animal studies are used to inform the selection of the effective human dose by establishing drug exposures that are safe and efficacious in animals. Tecovirimat efficacy has been extensively evaluated in the nonhuman primate (NHP) and rabbit lethal challenge models for prediction of efficacy in human smallpox [16,29,31]. The USFDA has indicated that both of these models are appropriate for evaluation of smallpox countermeasures. ...
Introduction:
Tecovirimat oral capsule formulation is approved in the US and Canada for treatment of smallpox and in the United Kingdom (UK) and European Union (EU) for treatment of multiple human orthopoxvirus diseases, including mpox. Smallpox is considered a serious threat, and there is currently an unprecedented global mpox outbreak.
Areas covered:
A brief summary of the threat of smallpox, the threat of increasing mpox spread in endemic regions, and the unprecedented emergence of mpox into non-endemic regions is presented. The tecovirimat intravenous formulation clinical development program leading to USFDA approval for smallpox treatment is discussed.
Expert opinion:
As of January 2023 tecovirimat is approved to treat mpox in the UK and EU. However, published clinical trial data evaluating tecovirimat efficacy and safety in mpox patients is pending. Increasing global prevalence of mpox highlights the potential benefits of a well-characterized, effective, and safe antiviral treatment for mpox infection. Ongoing trials in mpox patients may provide results supporting the use of tecovirimat to treat this disease. USFDA approval of tecovirimat for post-exposure prophylaxis in the event of a smallpox release, and the development of pediatric liquid formulations for patients under 13 kg, could provide additional public health benefits.
... ( La eficacia de Tecovirimat se evaluó en base a estudios en animales infectados con dosis letales de ortopoxvirus, en estudios sobre los efectos del medicamento en el cuerpo humano y en la forma en que el medicamento se absorbe, modifica y elimina del cuerpo en humanos y animales (farmacodinámica y farmacocinética). (48,52,53) El Tecovirimat inhibe la formación de la envoltura viral del virus de la viruela símica al actuar sobre la proteína viral p37, que está altamente conservada entre los ortopoxvirus (53). ...
... ( La eficacia de Tecovirimat se evaluó en base a estudios en animales infectados con dosis letales de ortopoxvirus, en estudios sobre los efectos del medicamento en el cuerpo humano y en la forma en que el medicamento se absorbe, modifica y elimina del cuerpo en humanos y animales (farmacodinámica y farmacocinética). (48,52,53) El Tecovirimat inhibe la formación de la envoltura viral del virus de la viruela símica al actuar sobre la proteína viral p37, que está altamente conservada entre los ortopoxvirus (53). ...
La viruela símica (monkeypox, MPX) es una enfermedad zoonótica viral, que pertenece al género Orthopoxvirus de la familia Poxviridae. El género Orthopoxvirus incluye los virus de la variola (que causa la viruela), el vaccínea (utilizado en la vacuna contra la viruela) y de la viruela bovina.(1,2) El virus se descubrió por primera vez en 1958 durante brotes sincrónicos en dos colonias de monos de investigación.(3) La enfermedad se identificó en 1970 en un niño de 9 meses en la República Democrática del Congo, desde entonces el número de casos en otros países
de África occidental y central ha aumentado durante la última década.(2) Se han identificado dos clados del virus de la viruela símica mediante secuenciación genómica: el clado de África occidental y el clado de África central
o cuenca del Congo los cuales difieren en virulencia y genéticamente; siendo esta última la de mayor virulencia (infección más grave)
... This stops the last steps of the virus maturing and getting out of an infected cell, which stops the virus from spreading in an infected host. 61,62 Even though this agent hasn't been tested on humans for monkeypox, studies have shown that animals treated with tecovirimat have a better chance of surviving lethal monkeypox virus infections than animals treated with a placebo. In a larger safety study of 359 people who took tecovirimat, the side effects of the placebo were mostly the same as those of tecovirimat. ...
... 61 There isn't any clinical data on how well cidofovir works against monkeypox in humans, but it has been found to be effective in vitro against lethal monkeypox virus infections in animals. 62 When treating with cidofovir through an IV route, normal saline and probenicid must be given simultaneously. Before and during treatment with brincidofovir, liver function tests must be done because brincidofovir may raise serum transaminases and serum bilirubin. ...
The world has been facing a back-to-back hit to life after widespread of viruses since the time of COVID-19. The pandemic had a devastating effect and created history in mankind, but that was not enough for the time. The viruses are been known to be the deadliest microbes by virtue of their ability to reside as inactive for long time and become active again along with new variants when the conditions are favourable. One such noted spread out of virus has been that of Monkeypox Virus in humans. A zoonotic orthopoxvirus that can infect humans, the monkeypox virus (MPV) can cause disease with varied morbidity and death in humans. It has been demonstrated that members of the Orthopoxvirus genus decrease antiviral cell defences, take advantage of host cell machinery, and postpone infection-induced cell death. The name Monkeypox was after its first observation in Macaque monkey but the virus’s origin has been linked to a number of rodents and small mammals. The virus was endemic to Africa and is closely related to notorious variola (smallpox) virus. They both affect people with a febrile rash sickness that is similar to smallpox but has less severity. Monkeypox can spread from person to person and it is frequently related to breathing droplets or direct contact with mucocutaneous lesions of an affected person. There is now no cure available for those who are affected, yet supporting therapies can be used to help people with their symptoms. To better comprehend and prevent human infections, additional study is required on the epidemiology, ecology, mutations and biology of the new virus strains in endemic locations.
... In particular, Phe52, Leu118, Cys120, Ser135, Asn312, Lys314, Asn329, and Asp331 amino acids were considered to form the binding site. For molecular docking we used the reference ligand-protein model (ST-246 [26,46]-p37), obtained as a result of molecular modeling described in [20]. Molecular docking was performed using the forced ligand positioning protocol (IFD) [47][48][49] with the following conditions: flexible protein and ligand; grid matrix size of 20 Å; amino acids (within a radius of 5 Å from the ligand) restrained and optimized, taking into account the influence of the ligand; the maximum number of positions was limited to 20; docking solutions were ranked by evaluating the following calculated parameters: docking score (based on Glide score minus penalties); parameter of model energy value (Emodel), including Glide score value, energy unrelated interactions, and the parameters of energy spent on formation of the laying of the compound in the binding site and binding energy of ligand and protein (IFD score). ...
... We considered the cavity containing Phe52, Leu118, Cys120, Ser135, Asn312, Lys314, Asn329, and Asp331 amino acids as a binding site as it was described in [19,20]. For the molecular docking procedure we used a ligand-protein reference model (Tecovirimat [26,46]-p37), obtained as a result of molecular modeling described in [20]. ...
Despite the fact that the variola virus is considered eradicated, the search for new small molecules with activity against orthopoxviruses remains an important task, especially in the context of recent outbreaks of monkeypox. As a result of this work, a number of amides of benzoic acids containing an adamantane fragment were obtained. Most of the compounds demonstrated activity against vaccinia virus, with a selectivity index SI = 18,214 for the leader compound 18a. The obtained derivatives also demonstrated activity against murine pox (250 ≤ SI ≤ 6071) and cowpox (125 ≤ SI ≤ 3036). A correlation was obtained between the IC50 meanings and the binding energy to the assumed biological target, the p37 viral protein with R 2 = 0.60.
... Tecovirimat has been documented by Grosenbach et al. [36] for the oral treatment of smallpox. It was further hailed as the first-in-class therapy for the emerging mpox outbreak [37]. ...
... Delaune and Iseni [38] highlighted the difficulties to develop new drugs targeting an eradicated disease under the FDA "animal efficacy rule" with the few, and imperfect, animal models available. According to this review, the study of Grosenbach et al. [36], allowed the validation of a dosing regimen for oral tecovirimat (600 mg twice daily). Almost a decade before tecovirimat was finally approved by the US FDA on July 13, 2018, it had been the subject of several review articles pointing to its potential in the treatment of orthopoxvirus infections, i.e., smallpox [39][40][41]. ...
Therapeutic and vaccine development for human poxvirus infections (e.g., monkeypox (mpox) virus, variola virus, molluscum contagiosum virus, orf virus) has been largely deserted, especially after the eradication of smallpox by 1980. Human mpox is a self-limited disease confined to Central and West Africa for decades. However, since April 2022, mpox has quickly emerged as a multi-country outbreak, urgently calling for effective antiviral agents and vaccines to control mpox. Here, this review highlights possible therapeutic options (e.g., tecovirimat, brincidofovir, cidofovir) and other strategies (e.g., vaccines, intravenous vaccinia immune globulin) for the management of human poxvirus infections worldwide.
... Tecovirimat is an antiviral drug approved for treating smallpox and licensed by European Medicines Agency for treating MPX [83]. Until now, tecovirimat was for severe MPX or a high risk of getting severe disease. ...
... It might help with short-term problems like pain, inflammation, abscesses, and scarring. It is taken orally twice a day for two weeks or intravenously [83,84]. ...
Monkeypox (MPX) belongs to the genus Orthopoxvirus (OPV), family Poxviridae, and sub-family Chordopoxvirinae. Human monkeypox (HMPX) is a viral zoonotic illness caused by the monkeypox virus (MPXV). Several non-endemic countries have confirmed MPX cases across the globe. Therefore, consider an outbreak to be a global health emergency. MPXV transmits from animals to humans via infected animals, and there is currently human-to-human transmission, notably among guys who have sexual relations with males. Healthcare interventions are required to stop outbreaks. These include strict isolation and care for MPX patients while they are still contagious or until the skin lesions dry out and crust over. JYNNEOS was approved as a vaccine for the prevention of MPXV. Tecovirimat is licensed to treat severe MPX or risk developing a serious disease. We should encourage international cooperation to conduct clinical trials investigating the effectiveness and safety of MPXV vaccines and antiviral medications. Precautions must be taken at the global level to prevent an MPXV outbreak.
... Thus, the approval of tecovirimat for smallpox was based on the "Animal Rule", a regulation allowing timely approval of drugs for serious conditions using animal models when studies in humans would be unethical or not possible [48]. In studies of nonhuman primates inoculated with lethal doses of MPXV, tecovirimat significantly reduced risk of death, viral load, and lesion counts, especially when given earlier in disease course [49]. However, tecovirimat was found to be less effective in immunocompromised animal models [50,51]. ...
... However, tecovirimat was found to be less effective in immunocompromised animal models [50,51]. Safety and tolerability of tecovirimat has been shown in phase I and II placebo-controlled trials of 449 healthy adults [49]. Tecovirimat has been used infrequently for the treatment of mpox [52,53]. ...
In May 2022, a new global outbreak of mpox (formerly, human monkeypox) emerged that was declared a public health emergency of international concern by the World Health Organization on July 23, 2022. With new patterns of person-to-person spread within sexual networks in nonendemic countries and several differences from the classic disease course, we performed a comprehensive review of existing literature on human monkeypox to discuss epidemiology, modes of transmission, clinical presentation and asymptomatic infection, diagnostics, therapeutics, and vaccines with the primary aim to identify important areas for future research of this new epidemic form of the disease. A comprehensive literature search was performed of all published literature to August 15, 2022. Historically, in regions of monkeypox virus endemicity, human outbreaks have occurred related to discrete zoonotic events. The animal reservoir is unknown, but the virus has been isolated from rodents. Traditionally, transmission occurred by direct or indirect contact with an infected animal. In nonendemic countries affected in the 2022 outbreak, almost exclusive person-to-person spread has been observed, and most cases are connected to sexual networks of gay, bisexual, and other men who have sex with men. After an incubation period of approximately 13 days, in traditional human cases affected persons developed a febrile prodrome preceding a rash that started on the face and body, spread centrifugally to the palms and soles and healed monomorphically over two to four weeks. However, in the 2022 outbreak, the febrile illness is often absent or occurs after the onset of the rash. The rash presents primarily in the anogenital region and face before disseminating throughout the body, with lesions displaying regional pleomorphism. There is a paucity of data for the role of antiviral agents or vaccines. The epidemiology and clinical course of mpox has changed in the 2022 epidemic from that observed with the endemic disease. There is an urgent need to establish rapid and collaborative research platforms to diagnose, treat and prevent disease and inform important public health and other strategies to stop the spread of disease.
... Our patient's clinical presentation was deemed refractory to tecovirimat treatment after failing to improve after two courses of tecovirimat therapy. While the optimal duration of tecovirimat treatment for mpox is unknown, initial courses of 14 days have been recommended by the CDC based on data extrapolated from human smallpox studies caused by the variola virus [35]. More recently, real-life experience of tecovirimat for mpox has been published and suggests that longer durations may be warranted for select cases, particularly in patients who are immunocompromised. ...
Purpose: To report a case of severe mpox in a newly diagnosed HIV patient concerning for Immune Reconstitution Inflammatory Syndrome (IRIS) and/or tecovirimat resistance and to describe the management approach in the setting of refractory disease. Case: 49-year-old man presented with 2 weeks of perianal lesions. He tested positive for mpox PCR in the emergency room and was discharged home with quarantine instructions. Three weeks later, the patient returned with disseminated firm, nodular lesions in the face, neck, scalp, mouth, chest, back, legs, arms, and rectum, with worsening pain and purulent drainage from the rectum. The patient reported being on 3 days of tecovirimat treatment, which was prescribed by the Florida department of health (DOH). During this admission, he was found to be HIV positive. A pelvic CT scan revealed a 2.5 cm perirectal abscess. Treatment with tecovirimat was continued for 14 days, along with an empiric course of antibiotics for treatment of possible superimposed bacterial infection upon discharge. He was seen in the outpatient clinic and initiated antiretroviral therapy (ART) with TAF/emtricitabine/bictegravir. Two weeks after starting ART, the patient was readmitted for worsening mpox rash and rectal pain. Urine PCR also returned positive for chlamydia, for which the patient was prescribed doxycycline. He was discharged on a second course of tecovirimat and antibiotic therapy. Ten days later, the patient was readmitted for the second time due to worsening symptoms and blockage of the nasal airway from progressing lesions. At this point, there were concerns for tecovirimat resistance, and after discussion with CDC, tecovirimat was reinitiated for the third time, with the addition of Cidofovir and Vaccinia, and showed an improvement in his symptoms. He received three doses of cidofovir and two doses of Vaccinia, and the patient was then discharged to complete 30 days of tecovirimat. Outpatient follow-up showed favorable outcomes and near resolution. Conclusion: We reported a challenging case of worsening mpox after Tecovirimat treatment in the setting of new HIV and ART initiation concerning IRIS vs. Tecovirimat resistance. Clinicians should consider the risk of IRIS and weigh the pros and cons of initiating or delaying ART. In patients not responding to first-line treatment with tecovirimat, resistance testing should be performed, and alternative options should be considered. Future research is needed to establish guidance on the role of Cidofovir and Vaccinia immune globulin and the continuation of tecovirimat for refractory mpox.
... (11) in Supporting Note-2] (Fig 6A). We assumed a simple one-compartment model (30) with the reported maximum drug concentrations in plasma (C max ) and half-life values of tecovirimat (15), cidofovir (7), atovaquone (13), mefloquine (17), and molnupiravir (31) by administration at approval doses (see Table S3). We found that cidofovir and molnupiravir show anti-viral effects after administration but which are rapidly declined, reflected by their short half-lives, whereas the anti-viral effects of tecovirimat and atovaquone are maintained at high levels during drug treatment (Fig 6A). ...
Background:
Mpox virus (MPXV) is a zoonotic orthopoxvirus and caused an outbreak in 2022. Although tecovirimat and brincidofovir are approved as anti-smallpox drugs, their effects in mpox patients have not been well documented. In this study, by a drug repurposing approach, we identified potential drug candidates for treating mpox and predicted their clinical impacts by mathematical modeling.
Methods:
We screened approved 132 drugs using an MPXV infection cell system. We quantified antiviral activities of hit drugs by measuring intracellular viral DNA and analyzed the modes of action by time-of-addition assay and electron microscopic analysis. We further predicted the efficacy of drugs under clinical concentrations by mathematical simulation and examined combination treatment.
Results:
Atovaquone, mefloquine, and molnupiravir exhibited anti-MPXV activity, with 50% inhibitory concentrations of 0.51-5.2 μM, which was more potent than cidofovir. Whereas mefloquine was suggested to inhibit viral entry, atovaquone and molnupiravir targeted post-entry process. Atovaquone was suggested to exert its activity through inhibiting dihydroorotate dehydrogenase. Combining atovaquone with tecovirimat enhanced the anti-MPXV effect of tecovirimat. Quantitative mathematical simulations predicted that atovaquone can promote viral clearance in patients by seven days at clinically relevant drug concentrations.
Conclusion:
These data suggest that atovaquone would be potential candidates for treating mpox.
... In these experiments, survival was 95% among non-human primates infected with mpox that received TCV, as compared to 5% in non-human primates that received This work is licensed under a Creative Commons Attribution 4.0 International License. placebo, with benefits also seen in number of lesions and viral load (4). A subsequent clinical trial in healthy human volunteers confirmed that a treatment course of 14 days was generally well tolerated, with only 1% of patients discontinuing treatment due to adverse events associated with TCV (4). ...
... Le virus de la variole n'étant plus en circulation, l'efficacité clinique a été extrapolée à partir d'études expérimentales animales dans lesquelles des sujets ont été inoculés avec d'autres orthopoxvirus, y compris des doses létales de mpox chez des primates non humains. Dans ces expériences, le taux de survie était de 95 % chez les primates non humains infectés par la mpox qui avaient reçu le TCV, contre 5 % chez les primates non humains qui avaient reçu un placebo, et des avantages ont également été observés en ce qui concerne le nombre de lésions et la charge virale (4). Un essai clinique ultérieur chez des volontaires humains en santé a confirmé qu'un traitement de 14 jours était généralement bien toléré, 1 % seulement des patients ayant interrompu le traitement en raison d'effets indésirables associés au TCV (4). ...
... Mpox can be fatal but is a much milder disease than smallpox. There is also no specific treatment recommended for Mpox by the World Health Organization, but some antivirals have been licensed for the treatment of Orthopoxviruses, such as tecovirimat [1,6]. The case fatality in outbreaks is between 1% and 10%, and younger age groups are known to be the most affected [1]. ...
Mpox presents typically with macular papular body rashes with similar-looking sores in genital or oral areas. It may be missed, or wrongly managed as sexually transmitted infections (STI), especially in settings where symptom-based treatment practices are sufficient for care. We describe a 40-year-old cisgender male, heterosexual Nigerian who developed some rash in the genital region associated with penile swelling. It was suspected to be syphilis and managed with presumptive antibiotics. Laboratory investigation (PCR) confirmed that it was a Mpox disease, and Case Study Owhonda et al.; Arch. Curr. Res. Int., vol. 23, no. 2, pp. 36-42, 2023; Article no.ACRI.97058 37 VDRLT was negative. Notably, in this case, the early symptoms were a paradigm case of Mpox disease presenting as an STI, which syndromically conformed more to an STI than the case definition for a suspected case of Mpox in our setting. Consequently, the expected early containment activities were delayed. This increased the potential of further disease spread. An Update of the standard case definition as well as a reclassification of the disease as a possible STI is recommended for enhanced surveillance, increased case detection, and reduction in the burden of unrecognized cases.
... However, there are many nuances to consider. Smallpox was eradicated when tecovirimat was developed, and its FDA approval was based on its efficacy in laboratory animal trials (including monkeypox virus) and its safety profile in healthy humans, but not its efficacy in treating human disease [83,84]. At the time of writing, there are no published randomized clinical trials to describe the efficacy of tecovirimat in mpox management. ...
Monkeypox virus infections (mpox) in humans have become increasingly common since the virus was first identified in 1970. Coverage of the ongoing mpox outbreak has emphasized the role of skin-to-skin contact in monkeypox virus transmission and has focused on the community of men who have sex with men. While close contact from sexual activity is currently the main mechanism of monkeypox virus transmission, the potential for contact sports to exacerbate the 2022 outbreak has largely been overlooked. Infectious diseases rapidly spread in sports with significant skin-to-skin contact (i.e., wrestling and other combat sports, American football, and rugby). Mpox has not yet reached the athletic community, but once it does, it may follow a similar pattern of other infectious skin diseases in sports. Thus, it is critical to initiate a discussion of the risk of mpox and potential preventive measures within a sports context. This Current Opinion aims to provide stakeholders within the sports community with a brief review of infectious skin diseases in athletes, an overview of mpox and why it is relevant to athletes, and recommendations to reduce the risk of monkeypox virus transmission within sports settings. Guidelines for sports participation in athletes exposed to mpox and those with suspected, probable, and confirmed cases of monkeypox are provided.
... The global situation urgently requires evidence of the efficacy and safety of antivirals against MPX [51]. Three potential bioavailable drugs, tecovirimat, brincidofovir, and cidofovir, have been tested in the United States of America (USA) and Europe to treat MPXV [52]. However, no clinical trials have been conducted to evaluate their efficacy and safety in patients with MPX. ...
Public health officials around the world are extremely concerned about the global outbreak of monkeypox (MPX), which has been claimed to have originated in Africa. As a result, studies into the origins and reasons behind the outbreak's rapid spread have been sped up. The goal of the current investigation is to determine whether the monkeypox virus (MPXV) is present in semi-nal fluid samples from MPX cases that have been verified. Up until 6 January 2023, PubMed, Scopus, Web of Science, Embase, and ScienceDirect databases were used to conduct a thorough evaluation of the literature. The search technique returned a total of 308 items. Fourteen studies reporting the presence of MPXV in the seminal fluid of MPX-confirmed cases were included after the duplicates (n = 158) and searches by title, abstract, and full text were eliminated. In 84 out of the 643 confirmed MPX cases (13.06 % or n = 643), MPXV was discovered in seminal fluid. Reverse transcriptase poly-merase chain reaction (RT-PCR) was used to identify MPXV, and samples taken from skin lesions (96.27%), pharynx or oropharynx (30.48%), and blood all had higher positivity rates than other samples (12.44 %). Additionally, 99.85% of respondents were male with a mean age of 36, 98.45% engaged in MSM (men who have sex with men) sexual conduct, and human immunodeficiency virus (HIV) accounted for 56.9% of all STD cases. This study offers proof that MPXV can be found in the seminal fluid of MPX sufferers. Our data imply that MPXV transmission is a possibility in these samples and that MSM are more vulnerable to it. The creation of hygienic standards is essential for the early identification of MPX cases.
... 19 A phase 3 trial 20 has shown tecovirimat appears to be well tolerated with only one adverse event recorded (pulmonary embolus) in the 359 people who received the drug. 20 The most common recorded adverse events were headache (16·99% affected), nausea (5·57%), diarrhoea (3·06%), vomiting (2·51%) and dizziness (2·51%). ...
A 48-year-old man with poorly controlled HIV presented with severe human monkeypox virus (hMPXV) infection, having completed 2 weeks of tecovirimat at another hospital. He had painful, ulcerating skin lesions on most of his body and oropharyngeal cavity, with subsequent Ludwig's angina requiring repeated surgical interventions. Despite commencing a second, prolonged course of tecovirimat, he did not objectively improve, and new lesions were still noted at day 24. Discussion at the UK National Health Service England High Consequence Infectious Diseases Network recommended the use of 3% topical and then intravenous cidofovir, which was given at 5 mg/kg; the patient made a noticeable improvement after the first intravenous dose. He received further intravenous doses at 7 days and 21 days after the dose and was discharged at day 52. Cidofovir is not licensed for use in treatment of hMPXV infection. Data for cidofovir use in hMPXV are restricted to studies in animals. Four other documented cases of cidofovir use against hMPXV have been reported in the USA in 2022, but we present its first use in the UK. The scarcity of studies into the use of cidofovir in this condition clearly shows the need for robust studies to assess efficacy, optimum dosage, timing, and route of administration.
... Consultation with the CDC Monkeypox Response Clinical Escalation Team (CDC Emergency Operations Center: 770-488-7100) and multidisciplinary consultation with infectious diseases specialists is strongly encouraged [30]. Tecovirimat was shown to be safe in healthy persons without mpox [31], and there have been few adverse events in initial use during the current outbreak [32], but data on the effectiveness of tecovirimat in treating mpox are limited [32]. Early clinical data and animal studies have shown it to be effective in decreasing the risk of death when given early in the course of infection [33,34]. ...
... [15] Chociaż skuteczność tego środka przeciwko małpiej ospie u ludzi nie została przetestowana, badania wykazały poprawę przeżywalności po zakażeniu śmiertelnymi dawkami wirusa ospy małpiej u zwierząt leczonych tecovirimatem w porównaniu ze zwierzętami otrzymującymi placebo w różnych stadiach choroby. [15,16,17] Tecovirimat jest dostępny w postaci doustnych kapsułek 200 mg. [22] Wnioski Wirus małpiej ospy został odkryty już ponad 60 lat temu, został uznany jednak za patogen endemiczny dla rejonu Afryki i zapomniany przez znaczną część świata naukowego na długie dekady. ...
The mokeypox is zoonotic disease caused by an orthopoxvirus, which was first isolated and identified in 1959 among captive monkeys transported to Copenhagen, Denmark from Africa for research purposes. Monkeypox in humans was initially diagnosed in 1970 in the Democratic Republic of the Congo and then it has spread to other regions of Africa. The monkeypox cases in Africa were neglected by the scientific community for past decades till 2022, when thousands of cases were reported from nonendemic countries around Europe and in the western hemisphere. Therefore monkeypox has recently been labelled as a public health emergency of international concern by the WHO. Monkeypox virus is believed to have several modes of transmission, all of which are associated with direct or indirect contact with infected animals or infected humans. The diagnosis of monkeypox infection is based on the history, clinical symptoms and laboratory tests such as PCR.The illness begins with nonspecific symptoms such as fever, lethargy, lymphadenopathy, myalgias and then it occures the rash first on the face and then across the body which lasts for 2–4 weeks. Most cases of monkeypox are mild and self-limited disease, which require only supportive treatments. However in very severe cases antiviral medications such as tecovirimat may be administered. Smallpox vaccination has been estimated to provide 85% cross-protection against monkeypox infection. The main problem is there is a huge population born only after the discontinuation of the smallpox vaccination campaign with lack of cross-protective immunity. The question is - the monkeypox is only old neglected foe or a new epidemiological threat?
... Apesar disso, como mostrado nos resultados obtidos no presente estudo, o tecovirimat em monoterapia segue sendo o antiviral mais seguro de que se tem conhecimento. Corroborando esta ideia, um estudo expandido de segurança realizado com 539 pacientes humanos mostrou que o perfil de efeitos adversos do placebo era bastante similar ao do tecovirimat, indicando a segurança geral no uso (GROSENBACH et al., 2018). ...
Análise da segurança e eficácia dos medicamentos antivirais para o tratamento da varíola dos macacos: uma revisão integrativa Analysis of the safety and efficacy of antiviral drugs for the treatment of monkeypox: an integrative review RESUMO Objetivo: Avaliar a segurança, a eficácia e uso de antivirais como tecovirimat, brincidofovir, cidofovir, entre outros, de acordo com as pesquisas recentes em humanos, animais e in vitro. Métodos: Revisão integrativa, executada em seis fases, utilizando-se os Descritores em Ciências da Saúde em inglês monkeypox AND (tecovirimat OR "Antiviral Agents"). Para isso, foram usadas as bases de dados U.S. National Library of Medicine (PUBMED), Biblioteca Virtual em Saúde (BVS) e Scientific Electronic Library Online (SCIELO). Assim, foram identificados 172 artigos, submetidos aos critérios de inclusão: idioma (inglês e português) e ano de publicação (últimos 5 anos) e aos critérios de exclusão, limitando artigos repetidos e que não respondiam ao problema da pesquisa, restando 35 artigos. Resultados: Dentre os antivirais avaliados, o tecovirimat sugere o melhor perfil de segurança nos modelos avaliados, além de um perfil de eficácia maior quando comparado aos demais. Conclusão: Pode-se concluir que o uso de antivirais no tratamento da varíola dos macacos em relação a segurança e a eficácia no combate a doença é majoritariamente favorável. Entretanto, as conclusões ainda não são totalmente precisas, tendo em vista a limitação dos escassos ensaios conduzidos em humanos, sendo necessários estudos em larga escala para melhor elucidar os perfis de segurança e eficácia dos medicamentos antivirais. ABSTRACT Objective: To evaluate the safety, efficacy and use of antivirals such as tecovirimat, brincidofovir, cidofovir, among others, according to recent research in humans, animals and in vitro.
... As a result, healthcare system tries to deal with the symptoms, term of sustainability, and try to minimize the consequences. The World Health Organization has published an interim appropriate [10,16,17] Monkeypox is a significant worldwide health risk that may spread across borders and spread quickly. While ideal disease management and treatment solutions for this extremely hazardous illness have yet to be established, the very first data suggest brincidofovir has limited efficiency; consequently, further research into tecovirimat in human monkeypox is essential. ...
... Treatment of human Monkeypox is mainly symptomatic as there are no drugs developed specifically for monkeypox treatment. Due to the cross sensitivity among the orthopoxviruses, an antiviral drug, tecovirimat, developed for management of smallpox is used in a small percentage of cases, specifically in individuals who have or are prone to developing severe form of the disease including immunocompromised persons and individuals with skin conditions such as eczema (69,70). Cidofovir is also used for treatment in some infected persons (60). ...
The current monkeypox outbreak is a public health emergency of international concern and is coming in the wake of the SARS-CoV-2 pandemic. Human monkeypox is a viral zoonotic infection caused by monkeypox virus, an enveloped double-stranded DNA virus of the genus Orthopoxvirus and family Poxviridae that also contain smallpox, cowpox, Orf, and vaccinia viruses. Online databases including PubMed, Google Scholar and Web of Science were searched to obtain relevant publications on the epidemiology, treatment, vaccines and the economic impacts of the current monkeypox (Mpox) outbreak.
... Treatment of human Monkeypox is mainly symptomatic as there are no drugs developed specifically for monkeypox treatment. Due to the cross sensitivity among the orthopoxviruses, an antiviral drug, tecovirimat, developed for management of smallpox is used in a small percentage of cases, specifically in individuals who have or are prone to developing severe form of the disease including immunocompromised persons and individuals with skin conditions such as eczema (69,70). Cidofovir is also used for treatment in some infected persons (60). ...
The current monkeypox outbreak is a public health emergency of international concern and is coming in the wake of the SARS-CoV-2 pandemic. Human monkeypox is a viral zoonotic infection caused by monkeypox virus, an enveloped double-stranded DNA virus of the genus Orthopoxvirus and family Poxviridae that also contain smallpox, cowpox, Orf, and vaccinia viruses. Online databases including PubMed, Google Scholar and Web of Science were searched to obtain relevant publications on the epidemiology, treatment, vaccines and the economic impacts of the current monkeypox (Mpox) outbreak.
... The use of antiviral medication should be considered an option for children under the age of eight, children suffering from conditions such as eczema and other skin disorders, as well as children with immunocompromised systems [1]. The safety experiments on about 360 volunteers were conducted as part of the approval process to determine whether tecovirimat has any adverse effects, and the results showed that its adverse effect profile was comparable to that of a placebo [73]. As far as side effects are concerned, headaches, nausea, and abdominal pain are the most commonly reported side effects. ...
In the wake of the emergence and worldwide respread of a viral infection called Monkeypox (Mpox), there is a serious threat to the health and safety of the global population. This viral infection was endemic to the western and central parts of Africa, but has recently spread out of this endemic area to various countries, including the United Kingdom (UK), Portugal, Spain, the United States of America (USA), Canada, Sweden, Belgium, Italy, Australia, Germany, France, the Netherlands, Israel, and Mexico. This is a timely review focusing on recent findings and developments in the epidemiology, clinical features, therapeutic targets, diagnosis, prevention mechanisms, research challenges and possible treatment for Mpox. To date (29 November 2022), there have been around 81,225 reported cases of Mpox. In most cases, this illness is mild; however, there is a fatality rate ranging from 1 to 10%, which might be increased due to associated complications and/or secondary infections. There is a real challenge in the diagnosis of Mpox, since its symptoms are very similar to those of other infections, including smallpox and chickenpox. Generally, to prevent/limit the risk and transmission of Mpox, the detection and isolation of infected individuals, as well as hand hygiene and cleanliness, are essential and effective approaches to control/combat this viral infection. Nevertheless, updated information about Mpox from different angles is lacking. Thus, this review provides updated and comprehensive information about the Mpox illness, which should highlight the global burden, pathogenicity, symptoms, diagnosis, prevention measures and possible treatment of this emerging disease.
... Brincidofovir and tecovirimat have been approved in the USA for the treatment of smallpox disease and have proven activity against monkeypox in animal studies. [23][24][25] Cytokine storm can lead to shock, hypoxemia, and secondary infection. Cytokine storm is associated with human monkeypox cases. ...
... In animals, studies have shown that tecovirimat treatment, when compared to placebo treatment, improves survival from deadly monkeypox virus infections at various illness phases [56]. Tecovirimat is also shown to reduce lesions and length of hospitalization; however, this agent is not approved for post-exposure prophylaxis [17,57]. According to the CDC's Emergency Access Investigational New Drug Protocol, tecovirimat may be used to treat infections caused by non-variola orthopoxviruses, such as monkeypox [58] (Table 3). ...
Monkeypox is a disease caused by Orthopoxvirus, which also includes the smallpox virus. Several endemics have been reported on the African continent, typically in the western and central regions. However, since 13 May 2022, there have been several cases reported from different member states; the number of confirmed cases in 1 month exceeded the total number of cases reported outside the African continent since the first case in 1970. The World Health Organization (WHO) and Centers for Disease Control (CDC) consider monkeypox as an important disease for global public health. The clinical manifestations and laboratory findings in patients with monkeypox remain unclear. In this brief review, we investigated and compared the different characteristics already reported in cases of monkeypox.
... According to many clinical trials, it has proven to be more effective against MPXV. This drug is safe and well-tolerable (Grosenbach et al. 2018). As well brincidofovir is also recommended as a first-line antiviral drug together with supportive treatment in the management of MPX (Adler et al. 2022). ...
Monkeypox (MPX) is a common zoonotic disease caused by a double-strand DNA MPX virus (MPXV). MPX was considered a sporadic rare disease causing a mild disease with a low capacity to spread among humans. The clinical picture of human MPX highly resembles smallpox, though early lymphadenopathy in human MPX is the distinguishing sign not present in smallpox. The incubation period is 1–3 weeks, and fever, headache, joint pain, myalgia, and nausea for about 3 days. Skin lesions that appear 1–3 days following fever and lymphadenopathy usually appear simultaneously on the face and periphery. By cross-reactivity and protection, the smallpox vaccine produced 85% protection against infection with Orthopoxviruses, including MPX. Antiviral drugs like tecovirimate and brincidofovir could be effective agents against the development of MPX. MPX epidemics are less reported and described as other life-threatening epidemics, leading to an unclear picture of this disease’s pathogenesis, epidemiology, and management. With the recent wide range of MPX outbreaks, immense research is mandatory to revise the importance of MPX pathogenesis and risk for epidemic development worldwide. Therefore, this critical study aimed to review MPX's pathogenesis, epidemiology, and management with possible repurposed drugs.
... Although the safety of tecovirimat and brincidofovir has been confirmed through human studies, their efficacy has been proved solely in animal models and few patients 23,24 . Therefore, antiviral use in treating human mpox remains under investigation 20 . ...
The first human infection with monkeypox virus was reported in 1970, and infections have subsequently been recorded in endemic areas such as Central and West Africa or linked to international travel to these regions. However, the emergence of the 2022 monkeypox outbreak has involved multiple non-endemic countries and continents without links to travel to endemic areas. The first cases in the current outbreak were reported in May of 2022. The primary mode of transmission is atypical and is thought to occur through direct contact with infected skin lesions. The rapid increase in case numbers prompted the World Health Organization to declare this disease outbreak as a public health emergency of international concern. Robust efforts are being made by global public health authorities to develop effective antiviral treatment options and vaccination strategies to reduce the spread of this disease. The objective of this manuscript is to provide a comprehensive review of the 2022 mpox outbreak with respect to its unique epidemiology, clinical features, complications, and management options.
... About 5% of patients with MPXV require antivirals. 11,14 There are still no well-established protocols for their use in pregnancy. ...
... 103,106 The therapeutic effects of tecovirimat on monkeypox disease have been well established in animal studies. 107,108 Of note, tecovirimat treatment significantly attenuates lethal MPXV infection-induced inflammatory effects in cynomolgus macaques. 104 Several clinical studies suggest that tecovirimat is safe and well tolerated in healthy human volunteers. ...
Human monkeypox is a viral zoonotic smallpox-like disease caused by the monkeypox virus (MPXV) and has become the greatest public health threat in the genus Orthopoxvirus after smallpox was eradicated. The host immune response to MPXV plays an essential role in disease pathogenesis and clinical manifestations. MPXV infection leads to skin lesions with the genital area as the main feature in the current outbreak and triggers a strong immune response that results in sepsis, deep tissue abscess, severe respiratory disease, and injuries to multiple immune organs. Emerging evidence shows that the immunopathogenesis of MPXV infection is closely associated with impaired NK-cell function, lymphopenia, immune evasion, increased antibodies, increased blood monocytes and granulocytes, cytokine storm, inhibition of the host complement system, and antibody-dependent enhancement. In this overview, we discuss the immunopathology and immunopathogenesis of monkeypox to aid the development of novel immunotherapeutic strategies against monkeypox.
... 21,27 Although, at present, there is no are no US FDA (Food and Drug Administration) approved treatments for Mpox specifically, some of antivirals, namely cidofovir, brincidofovir (a lipid-conjugate prodrug of cidofovir), and tecovirimat, having activity against smallpox, are reserved and used for the treatment of severe cases of monkeypox or in immunosuppressed individuals. 29,30 Apart from antiviral agents, FDA had previously approved VIGIV intravenous (vaccinia immune globulin) for the management of complications due to vaccinia immunisation, which includes progressive vaccinia and severe generalized vaccinia. 31 VIGIV provides passive immunity through specific antibodies against OPXV, which are retrieved from pooled human plasma who are vaccinated against smallpox. ...
Emerging and re-emerging zoonoses of diverse etiologies have caused significant morbidity and mortality recently. In the past two decades, several viral zoonoses, such as Bird flu, Ebola hemorrhagic fever, Hantavirus infection, Nipah virus disease, Rift Valley fever, Swine flu, West Nile fever, SARS, MERS, COVID-19 etc., have emerged from different parts of the world. The latest to the list is the “Monkey Pox”, which has recently been renamed as “Mpox” by WHO. The ongoing 2022 multi-country outbreak of monkeypox is the largest in history to occur outside of Africa. Monkeypox is an emerging zoonotic disease that for decades has been viewed as an infectious disease with significant epidemic potential because of the increasing occurrence of human outbreaks in recent years. With increasing case numbers being reported in the current outbreak, it is important for healthcare staff everywhere to update their knowledge of this zoonotic infection, including its prevention, clinical management, prophylaxis, and basics of infection control, to understand the broader implications of the current outbreak. We provide an overview of monkeypox virus infection to serve as a primer for healthcare staff who may encounter this condition in their practice.
... Tecovirimat, another antiviral that was designed and previously approved for the treatment of smallpox infection, was recently approved by the European Medical Association for the treatment of MPXV infection and is recommended in the treatment of severely ill individuals who are immunocompromised [23,24]. It has been an effective treatment that is generally well tolerated with minimal adverse effects [62][63][64][65]. ...
Amidst the ongoing monkeypox outbreak, global awareness has been directed towards the prevention of viral transmission and case management, with the World Health Organization declaring the outbreak a public health emergency of international concern. Monkeypox virus is one of several species in the Orthopoxvirus genus, with other species of the genus including the variola, cowpox, mousepox, camelpox, raccoonpox, skunkpox, and volepox viruses. Although the nomenclature of these species is based on the animal host from which they were originally isolated, transmission from animals to humans has been reported with several species. The progression of disease, following an incubation period, typically consists of a prodromal phase with systemic flu-like symptoms. Various organ systems may be affected in addition to the formation of pathognomonic skin lesions. As monkeypox poses a continued public health concern, the ophthalmic sequelae of monkeypox virus, especially those leading to vision loss, warrant consideration as well. This review provides a comprehensive summary of the ophthalmic implications of poxviruses in clinical and laboratory settings reported in the literature, as well as areas of unmet need and future research.
... In addition to nonspecific symptoms including fever and rash, common symptoms are muco-cutaneous lesions and lymphadenopathy [42][43][44]. Currently, the antipox viral agent tecovirimat, known to be effective in treating smallpox, has been recommended for individuals with symptoms of monkeypox disease [45][46][47][48]. ...
The recent monkeypox or mpox outbreak has been a global concern. The present study evaluated the global research outputs, research trends, and topics of published research on monkeypox using a bibliometric approach. The Scopus database was searched for terms associated with "monkeypox" or "monkey pox" up until 19 November 2022. Maps and bibliometric indicators of the retrieved documents were shown and analyzed. A total of 1,422 documents were obtained from Scopus. Other than monkeypox, the most commonly used terms included epidemic, disease outbreaks, smallpox vaccine, and orthopoxvirus. In total, 90.3% of the documents were published between 2002 and 2022. The United States, the United Kingdom, and India were the top three countries in terms of productivity. Most of the institutions were from the United States. The International Journal of Surgery, the Journal of Medical Virology, and the Travel Medicine and Infectious Disease are some of the top journals currently publishing research on monkeypox. Tecovirimat, coronavirus disease 2019 (COVID-19), homosexuality, and pandemic are emerging topics related to monkeypox.
We describe a rare case of severe disseminated monkeypox (MPox) virus infection complicated by peritonitis in a 44-year-old man living with well-controlled HIV. The patient was successfully treated with tecovirimat without requiring surgery. MPox should be considered in the differential diagnosis of non-bacterial peritonitis in patients at risk of infection.
Background:
Mpox was declared a Public Health Emergency of International Concern (PHEIC) by the World Health Organization (WHO) on 23 July 2022, following the identification of thousands of cases in several non-endemic countries in previous months. There are currently no licenced therapeutics for treating mpox; however, some medications may be authorized for use in an outbreak. The efficacy and safety of possible therapeutic options has not been studied in humans with mpox. There is a need to investigate the evidence on safety and effectiveness of treatments for mpox in humans; should any therapeutic option be efficacious and safe, it may be approved for use around the world.
Objectives:
There are two parts to this Cochrane Review: a review of evidence from randomized controlled trials (RCTs), and a narrative review of safety data from non-randomized studies. Randomized controlled trials review To systematically review the existing evidence on the effectiveness of therapeutics for mpox infection in humans compared to: a) another different therapeutic for mpox, or b) placebo, or c) supportive care, defined as the treatment of physical and psychological symptoms arising from the disease. Non-randomized studies review To assess the safety of therapeutics for mpox infection from non-randomized studies (NRS).
Search methods:
Randomized controlled trials review We searched the following databases up to 25 January 2023: MEDLINE (OVID), Embase (OVID), Biosis previews (Web of Science), CAB Abstracts (Web of science), and Cochrane CENTRAL (Issue 1 2023). We conducted a search of trial registries (Clinicaltrials.gov and International Clinical Trials Registry Platform (ICTRP)) on 25 January 2023. There were no date or language limits placed on the search. We undertook a call to experts in the field for relevant studies or ongoing trials to be considered for inclusion in the review. Non-randomized studies review We searched the following databases on 22 September 2022: Cochrane Central Register of Controlled Trials (CENTRAL; Issue 9 of 12, 2022), published in the Cochrane Library; MEDLINE (Ovid); Embase (Ovid); and Scopus (Elsevier). We also searched the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov for trials in progress.
Selection criteria:
For the RCT review and the narrative review, any therapeutic for the treatment of mpox in humans was eligible for inclusion, including tecovirimat, brincidofovir, cidofovir, NIOCH-14, immunomodulators, and vaccine immune globulin. Randomized controlled trials review Studies were eligible for the main review if they were of randomized controlled design and investigated the effectiveness or safety of therapeutics in human mpox infection. Non-randomized studies review Studies were eligible for inclusion in the review of non-randomized studies if they were of non-randomized design and contained data concerning the safety of any therapeutic in human mpox infection.
Data collection and analysis:
Randomized controlled trials review Two review authors independently applied study inclusion criteria to identify eligible studies. If we had identified any eligible studies, we planned to assess the risk of bias, and report results with 95% confidence intervals (CI). The critical outcomes were serious adverse events, development of disease-related complications, admission to hospital for non-hospitalized participants, pain as judged by any visual or numerical pain scale, level of virus detected in clinical samples, time to healing of all skin lesions, and mortality. We planned to perform subgroup analysis to explore whether the effect of the therapeutic on the planned outcomes was modified by disease severity and days from symptom onset to therapeutic administration. We also intended to explore the following subgroups of absolute effects: immunosuppression, age, and pre-existing skin disease. Non-randomized studies review One review author applied study inclusion criteria to identify eligible studies and extracted data. Studies of a non-randomized design containing data on the safety of therapeutics could not be meta-analyzed due to the absence of a comparator; we summarized these data narratively in an appendix.
Main results:
Randomized controlled trials review We did not identify any completed RCTs investigating the effectiveness of therapeutics for treating mpox for the main review. We identified five ongoing trials that plan to assess the effectiveness of one therapeutic option, tecovirimat, for treating mpox in adults and children. One of these ongoing trials intends to include populations with, or at greater risk of, severe disease, which will allow an assessment of safety in more vulnerable populations. Non-randomized studies review Three non-randomized studies met the inclusion criteria for the narrative review, concerning data on the safety of therapeutics in mpox. Very low-certainty evidence from non-randomized studies of small numbers of people indicates no serious safety signals emerging for the use of tecovirimat in people with mpox infection, but a possible safety signal for brincidofovir. All three participants who received brincidofovir had raised alanine aminotransferase (ALT), but not bilirubin, suggesting mild liver injury. No study reported severe drug-induced liver injury with brincidofovir.
Authors' conclusions:
Randomized controlled trials review This review found no evidence from randomized controlled trials concerning the efficacy and safety of therapeutics in humans with mpox. Non-randomized studies review Very low-certainty evidence from non-randomized studies indicates no serious safety signals emerging for the use of tecovirimat in people with mpox infection. In contrast, very low-certainty evidence raises a safety signal that brincidofovir may cause liver injury. This is also suggested by indirect evidence from brincidofovir use in smallpox. This warrants further investigation and monitoring. This Cochrane Review will be updated as new evidence becomes available to assist policymakers, health professionals, and consumers in making appropriate decisions for the treatment of mpox.
Although monkeypox (mpox) has been endemic in Western and Central Africa for 50 years, it has not received sufficient prophylactic and therapeutical attention to avoid evolving into an epidemic. From January 2022 to January 2023, more than 84,000 of mpox cases were reported from 110 countries worldwide. Case numbers appear to be rising every day, making mpox an increasing global public health threat for the foreseeable future. In this perspective, we review the known biology and epidemiology of mpox virus, together with the latest therapeutic options available for mpox treatment. Further, small molecule inhibitors against mpox virus and the future directions in this field are discussed as well.
Monkeypox is a serious public health issue in tropical and subtropical areas. Antivirals that target monkeypox proteins might lead to more effective and efficient therapy. The F13 protein is essential for the growth and maturation of the monkeypox virus. F13 inhibition might be a viable therapeutic target for monkeypox. The in silico fragment-based drug discovery method for developing antivirals may provide novel therapeutic options. In this study, we generated 800 compounds based on tecovirimat, an FDA-approved drug that is efficacious at nanomolar quantities against monkeypox. These compounds were evaluated to identify the most promising fragments based on binding affinity and pharmacological characteristics. The top hits from the chemical screening were docked into the active site of the F13 protein. Molecular dynamics simulations were performed on the top two probable new candidates from molecular docking. The ligand-enzyme interaction analysis revealed that the C2 ligand had lower binding free energy than the standard ligand tecovirimat. Water bridges, among other interactions, were shown to stabilize the C2 molecule. Conformational transitions and secondary structure changes in F13 protein upon C2 binding show more native three-dimensional folding of the protein. Prediction of pharmacological properties revealed that compound C2 may be promising as a drug candidate for monkeypox fever. However, additional in vitro and in vivo testing is required for validation.
Orthopoxvirus is one of the most notorious genus amongst the Poxviridae family. Monkeypox (MP) is a zoonotic disease that has been spreading throughout Africa. The spread is global, and incidence rates are increasing daily. The spread of the virus is rapid due to human-to-human and animals-to-human transmission. World Health Organization (WHO) has declared monkeypox virus (MPV) as a global health emergency. Since treatment options are limited, it is essential to know the modes of transmission and symptoms to stop disease spread. The information from host–virus interactions revealed significantly expressed genes that are important for the progression of the MP infection. In this review, we highlighted the MP virus structure, transmission modes, and available therapeutic options. Furthermore, this review provides insights for the scientific community to extend their research work in this field.
Introduction:
In May 2022, the World Health Organisation declared a multi-country monkeypox outbreak in non-endemic countries following cases reported from 12 member states that were not endemic for monkeypox virus.
Sources of data:
Pubmed search.
Areas of agreement:
The virology, epidemiology, transmission, incubation and aspects of infection control are described. Clinical features of previous and current outbreaks are described, with growing observations that the current outbreak presents with clinical features distinct from previous outbreaks.
Areas of controversy:
There are variations in clinical presentations seen in the current outbreak that have not been seen in prior outbreaks. More research is needed to investigate the reasons for these differences.
Growing points:
The higher numbers of HIV-positive patients in the current outbreak has allowed better description of the disease in patients co-infected with HIV and monkeypox. The absence of more severe symptoms in HIV-positive patients in the current outbreak could possibly be due to the fact that most of these patients had well-controlled HIV, although further characterization of this cohort of patients would be useful.
Areas for developing research:
Current treatment and vaccination options have been extrapolated from studies of other Orthopox viruses. There remains a need for more data on the safety and efficacy of these options in the context of monkeypox infections.
Background: Monkeypox virus infection is emerging as global outbreak in 2022. Basic knowledge about the disease, its transmission, clinical features and prevention should be provided to all healthcare providers. Aim: To assess knowledge of undergraduate medical students about Monkeypox infection. Methods: This cross-sectional study was conducted at Niazi Medical and Dental College, Sargodha between August and September 2022. Students from third to final year were included and a self-report questionnaire comprising of demographic data, source of information about infection and preventive measures based on obtainable facts from the United States Centers for Disease Control and Prevention and WHO was used.Descriptive statistical analysis was done on SPSS version 22. Results: 95.4% of participants knew about monkeypox infection out of which 87.9% reported virus as causative agent.45.4% stated direct contact as a mode of disease transmission.Two-fourth respondents didn’t know about the incubation period out of them majority were in final year.Majority learned about it through social media and most common reported symptoms were rash and fever. 34.5% were aware of the pre-emptive measures of the disease while only 1/3rd of participants were acquainted with availability of vaccine.One-fourth MBBS students, majority final year, had knowledge regarding active cases of Monkeypox in Pakistan. 2/3rd responders thought that Pakistan’s health system could not bear the burden of another outbreak. Conclusion: Knowledge of emerging monkeypox infection is limited in medical students, therefore, measures should be taken to arrange awareness programs and educational courses at institution and national levels. Keywords: Monkeypox, virus infection, global outbreak, incubation period, pre-emptive measures, medical student.
Background:
This study aims to comparatively analyze clinical features, treatment and patient outcomes between the previous and the 2022 mpox (monkeypox) outbreaks.
Methods:
Five bibliographic databases were searched for studies reporting clinical features, management and patient outcomes of mpox. Systematic review and meta-analysis were performed.
Results:
In total, 73 studies were included in the systematic review, of which 33 studies were subjected to meta-analysis. Previous outbreaks substantially affected children, whereas the 2022 outbreak primarily affected male adults, of which 94.66% (95% confidence interval (CI), 88.03-98.95) were men who have sex with men. Furthermore, 72.47% (95%CI, 51.04-89.71) performed high-risk sexual activity and the overall HIV prevalence was 37.65% (95%CI, 30.09-45.50). Skin lesions remain the typical symptom, however their anatomic distribution differs. Systemic manifestations are common, but rectal pain was unique to the 2022 outbreak. The estimated overall fatality during past outbreaks in Africa is 4.61% (95%CI, 2.39-7.35), whereas 6.34% (95%CI, 3.35-10.10) patients from the 2022 outbreak required hospitalization. Antiviral treatment in particular tecovirimat has been prescribed for a subset of patients, but the efficacy remains inconclusive.
Conclusions:
These findings are important for better understanding the disease and guiding adequate response to mpox outbreaks.
Monkeypox virus is a zoonotic orthopoxvirus that can cause Mpox (previously known as Human Monkeypox) [1], an illness clinically similar to smallpox, although with a far less severe course and lower mortality [2]. This article is protected by copyright. All rights reserved.
Objective:
This article reviews the published data encompassing the development, pharmacology, efficacy, and safety of brincidofovir, a nucleotide analogue DNA polymerase inhibitor developed for the treatment of smallpox.
Data sources:
A literature review was conducted in PubMed, MEDLINE, and Clinicaltrials.gov from inception up to December 2022, using terms Tembexa, brincidofovir, CMX001, smallpox treatment, and variola treatment.
Study selection and data extraction:
Data were limited to studies published in English language, which evaluated the efficacy and safety of brincidofovir.
Data synthesis:
Two surrogate animal models were included in the Food and Drug Administration's (FDA) decision to approve brincidofovir: ectromelia virus in mice and rabbitpox in rabbits. Phases 2 and 3 studies established safety for approval. Brincidofovir biweekly for the treatment of disseminated adenovirus disease resulted in all-cause mortality, ranging from 13.8% to 29%. In a study for cytomegalovirus prophylaxis, patients with clinically significant cytomegalovirus infection through week 24 posttransplant was 51.2% with brincidofovir and 52.3% with placebo.
Conclusions:
Brincidofovir adds a second oral agent to treat smallpox, with a different mechanism of action than tecovirimat. In the event of a smallpox outbreak, prompt treatment will be necessary to contain its spread. Brincidofovir shows efficacy in surrogate animal models. In healthy volunteers and individuals treated, or used as prophylaxis, for cytomegalovirus or adenovirus, the primary adverse events were gastrointestinal in addition to transient hepatotoxicity. Additionally, excessive deaths were observed in hematopoietic cell transplant patients receiving it as cytomegalovirus prophylaxis, requiring a black box warning.
Background
A global outbreak of the human monkeypox virus (HMPXV), first identified in May 2022, was declared a health emergency of international concern on 23 July 2022. Before the global outbreak, monkeypox cases were mostly confined to central and west African countries, where this virus is prevalent. Close contact, mainly sexual contact, is supposed to be the main route of transmission, and it is remarkable that the incidence is higher in men who have sexual relationships with other men.
Case summary
A 40-year-old Caucasian man arrived at the emergency department complaining of oppressive epigastric pain extending to the chest after a diagnosis of pharyngitis, which was suspected to be caused by the human monkeypox virus. Based on the clinical symptoms, physical examination, serum cardiac biomarkers, and electrocardiographic findings, he was diagnosed with myopericarditis. The real-time PCR for human monkeypox in skin lesions, urine, plasma, and the oropharyngeal swab was positive. The peak of troponin I was 20.6 ng/ml, and the electrocardiogram showed an upward concavity in the ST segment in diffuse leads, which was in agreement with the previous diagnosis. The presence of edema, subepicardial, and myocardial late gadolinium enhancement, and increased values on T1 mapping in the cardiac MRI were in agreement with the diagnosis of myopericarditis. Antiviral treatment with tecovirimat was started with excellent tolerability. After 6 days, the patient recovered and was discharged.
Discussion
To our knowledge, this is one of the first reported cases of myopericarditis due to human monkeypox infection, which was confirmed by a cardiac MRI following modified Lake Louise criteria. The short span between the onset of the mucocutaneous symptoms and the myocardial damage suggests a pathogenic association. Furthermore, the active viral replication in plasma samples and the negative results on real-time PCR for other viruses support this clinical association.
Opinion statement
Herein, we review the clinical course of mpox, treatment options, and prevention strategies in immunocompromised hosts. As there are limited publications on mpox in the immunocompromised, we also explore other human-infecting poxviruses. Poxviruses share genomic, structural, and for Orthopoxviruses, antigenic similarities, suggesting that study of one species can inform our expectations for host and pathogen interactions and treatment response in another. We attempt to make inferences from this review but also identify ongoing research needs for mpox in immunocompromised individuals. The yearly number of mpox cases has been increasing since the cessation of mass smallpox vaccination campaigns. A global mpox outbreak started in May 2022 placing immunocompromised individuals at heightened risk and necessitating a better understanding of how the disease course is modified by compromised immunity. Review of poxviridae case reports, including mpox, shows that many of the most severe cases have been in immunocompromised individuals. In vitro, animal studies, and limited case reports suggest that the therapeutics tecovirimat, cidofovir, brincidofovir, and vaccinia immune globulin IV may attenuate disease severity, but large-scale clinical trial data is needed to better evaluate efficacy. Vaccination is also an important countermeasure for protecting vulnerable populations.
The antiviral drugs tecovirimat, brincidofovir, and cidofovir are considered for mpox (monkeypox) treatment despite a lack of clinical evidence. Moreover, their use is affected by toxic side-effects (brincidofovir, cidofovir), limited availability (tecovirimat), and potentially by resistance formation. Hence, additional, readily available drugs are needed. Here, therapeutic concentrations of nitroxoline, a hydroxyquinoline antibiotic with a favourable safety profile in humans, inhibited the replication of 12 mpox virus isolates from the current outbreak in primary cultures of human keratinocytes and fibroblasts and a skin explant model by interference with host cell signalling. Tecovirimat, but not nitroxoline, treatment resulted in rapid resistance development. Nitroxoline remained effective against the tecovirimat-resistant strain and increased the anti-mpox virus activity of tecovirimat and brincidofovir. Moreover, nitroxoline inhibited bacterial and viral pathogens that are often co-transmitted with mpox. In conclusion, nitroxoline is a repurposing candidate for the treatment of mpox due to both antiviral and antimicrobial activity.
While human beings are still facing the challenges of the pandemic coronavirus disease (COVID-19), a new viral disease, monkeypox raises concerns among healthcare authorities about this new threat. Since May 2022, thousands of people have been affected by a continuous monkeypox outbreak linked to close contact transmission in numbers of nonendemic nations. The Food and Drug Administration (FDA) has not yet approved any medications to treat monkeypox in humans. However, medications created for smallpox patients, such as antivirals and other medical countermeasures, might also be effective against monkeypox. Tecovirimat (TPOXX), brincidofovir, cidofovir antivirals and Vaccinia Immune Globulin Intravenous (VIGIV) are the medical countermeasures for the treatment of monkeypox. The second and third generations of smallpox vaccinations have been developed after many years of research. Some of these vaccines may also be beneficial for monkeypox. Three vaccinations, MVA-BN, LC16, or ACAM2000 can be used for monkeypox. Two of these (MVA-BN and LC16) have received approval for the purpose of preventing monkeypox. Considering the current vaccine shortage, widespread immunisation is not advised. Therefore, prevention is the best policy to keep everyone safe. The current review highlights the treatment available for the management of monkeypox. It also reviewed the preventive measures that human beings should take to protect themselves from monkeypox infection.
Purpose
To report a case of ocular involving monkeypox infection in the United States during the 2022 outbreak, and to review the literature regarding its clinical manifestations and management known to date.
Observations
A 36-year-old man with well controlled HIV presented to the emergency department with anal pain, diffuse rash, right eye pain, and right eye redness after he tested positive for monkeypox one week prior. Ocular examination showed bilateral periorbital vesicular lesions, right eye conjunctival injection, and a single white plaque on his right medial bulbar conjunctiva. Macular, vesicular, and pustular lesions throughout his body, including the genital and perianal region, were also noted. His ocular and systemic symptoms completely resolved after treatment with a ten-day course of 1% trifluridine and moxifloxacin drops in both eyes, as well as two weeks of oral tecovirimat.
Conclusions
and Importance: In July of 2022, monkeypox virus was declared a global health emergency by the World Health Organization; however, there are no standard guidelines for monkeypox treatment. Data on its clinical presentation and course, especially pertaining to ocular manifestations, is limited. We highlight the importance of recognizing ophthalmic manifestations of monkeypox virus and a possible therapeutic approach to help guide the management of these patients.
The therapeutic efficacy of smallpox vaccine ACAM2000® and antiviral tecovirimat given alone or in combination starting on Day 3 post-infection were compared in cynomolgus macaque model of lethal monkeypox virus infection. Post-exposure administration of ACAM2000® alone did not provide any protection against severe monkeypox disease or mortality. By contrast, post-exposure treatment with tecovirimat alone or in combination with ACAM2000® provided full protection. Additionally, tecovirimat treatment delayed until Days 4, 5, or 6 post-infection was 83% (Days 4 and 5) and 50% (Day 6) effective, respectively.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
Naturally occurring smallpox has been eradicated but remains a considerable threat as a biowarfare/bioterrorist weapon (1). While effective, the smallpox vaccine is currently not recommended for routine use in the general public due to safety concerns (2). Safe and effective countermeasures, particularly those effective after exposure to smallpox, are needed. Currently, SIGA Technologies is developing the small-molecule oral drug, tecovirimat (previously known as ST-246) as a post-exposure therapeutic treatment of orthopoxvirus disease, including smallpox. Tecovirimat has been shown to be efficacious in preventing lethal orthopoxviral disease in numerous animal models (3-5). Furthermore, in clinical trials thus far, the drug appears to be safe, with a good pharmacokinetic profile. In this study, the efficacy of tecovirimat was evaluated in both a pre-lesional and post-lesional setting in non-human primates challenged intravenously with 1x10(8) plaque-forming units of Variola virus (VARV, the causative agent of smallpox), a model for smallpox disease in humans. Following challenge, 50% of placebo-treated controls succumbed to infection while all tecovirimat-treated animals survived regardless of whether treatment was started at 2 or 4 days post-infection. In addition, tecovirimat treatment resulted in dramatic reductions in dermal lesion counts, oropharyngeal virus shedding, and viral DNA circulating in the blood. Although clinical disease was evident in tecovirimat-treated animals, it was generally very mild and appeared to resolve earlier than placebo-treated controls that survived infection. Tecovirimat appears to be an effective smallpox therapeutic in non-human primates, suggesting that it is reasonably likely to provide therapeutic benefit in smallpox-infected humans.
Although smallpox has been eradicated, the United States government considers it a “material threat” and has funded the discovery
and development of potential therapeutic compounds. As reported here, the human efficacious dose for one of these compounds,
ST-246, was determined using efficacy studies in nonhuman primates (NHPs), together with pharmacokinetic and pharmacodynamic
analysis that predicted the appropriate dose and exposure levels to provide therapeutic benefit in humans. The efficacy analysis
combined the data from studies conducted at three separate facilities that evaluated treatment following infection with a
closely related virus, monkeypox virus (MPXV), in a total of 96 NHPs. The effect of infection on ST-246 pharmacokinetics in
NHPs was applied to humans using population pharmacokinetic models. Exposure at the selected human dose of 600 mg is more
than 4-fold higher than the lowest efficacious dose in NHPs and is predicted to provide protection to more than 95% of the
population.
ST-246 is being evaluated as a treatment for pathogenic orthopoxvirus infections in humans. To this end, a phase 2, double-blind,
randomized, placebo-controlled, multicenter trial was conducted to assess the safety, tolerability, and pharmacokinetics (PK)
of ST-246 when administered as a single daily oral dose (400 mg or 600 mg) for 14 days in fed adult volunteers. ST-246 was
safe and well tolerated, with no deaths or serious adverse events reported during the study. There was a low incidence of
treatment-emergent adverse events (TEAEs), the most common of which were mild nausea and headache. There were no clinically
significant results from laboratory assessments, vital sign measurements, physical examinations, or electrocardiograms. The
PK and dose proportionality of ST-246 were determined. The PK analysis showed that steady state was achieved by day 5 for
the ST-246 400-mg treatment group and by day 6 for the 600-mg group. The dose proportionality analysis showed that the 400-
and 600-mg ratio of dose-normalized peak drug concentration in plasma (Cmax) and relative exposure for each dosing interval (AUCτ) ranged from 80% to 85%. However, the 90% confidence intervals did not include 1.0, so dose proportionality could not be
concluded. Overall, ST-246 was shown to be safe, and the PK was predictable. These results support further testing of ST-246
in a multicenter pivotal clinical safety study for licensure application.
The vaccinia virus strain Western Reserve (WR) A34R gene encodes a C-type lectin-like glycoprotein, gp22-24, that is present in the outer membrane of extracellular enveloped virus (EEV) with type II membrane topology (S.A. Duncan and G.L. Smith, J. Virol. 66:1610-1621, 1992). Here we that a WR A34R deletion mutant (WR delta A34R) released 19- to 24-fold more EEV from infected cells than did WR virus, but the specific infectivity of the released virions was reduced 5- to 6-fold. Rupture of the WR delta A34R EEV outer envelope by freeze-thawing increased virus infectivity by five- to sixfold, because of the release of infectious intracellular mature virus. All other known EEV-specific proteins are incorporated into WR delta A34R EEV, and thus the loss of gp22-24 is solely responsible for the reduction of EEV specific infectivity. The WR delta A34R virus is highly attenuated in vivo compared with WR or a revertant virus in which the A34R gene was reinserted into WR delta A34R. This attenuation is consistent with the known important role of EEV in virus dissemination and virulence. Vaccinia virus strain International Health Department-J (IHD-J) produces large amounts of EEV and forms comets because of an amino acid substitution within the A34R protein (R. Blasco, R. Sisler, and B. Moss, J. Virol. 67:3319-3325, 1993), but despite this, IHD-J EEV has a specific infectivity equivalent to that of WR EEV. Substitution of the IHD-J A34R gene into the WR strain induced comet formation and greater release of EEV, while coexpression of both genes did not; hence, the WR phenotype is dominant. All orthopoxviruses tested express the A34R protein, but most viruses, including variola virus, have the WR rather than the IHD-J A34R genotype. The A34R protein affects plaque formation, EEV release, EEV infectivity, and virus virulence.
ST-246, a novel compound that inhibits egress of orthopoxvirus from infected cells, is being evaluated as a treatment for
pathogenic orthopoxvirus infections in humans. This phase I, double-blind, randomized, placebo-controlled, escalating multiple-dose
study was conducted to determine the safety, tolerability, and pharmacokinetics of ST-246 administered as a single daily oral
dose of 250, 400, or 800 mg for 21 days to nonfasting healthy human volunteers. ST-246 appeared to be well tolerated, with
no serious adverse events (AEs). Headache, for which one subject in the 800-mg group discontinued the study, was the most
commonly reported AE in all treatment groups. The multiple-dose pharmacokinetics of ST-246 was well characterized. The day
21 mean elimination half-lives were calculated at 18.8, 19.8, and 20.7 h for each of the 250-, 400-, and 800-mg/day dose groups,
respectively. Steady state was reached by day 6 (within 3 to 5 half-lives), saturable absorption was observed at the 800-mg
dose level, and the fraction of parent drug excreted in the urine was very low. Based on these results, administration of
400 mg/day ST-246 can be expected to provide plasma concentrations above the efficacious concentration demonstrated in nonhuman
primate models in earlier studies.
ST-246, a potent orthopoxvirus egress inhibitor, is safe and effective at preventing disease and death in studies of small-animal
models involving challenge by several different pathogenic poxviruses. In this report, the antiviral efficacy of ST-246 in
treatment of nonhuman primates infected with variola virus or monkeypox virus was assessed. The data indicate that oral dosing
once per day with ST-246 protects animals from poxvirus disease, as measured by reductions in viral load and numbers of lesions
and enhancement of survival.
Therapeutics for the treatment of pathogenic orthopoxvirus infections are being sought. In the absence of patients with disease,
animal models of orthopoxvirus disease are essential for evaluation of the efficacies of antiviral drugs and establishment
of the appropriate dose and duration of human therapy. Infection of nonhuman primates (NHP) by the intravenous injection of
monkeypox virus has been used to evaluate a promising therapeutic drug candidate, ST-246. ST-246 administered at 3 days postinfection
(which corresponds to the secondary viremia stage of disease) at four different doses (from 100 mg/kg of body weight down
to 3 mg/kg) once a day for 14 days was able to offer NHP 100% protection from a lethal infection with monkeypox virus and
reduce the viral load and lesion formation. In NHP, the administration of ST-246 at a dose of 10 mg/kg/day for 14 days resulted
in levels of blood exposure comparable to the levels attained in humans administered 400 mg in the fed state. These results
suggest that administration of an oral dosage of 400 mg once daily for 14 days will be effective for the prevention or treatment
of smallpox or monkeypox infections in humans.
There are two types of infectious vaccinia virus particles: intracellular naked virions and extracellular enveloped virions (EEV). To determine the biological role of the enveloped form of vaccinia virus, we produced and characterized a mutant that is defective in EEV formation. The strategy involved replacement by homologous recombination of the gene F13L, encoding a 37,000-Da protein (VP37) that is specific for the outer envelope of EEV, with a selectable antibiotic resistance marker, the Escherichia coli gpt gene. Initial experiments, however, suggested that such a mutation was lethal or prevented plaque formation. By employing a protocol consisting of high-multiplicity passages of intracellular virus from the transfected cells and then limiting dilution cloning, we succeeded in isolating the desired mutant, which was defective in production of plaques and extracellular virus but made normal amounts of intracellular naked virions. Electron microscopic examination indicated that the mutant virus particles, unlike wild type, were neither wrapped with Golgi-derived membranes nor associated with the cell surface. The absence of VP37 did not prevent the transport of the viral hemagglutinin to the plasma membrane but nevertheless abrogated both low-pH- and antibody-mediated cell fusion. These results indicate that VP37 is required for EEV formation and also plays a critical role in the local cell-to-cell transmission of vaccinia virus, perhaps via enveloped virions attached to or released from the cell membrane. By contrast, a mutated virus with a deletion of the K4L open reading frame, which is a homolog of the VP37 gene, was not defective in formation of plaques or EEV.
Vaccinia virus produces four different types of virion from each infected cell called intracellular mature virus (IMV), intracellular enveloped virus (IEV), cell-associated enveloped virus (CEV) and extracellular enveloped virus (EEV). These virions have different abundance, structure, location and roles in the virus life-cycle. Here, the formation and function of these virions are considered with emphasis on the EEV form and its precursors, IEV and CEV. IMV is the most abundant form of virus and is retained in cells until lysis; it is a robust, stable virion and is well suited to transmit infection between hosts. IEV is formed by wrapping of IMV with intracellular membranes, and is an intermediate between IMV and CEV/EEV that enables efficient virus dissemination to the cell surface on microtubules. CEV induces the formation of actin tails that drive CEV particles away from the cell and is important for cell-to-cell spread. Lastly, EEV mediates the long-range dissemination of virus in cell culture and, probably, in vivo. Seven virus-encoded proteins have been identified that are components of IEV, and five of them are present in CEV or EEV. The roles of these proteins in virus morphogenesis and dissemination, and as targets for neutralizing antibody are reviewed. The production of several different virus particles in the VV replication cycle represents a coordinated strategy to exploit cell biology to promote virus spread and to aid virus evasion of antibody and complement.
ST-246 is a low-molecular-weight compound (molecular weight = 376), that is potent (concentration that inhibited virus replication by 50% = 0.010 microM), selective (concentration of compound that inhibited cell viability by 50% = >40 microM), and active against multiple orthopoxviruses, including vaccinia, monkeypox, camelpox, cowpox, ectromelia (mousepox), and variola viruses. Cowpox virus variants selected in cell culture for resistance to ST-246 were found to have a single amino acid change in the V061 gene. Reengineering this change back into the wild-type cowpox virus genome conferred resistance to ST-246, suggesting that V061 is the target of ST-246 antiviral activity. The cowpox virus V061 gene is homologous to vaccinia virus F13L, which encodes a major envelope protein (p37) required for production of extracellular virus. In cell culture, ST-246 inhibited plaque formation and virus-induced cytopathic effects. In single-cycle growth assays, ST-246 reduced extracellular virus formation by 10 fold relative to untreated controls, while having little effect on the production of intracellular virus. In vivo oral administration of ST-246 protected BALB/c mice from lethal infection, following intranasal inoculation with 10x 50% lethal dose (LD(50)) of vaccinia virus strain IHD-J. ST-246-treated mice that survived infection acquired protective immunity and were resistant to subsequent challenge with a lethal dose (10x LD(50)) of vaccinia virus. Orally administered ST-246 also protected A/NCr mice from lethal infection, following intranasal inoculation with 40,000x LD(50) of ectromelia virus. Infectious virus titers at day 8 postinfection in liver, spleen, and lung from ST-246-treated animals were below the limits of detection (<10 PFU/ml). In contrast, mean virus titers in liver, spleen, and lung tissues from placebo-treated mice were 6.2 x 10(7), 5.2 x 10(7), and 1.8 x 10(5) PFU/ml, respectively. Finally, oral administration of ST-246 inhibited vaccinia virus-induced tail lesions in Naval Medical Research Institute mice inoculated via the tail vein. Taken together, these results validate F13L as an antiviral target and demonstrate that an inhibitor of extracellular virus formation can protect mice from orthopoxvirus-induced disease.
The pathogenicity and immunogenicity in mice of WR.cl and WR.c3, two mutants of the Western Reserve (WR) strain of vaccinia virus, mutated in the A33R and B5R proteins of the outer envelope of the virus, respectively, were studied. WR.c1 was the most attenuated virus, WR.c3 was somewhat more pathogenic, while WR was the most virulent of the three. While the WR and the WR.c3 viruses, intranasally inoculated into mice, spread efficiently to the different internal organs of the animal, including the brain, WR.c1 was restricted to the lungs only. Mice, intranasally infected with 500 plaque forming units of the WR, WR.c1, or WR.c3 viruses, were protected against infection with a lethal dose of the WR strain.
ST-246 was evaluated for activity against cowpox virus (CV), vaccinia virus (VV), and ectromelia virus (ECTV) and had an in
vitro 50% effective concentration (EC50) of 0.48 μM against CV, 0.05 μM against VV, and 0.07 μM against ECTV. The selectivity indices were >208 and >2,000 for CV
and VV, respectively. The in vitro antiviral activity of ST-246 was significantly greater than that of cidofovir, which had
an EC50 of 41.1 μM against CV and 29.2 μM against VV, with selectivity indices of >7 and >10, respectively. ST-246 administered once
daily by oral gavage to mice infected intranasally with CV beginning 4 h or delayed until 72 h postinoculation was highly
effective when given for a 14-day duration using 100, 30, or 10 mg/kg of body weight. When 100 mg/kg of ST-246 was administered
to VV-infected mice, a duration of 5 days was sufficient to significantly reduce mortality even when treatment was delayed
24 h postinoculation. Viral replication in liver, spleen, and kidney, but not lung, of CV- or VV-infected mice was reduced
by ST-246 compared to levels for vehicle-treated mice. When 100 mg/kg of ST-246 was given once daily to mice infected by the
intranasal route with ECTV, treatment for 10 days prevented mortality even when treatment was delayed up to 72 h after viral
inoculation. Viral replication in target organs of ECTV-infected mice was also reduced.
The threat of smallpox release and use as a bioweapon has encouraged the search for new vaccines and antiviral drugs, as well as development of new small-animal models in which their efficacy can be determined. Here, we reinvestigate a rabbit model in which the intradermal infection of rabbits with very low doses of either rabbitpox virus (RPV) or vaccinia virus Western Reserve (VV-WR) recapitulates many of the clinical features of human smallpox. Following intradermal inoculation with RPV, rabbits develop systemic disease characterized by extensive viremia, numerous secondary lesions on the skin and mucocutaneous tissues, severe respiratory disease, death by 9 days postinfection, and, importantly, natural aerosol transmission between animals. Contrary to previous reports, intradermal infection with VV-WR also resulted in a very similar lethal systemic disease in rabbits, again with natural aerosol transmission between animals. When sentinel and index animals were cohoused, transmission rates approached 100% with either virus, with sentinel animals exhibiting a similar, severe disease. Lower rates of transmission were observed when index and sentinel animals were housed in separate cages. Sentinel animals infected with RPV with one exception succumbed to the disease. However, the majority of VV-WR-infected sentinel animals, while becoming seriously ill, survived. Finally, we tested the efficacy of the drug 1-O-hexadecyloxypropyl-cidofovir in the RPV/rabbit model and found that an oral dose of 5 mg/kg twice a day for 5 days beginning 1 day before infection was able to completely protect rabbits from lethal disease.
The combination of ST-246 and hexadecyloxypropyl-cidofovir or CMX001 was evaluated for synergistic activity in vitro against vaccinia virus and cowpox virus (CV) and in vivo against CV. In cell culture the combination was highly synergistic against both viruses, and the results suggested that combined treatment with these agents might offer superior efficacy in vivo. For animal models, ST-246 was administered orally with or without CMX001 to mice lethally infected with CV. Treatments began 1, 3, or 6 days postinfection using lower dosages than previously used for single-drug treatment. ST-246 was given at 10, 3, or 1 mg/kg of body weight with or without CMX001 at 3, 1, or 0.3 mg/kg to evaluate potential synergistic interactions. Treatment beginning 6 days post-viral inoculation with ST-246 alone only increased the mean day to death at 10 or 3 mg/kg but had no effect on survival. CMX001 alone also had no effect on survival. When the combination of the two drugs was begun 6 days after viral infection using various dosages of the two, a synergistic reduction in mortality was observed. No evidence of increased toxicity was noted with the combination either in vitro or in vivo. These results indicate that combinations of ST-246 and CMX001 are synergistic both in vitro and in vivo and suggest that combination therapy using ST-246 and CMX001 for treatment of orthopoxvirus disease in humans or animals may provide an additional benefit over the use of the two drugs by themselves.
ST-246 is a novel, potent orthopoxvirus egress inhibitor that is being developed to treat pathogenic orthopoxvirus infections
of humans. This phase I, double-blind, randomized, placebo-controlled single ascending dose study (first time with humans)
was conducted to determine the safety, tolerability, and pharmacokinetics of ST-246 in healthy human volunteers. ST-246 was
administered in single oral doses of 500, 1,000, and 2,000 mg to fasting healthy volunteers and 1,000 mg to nonfasting healthy
volunteers. ST-246 was generally well tolerated with no serious adverse events, and no subject was withdrawn from the study
due to ST-246. The most commonly reported drug-related adverse event was neutropenia, which was found, upon further analysis,
not to be treatment related. ST-246 was readily absorbed following oral administration with mean times to maximum concentration
from 2 h to 3 h. Absorption was greater in nonfasting volunteers than in fasting volunteers. Administration of ST-246 resulted
in exposure levels predicted to be sufficient for inhibiting orthopoxvirus replication compared to exposure levels in nonhuman
primates in which ST-246 protected animals from lethal orthopoxvirus infection.
Reconstitution of horsepox virus from mail-order DNA reignites synthetic biology debate
Efficacy of the new antipoxvirus compound ST-246 was evaluated as treatment of monkeypox (MPX) virus infection in a ground squirrel model of the disease. Ground squirrels were given a lethal dose of MPX virus and were then treated orally at various times post-inoculation (pi) with 100 mg/kg/day of ST-246. Morbidity and mortality, clinical laboratory results, viral load, and pathology of placebo and treatment groups were compared. All animals that started treatment with ST-246 on days 0, 1, 2, and 3 pi survived lethal challenge with MPX virus; 67% of animals treated on day 4 pi also survived. In contrast, 100% of the placebo group died. Most of the ST-246-treated animals showed no evidence of clinical disease or alteration of baseline clinical laboratory values and had minimal histopathologic changes. These results suggest that ST-246 is a promising candidate for early treatment of severe orthopoxvirus infection.
The significance of extracellular enveloped vaccinia (EEV) for the in vitro and in vivo dissemination of vaccinia virus was investigated. The quantity of in vitro released extracellular virus correlated very closely with the ability of 13 vaccinia strains to cause long-range spread of infection (comet formation) in cell cultures infected at low m.o.i. but was not correlated with plaque size. The kinetics of virus spread after low m.o.i. was related to the amount of virus released from primary infected cells but not to their content of intracellular naked vaccinia (INV). Most extracellular vaccinia virus from IHD-J-infected RK-13 cells banded in CsCl density gradients as EEV (88%) while very little banded as INV (2%). Antisera to the enveloped prevented comet formation while antisera to INV did not. CsCl centrifugation of blood-borne extracellular virus from rabbits infected intravenously with vaccinia virus after cyclophosphamide treatment revealed that 64% of the virus banded as EEV but only 11% as INV. High in vitro EEV-yielding vaccinia strains were able to spread from the respiratory tract to the brains of mice and cause death. Low in vitro EEV-yielding vaccinia strains were generally not able to disseminate in vivo or cause mouse mortality. The notable exception to this trend was strain WR, which, although releasing small amounts of virus in vitro, could nevertheless very effectively disseminate in vivo, causing a high rate of mouse mortality. Treatment with anti-envelope serum protected mice from a lethal vaccinia infection whereas antiserum to inactivated INV did not. These results indicate that the in vitro dissemination of vaccinia infection is mediated by EEV and implicate EEV as having a role in the in vivo dissemination.
The structure, formation, and function of the virion membranes are among the least well understood aspects of vaccinia virus replication. In this study, we investigated the role of gp42, a glycoprotein component of the extracellular enveloped form of vaccinia virus (EEV) encoded by the B5R gene. The B5R gene was deleted by homologous recombination from vaccinia virus strains IHD-J and WR, which produce high and low levels of EEV, respectively. Isolation of recombinant viruses was facilitated by the insertion into the genome of a cassette containing the Escherichia coli gpt and lacZ genes flanked by the ends of the B5R gene to provide simultaneous antibiotic selection and color screening. Deletion mutant viruses of both strains formed tiny plaques, and those of the IHD-J mutant lacked the characteristic comet shape caused by release of EEV. Nevertheless, similar yields of intracellular infectious virus were obtained whether cells were infected with the B5R deletion mutants or their parental strains. In the case of IHD-J, however, this deletion severely reduced the amount of infectious extracellular virus. Metabolic labeling studies demonstrated that the low extracellular infectivity corresponded with a decrease in EEV particles in the medium. Electron microscopic examination revealed that mature intracellular naked virions (INV) were present in cells infected with mutant virus, but neither membrane-wrapped INV nor significant amounts of plasma membrane-associated virus were observed. Syncytium formation, which occurs in cells infected with wild-type WR and IHD-J virus after brief low-pH treatment, did not occur in cells infected with the B5R deletion mutants. By contrast, syncytium formation induced by antibody to the viral hemagglutinin occurred, suggesting that different mechanisms are involved. When assayed by intracranial injection into weanling mice, both IHD-J and WR mutant viruses were found to be significantly attenuated. These findings demonstrate that the 42-kDa glycoprotein of the EEV is required for efficient membrane enwrapment of INV, externalization of the virus, and transmission and that gp42 contributes to viral virulence in strains producing both low and high levels of EEV.
Biological weapons have recently attracted the attention and the resources of the nation. Discerning the nature of the threat
of bioweapons as well as appropriate responses to them requires greater attention to the biological characteristics of these
instruments of war and terror. The dominant paradigm of a weapon as a nuclear device that explodes or a chemical cloud that
is set adrift leaves us ill-equipped conceptually and practically to assess and thus to prevent the potentially devastating
effects of bioterrorism. Strengthening the public health and infectious disease infrastructure is an effective step toward
averting the suffering that could be wrought by a terrorist's use of a biological agent.
The potential consequences of a competently executed smallpox attack have not been adequately considered by policy makers.
The possibility of release of an aerosolized and/or bioengineered virus must be anticipated and planned for. The transmission
and infectivity of variola virus are examined. Arguments for and against pre-event vaccination are offered. The likely morbidity
and mortality that would ensue from implementation of a mass pre-event vaccination program, within reasonable boundaries,
are known. The extent of contagion that could result from an aerosolized release of virus is unknown and may have been underestimated.
Pre-event vaccination of first responders is urged, and voluntary vaccination programs should be offered to the public. Two
defenses against a vaccine-resistant, engineered variola virus are proposed for consideration. Methisazone, an overlooked
drug, is reported to be effective for prophylaxis only. The extent of reduction in the incidence of smallpox with use of this
agent is uncertain. It is useless for treatment of clinical smallpox. N-100 respirators (face masks) worn by uninfected members
of the public may prevent transmission of the virus.
The potential use of variola virus as a biological weapon has renewed efforts in the development of antiviral agents against orthopoxviruses. ST-246 [4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-di oxo-4,6-ethenocycloprop [f]isoindol-2(1 H)-yl)-benzamide] is an anti-orthopoxvirus compound active against several orthopoxviruses including vaccinia virus (VV), cowpox virus (CPV), camelpox virus (CMLV), ectromelia virus (ECTV) and variola virus in cell culture. The compound has been shown to inhibit the release of extracellular virus by targeting the F13L W protein and to protect mice from W, CPV and ECTV orthopoxvirus-induced disease.
The antiviral activity of ST-246 was assessed against extracellular and intracellular W, CPV and CMLV production in human embryonic lung (HEL) fibroblasts and primary human keratinocyte (PHK) cell monolayers, as well as in three-dimensional raft cultures.
ST-246 inhibited preferentially the production of extracellular virus compared with intracellular virus production in HEL and PHK cells (for W) and in PHK cells (for CMLV). In organotypic epithelial raft cultures, ST-246 at 20 microg/ml inhibited extracellular W and CMLV production by 6 logs, whereas intracellular virus yield was reduced by 2 logs. In the case of CPV, both extracellular and intracellular virus production were completely inhibited by ST-246 at 20 microg/ml. Histological sections of the infected rafts, treated with increasing amounts of drug, confirmed the antiviral activity of ST-246: the epithelium was protected and there was no evidence of viral infection. Electron microscopic examination confirmed the absence of intracellular enveloped virus forms in W-, CPV- and CMLV-infected cells treated with 10 microg/ml of ST-246.
These data indicate that ST-246 is a potent anti-orthopoxvirus compound; the mode of inhibition is dependent on the virus and cell type.
The potential use of smallpox as a biological weapon has led to the production and stockpiling of smallpox vaccine and the immunization of some healthcare workers. Another public health goal is the licensing of a safer vaccine that could benefit the millions of people advised not to take the current one because they or their contacts have increased susceptibility to severe vaccine side effects. As vaccines can no longer be tested for their ability to prevent smallpox, licensing will necessarily include comparative immunogenicity and protection studies in non-human primates. Here we compare the highly attenuated modified vaccinia virus Ankara (MVA) with the licensed Dryvax vaccine in a monkey model. After two doses of MVA or one dose of MVA followed by Dryvax, antibody binding and neutralizing titres and T-cell responses were equivalent or higher than those induced by Dryvax alone. After challenge with monkeypox virus, unimmunized animals developed more than 500 pustular skin lesions and became gravely ill or died, whereas vaccinated animals were healthy and asymptomatic, except for a small number of transient skin lesions in animals immunized only with MVA.
Orthopoxviruses, such as variola and monkeypox viruses, can cause severe disease in humans when delivered by the aerosol route, and thus represent significant threats to both military and civilian populations. Currently, there are no antiviral therapies approved by the U.S. Food and Drug Administration (FDA) to treat smallpox or monkeypox infection. In this study, we showed that administration of the antiviral compound ST-246 to rabbits by oral gavage, once daily for 14 days beginning 1h postexposure (p.e.), resulted in 100% survival in a lethal aerosolized rabbitpox model used as a surrogate for smallpox. Furthermore, efficacy of delayed treatment with ST-246 was evaluated by beginning treatment on days 1, 2, 3, and 4 p.e. Although a limited number of rabbits showed less severe signs of the rabbitpox disease from the day 1 and day 2 p.e. treatment groups, their illness resolved very quickly, and the survival rates for these group of rabbits were 88% and 100%, respectively. But when the treatment was started on days 3 or 4 p.e., survival was 67% and 33%, respectively. This work suggests that ST-246 is a very potent antiviral compound against aerosolized rabbitpox in rabbits and should be investigated for further development for all orthopoxvirus diseases.
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