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Vaccine xxx (xxxx) xxx Contents lists available at ScienceDirect Vaccine journal homepage: www.elsevier.com/locate/vaccine Review Monkeypox (Mpox) requires continued surveillance, vaccines, therapeutics and mitigating strategies Rachel L. Roper a,1,2,⇑, Alfredo Garzino-Demo b,c,1,2, Carlos Del Rio d,2, Christian Bréchot e,2, Robert Gallo f,2, William Hall g,2, José Esparza h,2, Marvin Reitz i,2, Raymond F. Schinazi j,2, Mark Parrington k,2, James Tartaglia l,2, Marion Koopmans m,2, Jorge Osorio n,2, Andreas Nitsche o,2, Tan Boon Huan p,2, James LeDuc q,2, Antoine Gessain r,2, Scott Weaver s,2, Suresh Mahalingam t,2, Alash’le Abimiku u,2, Anders Vahlne v,2, Joaquim Segales w,2, Linfa Wang x,2, Stuart N Isaacs y,2, Albert Osterhaus z,2, Richard H. Scheuermann aa,ab,ac,2, Grant McFadden ad,2 a Brody School of Medicine, East Carolina University, USA b Department of Molecular, Medicine, University of Padova, Padova, Italy c University of Maryland School of Medicine, Baltimore, MD, USA d Emory Center for AIDS Research, Emory University School of Medicine, Atlanta, GA, USA e University of South Florida School of Medicine, Tampa, FL, USA f Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA g Centre for Research in Infectious Diseases at University College Dublin, Dublin, Ireland h Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA i Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA j Center for ViroScience and Cure, Department of Pediatrics, Emory University School of Medicine, USA k Vaccine R&D, Sanofi, Waltham, MA, USA l Vaccine R&D, Sanofi, Swiftwater, PA, USA m Erasmus University Medical Center, Rotterdam, Netherlands n Global Health Institute, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA o Robert Koch Institute, Center for Biological Threats and Special Pathogens, German Reference Laboratory for Poxviruses, Seestrasse 10, 13353, Germany p DSO National Laboratories, Respiratory and Infectious Disease Program, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore q University of Texas Medical Branch, Galveston, TX, USA r Institut Pasteur, Université de Paris Cité, Paris, France s Institute for Human Infections and Immunity and Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA t Emerging Viruses, Inflammation and Therapeutics Group, Menzies Health Institute Queensland, Griffith University, Australia u Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA v Karolinska Institutet, Stockholm, Sweden w Unitat Mixta d’investigació IRTA-UAB en Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA) and Departament de Sanitat i Anatomia Animals, Facultat de Veterinàriaia, Universitat Autònoma de Barcelona, Spain x Programme for Research in Epidemic Preparedness and Response (PREPARE), and Programme in Emerging Infectious Diseases at Duke-NUS Medical School, Singapore y Division of Infectious Diseases Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA z Center of Infection Medicine and Zoonosis Research, University of Veterinary Medicine Hannover, Germany aa Department of Informatics, J. Craig Venter Institute, La Jolla, CA, USA ab Department of Pathology, University of California, San Diego, CA 92093, USA ac Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA ad Biodesign Center for Immunotherapy, Vaccines and Virotherapy, Arizona State University, USA a r t i c l e i n f o a b s t r a c t Article history: The widespread outbreak of the monkeypox virus (MPXV) recognized in 2022 poses new challenges for Received 7 October 2022 public healthcare systems worldwide. With more than 86,000 people infected, there is concern that Accepted 3 April 2023 MPXV may become endemic outside of its original geographical area leading to repeated human spillover Available online xxxx infections or continue to be spread person-to-person. Fortunately, classical public health measures (e.g., isolation, contact tracing and quarantine) and vaccination have blunted the spread of the virus, but cases Keywords: are continuing to be reported in 28 countries in March 2023. We describe here the vaccines and drugs ⇑ Corresponding author at: East Carolina University, Brody Medical School, Greenville, NC 27858, USA. E-mail address: roperr@ecu.edu (R.L. Roper). 1 These authors contributed equally to this work. 2 All authors are affiliated with The Global Virus Network https://doi.org/10.1016/j.vaccine.2023.04.010 0264-410X/Ó 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Please cite this article as: R.L. Roper, A. Garzino-Demo, C. Del Rio et al., Monkeypox (Mpox) requires continued surveillance, vaccines, therapeutics and mitigating strategies, Vaccine, https://doi.org/10.1016/j.vaccine.2023.04.010 R.L. Roper, A. Garzino-Demo, C. Del Rio et al. Vaccine xxx (xxxx) xxx Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2. Diagnostics and surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3. Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4. Therapeutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5. Action Plan: What needs to be done. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 6. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Monkeypox available for the prevention and treatment of MPXV infections. However, although their efficacy against Poxvirus monkeypox (mpox) has been established in animal models, little is known about their efficacy in the cur- Vaccine rent outbreak setting. The continuing opportunity for transmission raises concerns about the potential for Anti-virals evolution of the virus and for expansion beyond the current risk groups. The priorities for action are clear: Orthopoxvirus vaccine 1) more data on the efficacy of vaccines and drugs in infected humans must be gathered; 2) global col- Smallpox vaccine mpox laborations are necessary to ensure that government authorities work with the private sector in devel- oped and low and middle income countries (LMICs) to provide the availability of treatments and vaccines, especially in historically endemic/enzootic areas; 3) diagnostic and surveillance capacity must be increased to identify areas and populations where the virus is present and may seed resurgence; 4) those at high risk of severe outcomes (e.g., immunocompromised, untreated HIV, pregnant women, and inflammatory skin conditions) must be informed of the risk of infection and be protected from com- munity transmission of MPXV; 5) engagement with the hardest hit communities in a non-stigmatizing way is needed to increase the understanding and acceptance of public health measures; and 6) reposito- ries of monkeypox clinical samples, including blood, fluids, tissues and lesion material must be estab- lished for researchers. This MPXV outbreak is a warning that pandemic preparedness plans need additional coordination and resources. We must prepare for continuing transmission, resurgence, and repeated spillovers of MPXV. Ó 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). 1. Introduction cases of human transmission to pets have already been reported, but this is not universally accepted. Historically, Monkeypox (mpox) is a disease caused by a zoono- MPXV has been enzootic in the Democratic Republic of Congo tic poxvirus, likely transmitted from several small rodent reser- (DRC), where the first, often severe human cases and outbreaks voirs in Africa.[1] Spillover infections from rodents are not well were described since 1970, and in West Africa, where there have understood, but human-to-human transmission involves contact been sporadic reports of human disease[10–18]. Over the years, and occasionally exposure to larger respiratory droplets[2,3]. There the incidence of spillovers of virus from animals into humans are distinct virus lineages: the DRC/Central African lineage desig- seems to have increased, but information on the epidemiology nated as clade I (with a higher reported Case-Fatality Rate [CFR]) and ecology of these spillovers in the African region is limited. Out- and the West African lineage designated as clade II[4] (which side of Africa, the first significant outbreak occurred in 2003, was recently subdivided into IIa and IIb or proposed as clade 3 resulting in>90 cases in the US[19–21]. The outbreak was eventu- [5]). Clade IIb is the origin from which the current outbreak was ally traced to rodents imported from Ghana, infected with Clade II seeded. Most people infected with the currently circulating clade virus. MPXV was transmitted in animal distribution facilities to IIb monkeypox virus (MPXV) develop non-life-threatening symp- local rodent species, including prairie dogs (genus Cynomys) sold toms within three weeks after infection, which may include some as pets, and subsequently transmitted to humans [21–23]. Two or all of the following: headache, fever, respiratory symptoms, children were hospitalized with serious illnesses, but there were swollen lymph nodes with a skin rash or lesions developing 1–4- no deaths. The outbreak was quickly contained, without sustained days after symptom onset[2,3,6–9]. In immunocompetent hosts, human-to-human transmission or establishment of the virus in the lesions typically heal within 4 weeks after disease onset free-living wild animal species. [2,3,6–9]. Serious complications may occur in certain populations, Subsequent cases of infections reported outside of Africa were especially in children, pregnant women, older adults, and immuno- in individuals who traveled to Nigeria and were diagnosed upon compromised patients, and may include: non-healing skin lesions, their return home. None of these cases are known to have resulted pneumonia, encephalitis, sepsis, loss of vision after eye infection, in significant further spread of the virus[10–17]. In 2022, a case of and adverse pregnancy outcomes. Small studies document case monkeypox was contracted by a traveler to Nigeria who was diag- fatality rates reported for monkeypox caused by MPXV clade I in nosed on return to the United Kingdom (UK). Subsequent cases the African region to be between 3 and 11%. Lower case fatality reported in the UK did not report travel to Africa or contact with rates were observed during the current outbreak caused by clade the initial case, suggesting community transmission[2,3,7]. II virus. Besides humans, many diverse animal species can become According to the World Health Organization, https://world- infected with the MPXV, via direct contact or fomites. Wild animal healthorg.shinyapps.io/mpx_global/#23_Tables>86,000 monkey- species that become infected with the MPXV can become new pox cases have been confirmed as of March 15, 2023; reservoirs in a previously unaffected geographic region. Indeed, with > 30,000 cases in the US; > 10,000 in Brazil; 7,000 in Spain; 2 R.L. Roper, A. Garzino-Demo, C. Del Rio et al. Vaccine xxx (xxxx) xxx and > 3,000 each in Germany, the UK, France, Columbia, Mexico, healthcare workers, similar to the home COVID antigen tests may and Peru, with 110 countries reporting cases (including 99 non- seem straightforward. However, the judicious use of such assays endemic countries). There have been 112 deaths recorded as of requires in-depth knowledge of the infection kinetics in relation March 28, 2023, and the infections are continuing globally with to test performance, not only for case ascertainment but for guid- 28 countries reporting cases in the preceding 21 days. Deaths have ing isolation and quarantine measures. been associated with encephalitis, uncontrolled infections in Active surveillance is also critical to detect unrecognized cases patients with advanced HIV, septic shock, and other comorbidities. because transmission can occur from people with mild or inappar- It is possible that co-infection with various other viruses might also ent symptoms. Indeed, a US CDC serology study in fall of 2022 exacerbate the disease. Complete genome sequences from over found strong evidence for 3 cases of previously undetected mon- 1,400 samples have been deposited in open access public data- keypox among a sample of 74 persons (1.4%) experiencing home- bases (e.g., https://www.bv-brc.org/view/Taxonomy/10244#view_ lessness[34]. Appropriate case tracking is important to notify tab=overview) to support comparative genomics analysis. household, professional, and community contacts of MPXV- The vast majority of cases reported globally have been observed infected individuals so that they can seek post-exposure prophy- in males (96.4%), and among cases with known sexual orientation, laxis. Many laboratories now have the ability to monitor for the 85% of the cases have been identified in subgroups of men who presence of MPXV nucleic acids in sewer water, which is a sensitive have sex with men (MSM). The presence of lesions in genital, peri- means to detect the presence of other viruses (e.g., SARS-CoV-2 or anal, and oral areas is consistent with transmission via sexual con- poliovirus) in geographical areas, sometimes even before human tact. Monkeypox is not defined as a sexually transmitted disease infections were apparent[35–40]. Indeed a Wastewater Scan dash- because any close contact can cause transmission, not just sexual board is available in the United States for SARS-Co-V2, influenza, contact, although MPXV has been detected in semen [24]. Women human metapneumovirus, RSV, norovirus, and monkeypox account for 3.6% of cases, with exposure in the household setting https://data.wastewaterscan.org/tracker/?charts=&se- accounting for 42% of cases and via sexual contact for 41% of cases. lectedChartId=8cf27d. Some viruses can be detected in the air in With continuing human-to-human spread during the current glo- building HVAC systems (e.g., SARS-CoV-2) [41]. For MPXV, detec- bal outbreak, the possibility of widening of the circulation into tion on surfaces may be of added value since MPXV can cause the rest of the community continues to be a serious concern. How- virus-laden lesions on the hands and palms, and thereby contami- ever, by March 2023, the transmission of MPXV has decreased sig- nate surfaces. Infectious MPXV particles can persist on fomites for nificantly to only  150 cases/week (down from the peak weeks[42,43]. A child in the Netherlands was infected with MPXV of > 6,000/week). While there is great concern that children would with no human source contact identified, thus suggesting commu- become infected more frequently, only  1% of cases have been nity surface fomite transmission[44]. reported in ages 0–17 (patient age was available in 82,000 cases): In addition to increasing local surveillance, it is important to 0.2% of cases in US are age 15 or under. While there is potential develop an internationally accepted single case definition of mon- for transmission in places with regular close contact between indi- keypox. The WHO has provided interim guidance in December viduals, such as daycare centers, schools, universities, workplaces, 2022 for suspected, probable, and confirmed monkeypox cases, places of worship, jails, only 1 school setting transmission was https://www.who.int/publications/i/item/WHO-MPX-Surveil- identified. This lack of wider community spread is reassuring con- lance-2022.4. Currently, a single PCR or sequencing positivity is sidering the fact that the replication-competent vaccine strain, vac- considered sufficient for defining an infection, but such testing cinia virus (a close relative of MPXV), was found to spread and must be widely available, especially in low and middle income infect several patrons in a martial arts gym[25]. Since MPXV can countries (LMICs), for effective for worldwide surveillance. Impor- cause lesions on the hands, it seems MPXV would be even more tantly, as long as cases of MPXV infection in humans occurs, the likely to spread under similar conditions. Evidence from the cur- likelihood of reverse zoonosis to pets, livestock and eventually wild rent outbreak indicates that MPXV is more transmissible in animals is increasing. Therefore, surveillance of individual animals humans than vaccinia virus. Vaccinia virus can also cause multiple or animal populations in close contact with affected patients or widespread lesions and genital lesions[26–33], but it has never should be performed to detect and possibly prevent establishment caused such widespread infection and transmission in humans. of animal reservoirs. The possible spread of MPXV into animal reservoirs remains a great concern because strong evidence suggests that vaccinia virus used as the smallpox vaccine in humans spread into cattle herds, form- 3. Vaccines ing endemic reservoirs. These constitute a serious risk to animal and public health, with multiple zoonotic human outbreaks docu- While vaccines were not developed for the prevention of mon- mented[26]. If MPXV finds a foothold in a new animal reservoir, keypox per se, the existing licensed smallpox vaccines have been the likelihood of continued outbreaks of MPXV in humans will be deployed because all three viruses (variola virus [the causative greatly increased. agent of smallpox], MPXV, and the vaccinia virus used as a vaccine) are within the Orthopoxvirus genus[45,46], and are closely related at both the genome and protein levels, leading to immune 2. Diagnostics and surveillance responses that may be expected to offer adequate cross- protection. The close genetic relationship between these viruses An essential pillar of outbreak preparedness is the ability to is demonstrated in bioinformatics DotPlots comparing their gen- detect and track cases. It is essential to develop and distribute val- omes (Fig. 1). The genomes were analyzed using the tools available idated diagnostic assays worldwide to facilitate rapid identification at the Viral Bioinformatics Research Centre https://4virology.net/ of cases to interrupt chains of transmission. Reliable diagnostics [46,47]. A dot appears on the graph at each location where a are important because MPXV lesions may be confused with sec- nucleotide is identical between the genomes, yielding a gray back- ondary syphilis, herpesvirus (chickenpox or simplex [28,29]) infec- ground. If there is substantial identity across an area of the gen- tions, or molluscum contagiosum (a poxvirus that commonly ome, the dots form a visible diagonal line showing the similarity infects children). Including monkeypox testing in clinics that see of the genome sequences in that area. Variola virus, MPXV, and patients with sexually transmitted diseases should be considered. vaccinia virus show nearly continuous diagonal lines, with varia- The development of rapid point of care tests that can be used by tion and gaps occurring mostly at the ends of the genome (Fig. 1 3 R.L. Roper, A. Garzino-Demo, C. Del Rio et al. Vaccine xxx (xxxx) xxx Fig. 1. Dotplots comparing viral genomes at each nucleotide position. In each plot, the first virus name shown is plotted horizontally with the first nucleotide position on the left, and the second viral genome named is plotted vertically with the first nucleotide at the top. Genome sequences are vaccinia ACAM2000, Variola major India 3 1967, MPX monkeypox Cop58, Modified Vaccinia Ankara MVA-1721, and Molluscum contagiosum virus. Genome nucleotide identity is indicated by a diagonal line. a-c). This pattern occurs because Orthopoxviruses are relatively which the vaccine does not protect. The limited sequence identity conserved in the central region of the genomes and vary more near is clear. The vaccinia virus vaccine only protects from the ortho- the termini, which encode gene products more associated with poxviruses and not molluscum contagiosum infection because, host-range and virulence factors. However, a close genetic relation- although both are poxviruses, they belong to different genera ship between a vaccine virus and a pathogenic virus, does not nec- and are too distantly related to provide cross-protection. essarily mean that adequate cross-protection will always be A study published in 1988 found that subjects that were vacci- induced by the vaccine virus. In the case of the immunogenicity nated during the smallpox eradication program with Dryvax, the of the Dryvax vaccinia virus, T cell responses in samples from calf-skin-grown vaccinia vaccine from which ACAM2000 was recipients showed a high degree of MPXV cross-reactive T cells derived, were 85% protected from MPXV infection and disease [48]. severity in an endemic setting[56]. However, there is little data Another smallpox vaccine, the live but replication-deficient on the efficacy of the currently available vaccines in humans Modified Vaccinia Virus Ankara (MVA, in the vaccine Jynneos, against MPXV infection during the present outbreak especially in Imvamune, Imvanex from Bavarian Nordic), is used in the US and the setting of transmission occurring largely through sexual con- Europe for post-exposure MPXV prophylaxis. In regions that have tact in MSM. One trial in DRC showed immunogenicity of the Jyn- sufficient vaccine available, Jynneos is used for pre-exposure MPXV neos vaccine, but data on protective efficacy are not yet available prophylaxis in high-risk individuals and communities. The MVA [49]. In the current outbreak, the US CDC data on > 200,000 Jynneos strain, has six major deletion sites with loss of about 20% of the MVA vaccinated individuals showed monkeypox incidence among genome[46], visible as gaps in the diagonal line of the dot-plot unvaccinated individuals was 7.4 (95% CI = 6.0–9.1) times higher comparison (Fig. 1d). These deletions are attenuating because of compared to those vaccinated with 1 dose, and 9.6 times (95% reduced replication capacity in mammalian cells, conferring an CI = 6.9–13.2) higher compared to those who had received 2 excellent safety profile for MVA[49–51], but the vaccine is missing doses  14 days earlier[50]. While the Jynneos MVA vaccine is pre- antigens that are present in both the pathogenic orthopoxviruses ferred because of its safety profile, the durability of the vaccine and the live-attenuated replicating vaccine ACAM2000 vaccinia protection is unknown, and recent data show that MVA induces strain (derived from the New York Board of Health (NYBOH) strain relatively low levels of MPXV neutralizing antibodies[51]. This that was used in the smallpox eradication program in the US) emphasizes the necessity for continuing human clinical trials to (Fig. 1 a-d). Indeed, the MVA strain fails to induce some major T cell assess its long term efficacy against MPXV infection. and antibody responses elicited by the replication competent par- After smallpox eradication, vaccination of the public with live ental vaccinia virus[52–55]. Both MVA and ACAM2000 vaccines replicating vaccinia (e.g., Dryvax, now ACAM2000) was discontin- induce protective immunity against MPXV in animal models, but ued due to significant rates of adverse events, including dissemi- it is noteworthy that the MVA Jynneos vaccine was approved as nated vaccinia, progressive vaccinia, eczema vaccinatum, and a 2-dose regimen, while the live-attenuated, replicating encephalitis[30–33,57]. It has been estimated that 25% of the US ACAM2000 is effective after 1 administration. Fig. 1e demonstrates population would be at a greater risk of adverse event from the live the genetic distance between vaccinia virus and the human pox- replicating ACAM2000 due to immunosuppression, inflammatory virus molluscum contagiosum virus (Genus Molluscipox), from skin conditions (e.g., eczema), or who are pregnant, or have heart 4 R.L. Roper, A. Garzino-Demo, C. Del Rio et al. Vaccine xxx (xxxx) xxx abnormalities[31,32,57], and it has been predicted that 1 out of cially with long-term treatment in immunocompromised individu- every 450 people vaccinated would have a serious adverse reaction als. Drug combinations should be considered to delay or prevent resulting in hospitalization[33]. Thus, in the absence of a smallpox MPXV mutants from being selected during prolonged single drug exposure event, the use of ACAM2000 is contraindicated for many, treatment. >6,800 US monkeypox patients have received TPOXX however, it is routinely administered to military personnel in the (including 13 age 5 or under, 173 females, 4,869 males, and 113 US and other countries because of continuing bioterrorism/biowar- transgender) https://www.cdc.gov/poxvirus/mpox/response/ fare concerns. Under normal use, an ACAM2000 vaccination causes 2022/demographics-TPOXX.html March 8, 2023). Anecdotal evi- the occurrence of an oozing lesion in vaccinated patients, which dence suggests good efficacy in humans with monkeypox, but pla- can spread the virus infection to contacts [27–30]. Because of these cebo controlled human clinical trials are ongoing in the United problems, ACAM2000 was not routinely used during the current States (STOMP trial, https://actgnetwork.org/studies/a5418- global monkeypox outbreak. Development of a single-dose vaccine study-of-tecovirimat-for-human-monkeypox-virus-stomp/), in with efficacy similar to ACAM200 but with a safety profile like the Democratic Republic of Congo (https://clinicaltrials.gov/ct2/ MVA is desirable. show/record/NCT05559099), and in Brazil https://clinicaltri- Robust, longer term clinical trials are needed to document the als.gov/ct2/show/NCT05597735?term=tecovirimat&cond=mon- efficacy of ACAM2000 or Jynneos against MPXV infection, as well keypox&draw=2&rank=4. as to evaluate the route and dose of the vaccine (subcutaneous Another drug approved for smallpox that can be used against vs intradermal) in real-world efficacy settings. Trials must include MPXV is Brincidofovir, (Tembexa), a lipid-conjugated prodrug of enough persons who may be exposed to the virus for sufficient cidofovir, an analog of 20 -deoxycytidine that inhibits the viral power in a Phase III trial to demonstrate efficacy. In addition, the DNA polymerase[64–67]. However, liver function needs to be mon- ethical selection of an appropriate negative control group is chal- itored carefully in person receiving this drug, especially when co- lenging. In preliminary unpublished data from US CDC, the control administered with HIV drugs cobicistat and fostemsavir. Fortu- group for the retrospective study was composed of patients with nately, Brincidofovir does not cause nephrotoxicity like cidofovir, an incident HIV diagnosis or HIV pre-exposure prophylaxis pre- its parent molecule[67,68]. While this drug was not widely avail- scription[50]. able during the height of the monkeypox outbreak, in the U.S. it It will also be desirable to evaluate the use of vaccines both pre- is available under an EA-IND for monkeypox treatment[69]. Effi- and post-exposure. Availability of the preferred, safer non- cacy data for Brincidofovir are lacking, but it is currently used as replicating MVA vaccine, produced by Bavarian Nordic has been off-label drug treatment in monkeypox patients [70]. Brincidofovir limited. To allow vaccination of more people, intradermal injection and cidofovir have a range of undesirable side effects that limit of a lower dose has been widely used in the U.S, and preliminary their use in the clinic. Finally, and most critically, the availability data show that the subcutaneous and intradermal administration of these drugs is currently very limited for global use. The MPXV both provided at least short-term protection[50]. Furthermore, outbreak argues for immediate action by government agencies to ’ring vaccination’ strategies, in which exposed individuals and coordinate with drug manufacturers to produce and make avail- close contacts are vaccinated, are a practical and immediate able adequate quantities of MPXV therapeutics and to develop approach to preventing MPXV transmission. Governments world- agreements with pharmaceutical companies, including prices com- wide will have to promote the quick manufacturing and approval patible with massive deployment during public health emergen- of doses sufficient to quell this outbreak and prepare for resur- cies. The plans for drug availability must also make provisions gence and additional spillover events. Deployment of vaccines for delivering sufficient quantities to Africa, to decrease infections must include African countries where MPXV is endemic. If wide- and transmission in endemic areas. The next set of priorities will spread vaccination against MPXV is made available in Africa, it will be, as for vaccines, to gather data on safety and efficacy in human not only provide protection there, but also significantly protect the trials. In addition, it will be necessary to assess which drugs can be rest of the world from future monkeypox outbreaks. used for monkeypox prophylaxis to limit the spread of MPXV in family and workplace contacts and especially in health care facili- ties. In the medium- to long-term, the development of new antivi- 4. Therapeutics ral compounds continues to be a pressing, unmet need as drug resistance may develop. Here too, government agencies can do Similar to vaccine development, therapeutics have also been much to facilitate both basic and applied research toward new developed to treat the closely related smallpox (variola) virus, antiviral remedies. While monoclonal antibodies can be effective which while eradicated, remains a major bioterrorism class A agent in treating viral diseases and are often evaluated as therapeutic threat to humans. Specific therapeutic antiviral agents against agents in emergency situations, their use will not always be prac- MPXV have not been included in the approval process as this virus tical, especially in nations with less advanced health care systems. was until recently considered a pathogen of lesser importance for There is a report of the polyclonal human antibody vaccinia humans. However, antiviral drugs developed for smallpox may also immune globulin (VIG-IV) having therapeutic value [71]. However, be effective against the MPXV infection because of the close rela- priority should be given to small molecule antivirals which could tionship and sequence similarity between the viruses (Fig. 1). In be widely used. Given the limited number of current infections 2018, the US FDA approved TPOXX, also known as tecovirimat or and geographical distribution of cases, pharmaceutical companies ST-246, specifically to treat smallpox. The decision was based are unlikely to fund the development of new drugs. Therefore, gov- exclusively on animal data showing protection from both smallpox ernment agencies should support the discovery and development and monkeypox[58–61]. TPOXX is currently being used in the U.S. of new therapeutics. under an Expanded Access IND investigational new drug (EA-IND) protocol for treatment of monkeypox[62]. This drug targets the maturation of variola virus and related poxviruses by blocking 5. Action Plan: What needs to be done the viral F13 protein, also known as OPG057 or VP37 in vaccinia, a component of the viral outer envelope required for the spread Surveillance. The rapid decline of monkeypox cases in many of virus particles within an animal or human [63]. Since a single countries should not induce complacency. MPXV has shown its mutation can confer resistance to TPOXX there are concerns that propensity for spillover into humans from animal reservoirs and with widespread use, the efficacy of this drug could be lost, espe- sustained human-to-human spread. Resurgence and continuing 5 R.L. Roper, A. Garzino-Demo, C. Del Rio et al. Vaccine xxx (xxxx) xxx spillover events are likely, so surveillance is key. Health care facil- Acknowledgments ities must remain vigilant to detect monkeypox disease, especially when caring for elderly and immunocompromised patients, who We would like to thank Drs. Ming Fan at East Carolina Univer- together with young children, have the highest risk of severe com- sity and Dara Wambach and her team at Johnson & Johnson for plications of monkeypox. 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East Carolina University that includes: employment and non- [28] Egan C, Kelly CD, Rush-Wilson K, Davis SW, Samsonoff WA, Pfeiffer H, et al. financial support. Rachel Roper has patent #Patent No 8202521 Laboratory-confirmed transmission of vaccinia virus infection through sexual issued to East Carolina Univeristy. Roper serves as a reviewer for contact with a military vaccinee. J Clin Microbiol 2004 Nov;42(11):5409–11. [29] Centers for Disease C, Prevention. Vaccinia virus infection after sexual contact Vaccine, but not in an editorial role. (R Roper) Tartaglia, James is with a military smallpox vaccinee -Washington, 2010. MMWR Morb Mortal an employee of Sanofi and holds stock options. Wkly Rep 2010;59(25):773-5. 6 R.L. Roper, A. Garzino-Demo, C. Del Rio et al. Vaccine xxx (xxxx) xxx [30] Lederman E, Miramontes R, Openshaw J, et al. Eczema vaccinatum resulting 43 U.S. Jurisdictions, July 31-October 1, 2022. 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