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Monkeypox: Considerations as a New Pandemic Looms

Published:August 24, 2022DOI:https://doi.org/10.1016/j.jid.2022.08.030
      • With two different vaccines licensed for the prevention of orthopoxvirus infections, availability and safety profiles should be considered before administration.
      • Human monkeypox virus spillover into naive indigenous animal reservoirs will facilitate future outbreaks.
      • Individuals with underlying conditions (HIV, atopic dermatitis, cancer) represent vulnerable populations that should be notified of risks.
      Monkeypox virus is an emerging pathogen that is endemic in African rodent populations and has been spilling over into the human population since the 1970s with increasing frequency. Some of these spillovers have resulted in the spread of monkeypox out of Africa to multiple countries across the globe, with the current outbreak being the most extensive. As of July 23, 2022, the World Health Organization (WHO) had declared the ongoing outbreak a global public health emergency. Since the first documented infection in May, human monkeypox case numbers have increased exponentially. On June 2, 2022, the confirmed case count was 780 infections across 27 different countries. Two months later, on August 2, 2022, this number had risen to 25,047, and 49 more nonendemic countries had reported cases (Figure 1) (

      Centers for Disease Control and Prevention. 2022 Monkeypox Outbreak Global Map https://www.cdc.gov/poxvirus/monkeypox/response/2022/world-map.html (accessed 22 June 22).

      ).
      Figure thumbnail gr1
      Figure 1Monkeypox cases and nonendemic countries detecting infections since the first case was identified in the UK. Graphed from data collected by the United States Department of Health and Human Services (

      Centers for Disease Control and Prevention. 2022 Monkeypox Outbreak Global Map https://www.cdc.gov/poxvirus/monkeypox/response/2022/world-map.html (accessed 22 June 22).

      ). #, number; UK, United Kingdom.
      Monkeypox virus is thought to reside primarily in rodent populations of west and central Africa, including multiple squirrel species (rope, sun, tree), giant pouched rats, and African dormice. Other animal species, including nonhuman primates, anteaters, hedgehogs, shrews, and prairie dogs, are also known to be susceptible to monkeypox virus infections. There currently exist two clades of monkeypox virus: Clade I, which was previously known as the central African or Congo Basin clade and Clade II, which was formely the west African clade. These two clades are genetically distinct, and this is reflected in their difference in mortality rate, which is approximately 10% for Clade I and 0‒2.6% for Clade II (
      • Beer E.M.
      • Rao V.B.
      A systematic review of the epidemiology of human monkeypox outbreaks and implications for outbreak strategy.
      ). Historically, cases of monkeypox outside of endemic regions typically resulted from presymptomatic infected travelers returning from African countries and subsequently developing symptomatic disease. An exception was the 2003 United States outbreak that resulted in 47 confirmed monkeypox cases. This outbreak was initiated through the import of monkeypox virus‒infected exotic rodents from Africa and subsequent spread to captive prairie dogs and humans. No human-to-human transmission occurred during this outbreak. In stark contrast, the ongoing global monkeypox virus outbreak is spreading directly from infected humans to close; prolonged human contacts.
      The Centers for Disease Control and Prevention (CDC) has substantial experience in handling orthopoxvirus outbreaks; both from the smallpox eradication campaign and previous monkeypox virus outbreaks occurring in the United States and Africa. Furthermore, the United States and other countries have been preparing for the potential reintroduction of orthopoxviruses to the human population and have stockpiled both vaccines (ACAM2000 and JYNNEOS) and antiviral agents, including the smallpox-approved drugs tecovirmat and brincidovir as well as the non-smallpox approved drug cidofovir. Besides the JYNNEOS vaccine, none of these interventions are Food and Drug Administration (FDA) approved for monkeypox, but because there exists a high genetic similarity between the variola and monkeypox viruses, these interventions are expected to be effective treatments.
      With regard to the comments mentioned earlier, multiple considerations need to be rapidly addressed during the ongoing monkeypox virus outbreak, which have not yet been widely discussed. These include the choice of interventions used for monkeypox virus infections and deployment methods, monitoring of infections in indigenous animal populations, and notifying vulnerable populations as cases continue to increase and spread globally.

      Smallpox vaccines being used to prevent monkeypox virus infections

      Two types of smallpox vaccines currently exist: replication-competent and attenuated vaccinia viruses. Replication competent smallpox vaccines are based on the original vaccine popularized by Edward Jenner. These vaccines contain a single wild-type clone of the orthopoxvirus, vaccinia virus, which is propagated in cell culture. Alternatively, attenuated vaccines exist that contain a strain of vaccinia that was propagated in nonmammalian cells to be unable to replicate efficiently in mammalian hosts. Vaccine stockpiles across the globe consist of both replication-competent and attenuated vaccines. In the United States, two vaccines are licensed by the FDA: ACAM2000 and JYNNEOS. ACAM2000 is derived from the highly effective smallpox vaccine (Dryvax) that was used during the smallpox eradication campaign, has similar contraindications to the original Dryvax vaccine, and most likely has a comparable side effect profile (Table 1). The attenuated vaccine, JYNNEOS, contains a strain of vaccinia virus known as modified vaccinia Ankara. This strain was developed by multiple passages in chicken embryo fibroblast cells and is now unable to replicate in mammalian cells owing to large deletions of its genome. JYNNEOS has minimal side effects and is therefore safer in immunocompromised individuals, but is in short supply globally. To increase stockpiles, the United States as well as multiple countries in the European Union have recently ordered millions of doses from the company that developed the vaccine (
      Reuters
      U.S., EU clear manufacturing plant for Bavarian Nordic's monkeypox vaccine.
      ). Unfortunately, current projections suggest that many of these orders will not be completely fulfilled until the end of 2022 or the beginning of 2023.
      Table 1Side Effect Profile of DryVax, which Most Likely Will Be Mirrored in Replication-Competent Vaccines such as ACAM2000
      Side Effects of DryVax
      LocalSystemicSevere
      PruritusHeadacheEncephalitis
      ErythemaFatigueEncephalomyelitis
      PainMalaiseEncephalopathy
      SwellingFeverMyocarditis
      NauseaPericarditis
      DiarrheaIschemic heart disease
      ConstipationNonischemic dilated cardiomyopathy
      VomitingOcular complications (blindness)
      Generalized vaccinia
      Severe vaccinial skin infections
      Eczema vaccinatum
      Several notable differences exist between the two vaccines licensed in the United States. Specifically, ACAM2000 is a single-dose vaccine delivered by scarification of the skin with a bifurcated needle, whereas JYNNEOS requires two subcutaneous injections delivered approximately 4 weeks apart. Neither vaccine type (replication competent or attenuated) has been tested in clinical trials for postexposure prophylaxis (PEP) to monkeypox virus, but on the basis of animal models, they are indicated for this usage by the CDC and WHO. With the extended timeline required for vaccination with attenuated vaccines, these may be less effective at preventing disease when used for PEP than replication-competent versions. As of August 1, only six deaths in unvaccinated individuals have been reported during the ongoing outbreak. This suggests that even limited vaccine efficacy from PEP may provide some alleviation of severe symptoms.
      After inoculation, ACAM2000 forms a characteristic skin lesion or take at the site of delivery, which does not occur with JYNNEOS (
      • Baden L.R.
      • Damon I.K.
      On the "take" as a biomarker.
      ). This physical characteristic of vaccination provides a visual reassurance that the vaccine was administered and that a productive immune response has occurred. The take also rapidly enables the identification of vaccine failures in primary vaccinations. Of concern is that this skin lesion contains an actively replicating virus that can be shed, which functions as a source of spread to individuals with underlying conditions such as immunosuppression or inflammatory diseases. A notable example is patients with the chronic inflammatory skin disease atopic dermatitis (AD). When individuals with AD come in contact with an immunized person shedding virus, they are at enhanced risk of vaccinia virus infection and subsequently developing a severe, potentially life-threatening complication known as eczema vaccinatum (Figure 2a) (
      • Vora S.
      • Damon I.
      • Fulginiti V.
      • Weber S.G.
      • Kahana M.
      • Stein S.L.
      • et al.
      Severe eczema vaccinatum in a household contact of a smallpox vaccinee.
      ). Although JYNNEOS is thought to be safer in these regards, many strategic stockpiles across the world are still dominated by replication-competent vaccines such as ACAM2000. Currently, the rate of AD is estimated to be upward of 20% of a nation’s population and is predominantly observed in children. Proper screening and contact tracing will be required to avoid the severe side effects (such as eczema vaccinatum) observed during the smallpox eradication campaign. As more people become vaccinated, there needs to be a full assessment of the tradeoff between replication-competent and attenuated vaccines to effectively prevent disease and avoid putting individuals with underlying conditions at risk.
      Figure thumbnail gr2
      Figure 2Clinical presentation in humans of orthopoxvirus-based infections. (a) Replication-competent smallpox vaccine‒associated disseminated disease in a child with atopic dermatitis (eczema vaccinatum) and (b) a current case of monkeypox virus: a male patient aged 32 years with lesions affecting the genital area. Consent to publish images was provided by the parents of the child with eczema vaccinatum and from the subject who was infected with the monkeypox virus. The image of the child with (a) eczema vaccinatum was adapted from
      • Vora S.
      • Damon I.
      • Fulginiti V.
      • Weber S.G.
      • Kahana M.
      • Stein S.L.
      • et al.
      Severe eczema vaccinatum in a household contact of a smallpox vaccinee.
      with permission of the Infectious Diseases Society of America. The image of the current case of (b) monkeypox virus was provided courtesy of Carina Borst, Department of Dermatology, Medical University of Vienna (Vienna, Austria).

      Monkeypox becoming endemic in new countries

      During the 2003 monkeypox virus outbreak in the United States, the virus was transmitted to people through prairie dogs purchased as pets. These domestic animals were infected by exposure to the bedding of monkeypox virus‒infected exotic rodents (rope squirrels, Gambian rats, dormice) imported from Africa (
      • Guarner J.
      • Johnson B.J.
      • Paddock C.D.
      • Shieh W.J.
      • Goldsmith C.S.
      • Reynolds M.G.
      • et al.
      Monkeypox transmission and pathogenesis in prairie dogs.
      ). This led to the concern that animals infected with monkeypox virus may escape and/or be released into the wild and subsequently infect rodent or other small mammal populations in the United States, which could enable the virus to become endemic in a new country. If this occurred, it could lead to reinfections back into the human population. For example, in South America, an orthopoxvirus circulating in the wild is causing increasingly frequent infections in humans and domesticated cattle. This orthopoxvirus is believed to be a feral vaccinia virus that escaped through some unknown mechanism into the wild during the smallpox vaccination campaign (
      • Moussatché N.
      • Damaso C.R.
      • McFadden G.
      When good vaccines go wild: feral Orthopoxvirus in developing countries and beyond.
      ). These two situations highlight the zoonotic potential of orthopoxviruses, suggesting the potential of transmission of the current monkeypox strain from humans to indigenous animal populations, which would allow the virus to expand its endemicity outside of Africa. This could occur by two possible mechanisms. First is the spread of monkeypox virus to rodents or small mammals kept as pets from their infected owners. These rodents or small mammals could subsequently pass the infection on to wild animals either directly or indirectly through contaminated bedding, thus spreading the disease into local populations. The second would be through contaminated waste such as clothing or dressings used to cover monkeypox lesions. If not properly sterilized before being discarded, the virus could inadvertently spread to rodents that infest the waste management system and interact with contaminated material. Therefore, care should be taken to limit the potential spread to indigenous animal populations, and local animals (both domesticated and wild) should be closely monitored for infections. As this outbreak continues, surveillance of local rodent and small mammal populations will be a key aspect of determining whether monkeypox virus will become endemic in new nations. To prevent endemicity from occurring, it may be necessary to vaccinate or curtail wild animal populations. If monitoring and/or intervention are not undertaken, then monkeypox virus outbreaks could become a common occurrence as the virus transmits back and forth between humans and new animal reservoirs.

      Populations at potential risk for enhanced orthopoxvirus-based disease

      Historically, people who are immunocompromised (with AIDS), are pregnant, or have chronic skin conditions (such as AD) were precluded from getting a smallpox vaccination with replication-competent vaccines because they could experience life-threatening complications. This is a serious contraindication because cutaneous viral infections, as are initiated from replication-competent smallpox vaccines, can quickly become disseminated and life threatening in these populations. In the current global monkeypox outbreak, both men and women have been infected. A large proportion of the cases are being detected in the men who have sex with men population, in addition to other groups such as people who have multiple sexual partners (
      • Thornhill J.P.
      • Barkati S.
      • Walmsley S.
      • Rockstroh J.
      • Antinori A.
      • Harrison L.B.
      • et al.
      Monkeypox virus infection in humans across 16 countries - April–June 2022 [e-pub ahead of print].
      ). Within these populations exist increased numbers of HIV-positive individuals and patients with AIDS. Because the HIV/AIDS epidemic began shortly after the eradication of smallpox and discontinuation of general vaccination with replication-competent smallpox vaccines, it is unclear exactly what complications after vaccination with a replication-competent vaccine may arise in this population. There are isolated incidences of HIV-positive individuals being vaccinated against smallpox. From these anecdotal occurrences, people with HIV but not AIDS status (>200 CD4+ cells/μl) showed a normal vaccine take with no complications, whereas an individual with HIV/AIDS developed disseminated vaccinia infection after vaccination (
      • Redfield R.R.
      • Wright D.C.
      • James W.D.
      • Jones T.S.
      • Brown C.
      • Burke D.S.
      Disseminated vaccinia in a military recruit with human immunodeficiency virus (HIV) disease.
      ). Therefore, as the pandemic proceeds, public health outreach that focuses on educating this population about the complications of live virus vaccination and the potential of infection will be critical.
      The strain of monkeypox virus causing the current global outbreak is not highly pathogenic, as seen by the absence of a substantial mortality rate. As the virus spreads, immunocompetency will likely be a confounder for severe disease risk. Populations that fall into the immunocompromised category include transplant patients and patients with cancer in addition to patients with genetic-based immunodeficiencies. These individuals will most likely experience an increased likelihood of severe disease and so should be actively informed of this possibility. An additional patient population for whom we currently have no previous data on their response to monkeypox virus infection are individuals with AD. Considering that the most common symptom of the current outbreak is a rash and/or skin lesions (Figure 2b) (
      • Thornhill J.P.
      • Barkati S.
      • Walmsley S.
      • Rockstroh J.
      • Antinori A.
      • Harrison L.B.
      • et al.
      Monkeypox virus infection in humans across 16 countries - April–June 2022 [e-pub ahead of print].
      ), the epidermis is likely a major site of infection, and therefore individuals with skin-affected diseases may have increased susceptibility to monkeypox virus disease. As mentioned previously, when patients with AD come in contact with vaccinia virus, either through direct inoculation or by exposure to a vaccinated individual shedding virus, they can experience life-threatening infections. Furthermore, disseminated and/or severe infections can also occur in patients with AD when they come in contact with other viruses that cause cutaneous infections such as herpes simplex viruses (eczema herpeticum). From these observations, we can extrapolate that monkeypox virus may cause similar disseminated disease in patients with AD. Over the past few weeks, several countries (the United States, The Netherlands) have reported monkeypox cases in young children, who appear to suffer from more severe monkeypox disease (
      • Tutu van Furth A.M.
      • van der Kuip M.
      • van Els A.L.
      • Fievez L.C.
      • van Rijckevorsel G.G.
      • van den Ouden A.
      • et al.
      Paediatric monkeypox patient with unknown source of infection, the Netherlands, June 2022.
      ). Given that the current outbreak is beginning to spread to children, who are disproportionately affected by diseases such as AD, greater disease severity could conceivably be observed in the near future.
      As monkeypox virus continues to spread, it is likely that at-risk populations (patients with HIV/AIDS, patients with cancer, children, patients with AD, etc.) will become infected by monkeypox virus or be exposed to individuals inoculated with replication-competent vaccines. By initiating targeted public health interventions early, such as prophylactic vaccination with attenuated vaccines (JYNNEOS), it should be possible to minimize the impact of the monkeypox virus outbreak in populations that are likely to be disproportionately susceptible and may develop more severe disease. Going forward, if we employ many of the lessons learned from the ongoing COVID-19 pandemic, we should be able to greatly minimize the impact (both economic and public health) of the evolving monkeypox virus outbreak. This will include best practices for protecting at-risk populations and preventing monkeypox virus from taking hold in indigenous animal populations, which should help to minimize severe morbidity and/or mortality as well as prevent future outbreaks.

      Conflict of Interest

      The authors state no conflict of interest.

      Acknowledgments

      We would like to acknowledge the subject who provided consent for the use of the image showing the clinical manifestation of monkeypox disease and the parents who provided consent for the use of the image of their child who developed eczema vaccinatum. The image of the child with eczema vaccinatum (Figure 2a) was adapted from
      • Vora S.
      • Damon I.
      • Fulginiti V.
      • Weber S.G.
      • Kahana M.
      • Stein S.L.
      • et al.
      Severe eczema vaccinatum in a household contact of a smallpox vaccinee.
      with the permission of the Infectious Diseases Society of America . The image of the current case of monkeypox virus (Figure 2b) was provided courtesy of Carina Borst, Department of Dermatology , Medical University of Vienna (Vienna, Austria).

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