Monkeypox — Past as Prologue

List of authors.
  • H. Clifford Lane, M.D.,
  • and Anthony S. Fauci, M.D.


In this issue of the Journal, Thornhill et al. report on 528 persons with monkeypox in a cohort spanning 16 countries on five continents.1 The authors provide important demographic, epidemiologic, and clinical details on the largest reported cohort of patients in the latest emerging infectious disease outbreak of global importance. Diagnosis relied on polymerase-chain-reaction (PCR) assays of swab specimens taken from lesions, predominantly in the skin, anogenital region, nose, or throat. The authors note a diverse set of dermatologic and oropharyngeal clinical manifestations that in many instances could be confused with a variety of other illnesses, including several sexually transmitted infections. Most of the patients had 10 or fewer lesions, with 10% having a single genital lesion, findings consistent with other early reports. Lesions ranged in appearance from maculopapular to vesiculopustular to crusted, with the anogenital region the most common site. The Supplementary Appendix of the article (available with the full text of the article at NEJM.org) contains an excellent array of images of lesions to aid in case recognition. Although there were no fatalities within the cohort, 13% of the persons with infection were hospitalized for management of pain or secondary infections.

Monkeypox has been recognized as an endemic disease in central and western Africa since 1970, when it was diagnosed in a 9-month-old child in the Democratic Republic of Congo who had not been vaccinated against smallpox.2 Since then, cases have been reported from central and western Africa and can be classified on the basis of molecular characteristics into two major groups, often referred to as the Congo Basin (clade I) and West African (clades IIa and IIb [formerly clades 2 and 3]) groups.3,4 The West African clades cause disease most closely resembling the currently emerging outbreak in countries in which the disease is not endemic, whereas the Congo Basin clade causes a more severe disease, with an associated 10% mortality. Early genomic analyses suggest that the current global outbreak is caused by clade IIb viruses similar to those that caused a Nigerian outbreak in 2017 and 2018, which included cases that were exported to the United Kingdom, Israel, and Singapore in 2018 and 2019; the viruses in the current outbreak are characterized by a pattern of evolutionary changes potentially driven by apolipoprotein B messenger RNA–editing catalytic polypeptide-like 3 (APOBEC3) enzymes.5 It is noteworthy that there appears to have been a recent change in the epidemiologic characteristics of monkeypox in Africa, where cases are now occurring in new geographic areas, perhaps facilitated by climate change and deforestation leading to changes in the environmental interface between humans and the animal reservoir (or reservoirs).6

The emerging epidemiologic pattern of these cases bears a striking resemblance to the early cases of HIV/AIDS. In the present study, men who identified as homosexual or bisexual accounted for 98% of cases. The classic mode of transmission of monkeypox virus infection is thought to be direct lesion-to-skin contact. Thus far, there has been very little evidence of household spread of any form of monkeypox other than among caregivers, which suggests that this infection is not spread through casual contact and probably requires prolonged or repeated exposure to virus-shedding lesions. In the present study, the finding of PCR positivity in 29 of 32 semen samples, the presence of lesions isolated to the oropharynx in 23% of the persons with infection, and the observation that 73% of persons in the cohort had lesions in the anogenital area suggest that sexual transmission may also play a role. Given how little we know about the epidemiologic characteristics of the current outbreak, it is prudent to heed an observation made during the first year of the HIV/AIDS pandemic: “… any assumption that it will remain restricted to a particular segment of our society is truly an assumption without a scientific basis.”7 Thus, additional detailed epidemiologic and observational cohort studies, serosurveys, and ongoing surveillance for new cases are of critical importance.

If one compares the situations at the start of the AIDS, Covid-19, and current global monkeypox outbreaks, certain interesting similarities and differences are apparent. In the case of AIDS, the etiologic agent was unknown, and no effective specific countermeasures were available. Today, we know the cause and have effective therapies; however, it took years to get to that point, and we still lack a vaccine. In the case of Covid-19, we quickly identified the etiologic agent; however, we lacked effective countermeasures. Today, we have effective diagnostics, vaccines, and therapies, after approximately a year of intense research and development. In contrast, in the case of monkeypox, the etiologic agent has been known for decades. One licensed monkeypox vaccine — the nonreplicating modified vaccinia Ankara (Jynneos [called Imvamune in Canada and Imvanex in Europe], Bavarian Nordic) — and one vaccine that is available for monkeypox under the FDA Expanded Access Investigational New Drug mechanism (live virus vaccinia [ACAM2000, Emergent BioSolutions]) are in the Strategic National Stockpile. In addition, two drugs (tecovirimat and brincidofovir) had already been licensed through the “Animal Rule” for the closely related virus variola (which causes smallpox). Studies of the disease and its animal reservoirs had been ongoing in Africa,8 and a randomized, placebo-controlled trail of tecovirimat was close to starting in the Democratic Republic of Congo.9 Thus, the challenge to the public health and research communities during this time of emergency response is to ensure the efficient and equitable availability and distribution of existing countermeasures to those in need of them while at the same time conducting the rigorous studies needed to define what the clinical efficacy may be, understand any potential safety concerns, and guide proper utilization.

The current monkeypox outbreak provides a new set of challenges to patients as well as to the medical and biomedical research communities. At the time that the article by Thornhill et al. was published online, approximately 14,000 cases had been reported in the world; at the time this editorial was being written (approximately 2 weeks later), that number had doubled.10 Lessons learned during the responses to AIDS and Covid-19 should help us to marshal a more efficient and effective response to monkeypox, and the response to monkeypox should, in turn, help to inform our response to the inevitable next emerging or reemerging infectious disease of pandemic potential.

Funding and Disclosures

Disclosure forms provided by the authors are available with the full text of this editorial at NEJM.org.

This editorial was updated on August 25, 2022, at NEJM.org.

Author Affiliations

From the Division of Clinical Research (H.C.L.) and Office of the Director (A.S.F.), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.

Supplementary Material

References (10)

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