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  • Pre-Collegiate Global Health Review

Monkeypox: An Unintended Consequence of Smallpox Eradication

Adwaith Hariharan, Biotechnology High School, Freehold, New Jersey, USA


40 years ago, the World Health Organization (WHO) certified smallpox as eradicated. As a result, most nations stopped routine smallpox immunizations after 1980. A benefit of smallpox vaccines was that they provided protection against other infectious diseases caused by orthopox viruses like monkeypox and cowpox. Estimates suggest more than 70% of the world's population is no longer immune to the smallpox virus or, via cross-protective immunity, to other orthopox viruses, like monkeypox. The monkeypox outbreak is an unintended consequence of the termination of routine smallpox vaccination in most countries after smallpox was certified eradicated 40 years ago. A self-limiting disease, monkeypox lasts 2-4 weeks. It is transmitted principally through bodily fluids and skin-to-skin contact with lesions, with limited respiratory spread. Declining vaccination coverage could lead to additional non-linear increases in human-to-human transmission. Understanding genomic evolution and dynamic epidemiology is necessary to curb its spread. A multi-pronged strategy to lessen the burden of human monkeypox infection in endemic areas includes alternative vaccine programs, education, and behavioral measures.


1980 – Smallpox eradicated: WHO declares eradication of smallpox, the world's first and only successful disease eradication program. A watershed moment in the history of public health (WHO, 1980).

2022 - Pox Swap: WHO declares monkeypox (a cousin of smallpox) outbreak a Public Health Emergency of International Concern (PHEIC). With more than 22,500 cases officially recorded as of July 2022, the outbreak has now reached 79 countries (WHO, 2022).

The eradication of smallpox ended at least 3,000 years of blindness, disfigurement, and death caused by the disease (WHO, 1980). It is considered a crowning achievement of public health. However, the downside was the termination of the global immunization program, which provided protection against new pox viruses (Hussain, 2019). The vaccinia virus vaccine that eradicated smallpox also provided protection against other orthopox infections including monkeypox, which has been increasingly infecting humans in Africa from its animal hosts since the 1970s (Henderson, 1999; Zeliadt, 2010). The human epidemiology of the Monkeypox virus is shifting with sporadic outbreaks in endemic sub-Saharan Africa due to its prevalence in yet unidentified animal reservoirs (Heymann, 2021).

According to estimates, more than 70% of the world's population is no longer immune to the smallpox virus, and through cross-immunity, to closely related orthopox viruses like monkeypox (Jezek, 1988; Rimoin, 2017). Recent outbreaks of monkeypox in Israel, Australia, and North America demonstrate once again how rapidly an infectious disease that first manifests in one region can move to other non-endemic nations and raise alarm.

Figure 1: Monkeypox cumulative counts - confirmed cases and number of countries with cases (as of November 9, 2022).

Monkeypox is a zoonotic disease transmitted from animals like rodents or primates (primary carriers) to humans (secondary carriers). Direct contact with infected animals or individuals can lead to the spread of the monkeypox infection in humans (Breman, 1980). The current outbreak involves human-to-human transmission mainly by direct contact with bodily fluids, wounds, or scabs of an infected person. Airborne exposure through respiratory droplets is possible but less common, therefore understudied (CDC, 2022).

Monkeypox is a relatively stable double-stranded DNA orthopox virus that manifests as fever, muscle aches, lethargy, other flu-like symptoms and lesions. Two clades of the monkeypox virus have been identified through genetic sequencing - the Congo Basin clade and the West African clade (Likos, 2005). The Congo Basin clade is reportedly more virulent, with case fatality rates of up to 11%, whereas the West Nile clade has reported case fatality rate of 1%-5% (Doshi, 2019; Rimion, 2010).

The current monkeypox outbreak is attributed to declining smallpox vaccine-induced immunity in the endemic populations. This caused the human-to-human transmission to exceed the threshold, resulting in sustained spread of the disease (Fine, 1988). Additionally, the recent outbreak is of concern as it has involved multiple chains of transmission in clusters across non-endemic countries (WHO, 2022). It is suspected that a community spread through a significant number of asymptomatic carriers may be the cause. To date, most cases have involved men who have sex with men (MSM), particularly those with new or many partners (WHO, 2022). According to a recent WHO epidemiologic study, 98.8% of cases with available data are male, with 98.1% identifying themselves as homosexual or bisexual. Epidemiologic studies show that the most common mechanism of transmission is through close skin-to-skin physical contact with lesions through touch, bodily fluids, and clothes, not exclusive to sexual activity (Osterholm, 2022). Although there is a possibility of respiratory droplet transmission, there is no evidence of airborne transmission, as seen in COVID-19. Additionally, unlike HIV, there is no chronic carrier with monkeypox, reducing the risk of ongoing transmission (European CDC, 2022).

Figure 2: 2022 Monkeypox Outbreak Global Map. (Data as of 09 Nov 2022 5:00 PM EDT). Courtesy: Center for Disease Control and Prevention (CDC).

A self-limiting infection, monkeypox has a stable DNA which is not prone to fast mutation. Therefore, it has limited pandemic potential. However, human-to-human transmission raises the possibility that the virus may genetically mutate allowing a rapid and efficient spread among humans (Zeliadt, 2010). Apart from the direct impact on individual susceptibility, a declining vaccination coverage could lead to an additional non-linear increase in human-to-human transmissions. In the absence of vaccine protection, the opportunity for inter-generational transmission within households, particularly between parents and children is very high. Contact tracing and mathematical modelling analysis should be used to investigate such non-linear spreads.

Understanding the genomic evolution and dynamic epidemiology of the orthopox viruses is vital in providing clues about reservoirs and intermediate hosts (Simpson 2020). In-field genomic diagnostics and effective disease prevention approaches are crucial steps to prevent further outbreaks. Use of novel antiviral drugs for therapy and next-generation vaccination like the non-replicating smallpox vaccinations are crucial in stopping the spread of monkeypox. A multi-pronged strategy is needed to reduce monkeypox infections. These strategies include:

  • Health education programs that address the prevention of animal-to-human spread by teaching the handling of animal reservoir species.

  • Isolation of acutely ill patients and barrier nursing strategies to prevent human-to-human transmission

Vaccination is still a viable option to other control methods. However, given the inadequate healthcare infrastructure in endemic areas, it would be logistically very challenging to reinstate the smallpox vaccine as part of a routine immunization program. Additionally, vaccines may not be the best recourse, given their adverse effects in immune-compromised individuals. Alternative vaccines like the attenuated live vaccine approach - LC16M8, or the modified replication-defective vaccinia approach - Ankara vaccinia, can be considered (Kenner, 2006; Parrino, 2007). Targeted vaccinations for at-risk populations like the healthcare workers in the endemic regions and the individuals exposed to the disease-causing animal reservoirs should be considered.

WHO's declaration of monkeypox a Public Health Emergency of International Concern (PHEIC) is intended to focus a global response to contain the outbreak. The global spread of Monkeypox once again reiterates the fact that infectious diseases know no boundaries. Wise allocation of resources along with behavioral changes in endemic countries can progressively lead to disease management and response efforts and make adequate and useful contributions to the national and international action required to lessen the effects of new infectious diseases. Experts also agree that a better understanding of the genomic evolution of the orthopox viruses and the potential use of new generation non-replicating smallpox vaccines and antiviral medications can curb the spread of orthopox viruses like the Monkeypox. Declaring monkeypox a global health emergency is a preventative step – not a reason for panic.


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