Monkeypox in the Post-Smallpox Vaccination Era

Abstract & Commentary

By Brian G. Blackburn, MD, and Michele Barry, MD, FACP

Dr. Blackburn is Clinical Assistant Professor in the Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Palo Alto, CA. Dr. Barry is Senior Associate Dean of Global Health, Stanford University School of Medicine, Palo Alto, CA.

Dr. Barry serves as a consultant for the Ford Foundation, and her program receives funding from the Johnson & Johnson Corporate Foundation. Dr. Blackburn reports no financial relationships related to this field of study.

Synopsis: Monkeypox incidence increased 20-fold from the early 1980s to 2005-07 in the Democratic Republic of Congo (DRC). The risk of monkeypox was higher in younger and unvaccinated individuals, and likely indicates that decreasing immunity in the population three decades after the cessation of smallpox vaccination campaigns is contributing to the resurgence of this disease.

Source: Rimoin AW, et. al. Major increase in human monkeypox incidence 30 years after smallpox vaccination campaigns cease in the Democratic Republic of Congo. PNAS 2010;37:16262-7.

Monkeypox is an orthopoxvirus related to variola that causes a clinically similar illness to smallpox, albeit less severe.1 Although initially described in primates, rodent species such as African squirrels, giant pouched rats, and dormice appear to be the primary reservoirs in nature. Humans acquire the disease both from animals and human-to-human transmission. Although an outbreak was reported in the United States in 2003 related to the importation of exotic pets, monkeypox has been found in nature only in Central and West Africa.1,2

Smallpox vaccination confers about 85% protection against monkeypox, but vaccination campaigns ceased following the eradication of this disease.1 Although systematic surveillance for monkeypox had been ongoing in the immediate post-smallpox vaccination era within some parts of Africa, such surveillance has not been well maintained subsequently. Overall, the largest numbers of monkeypox cases have been reported from the DRC, and smallpox vaccination officially ended there in 1980.1,3

To better delineate recent monkeypox epidemiology and transmission, an active surveillance program was re-instituted during 2005-07 in areas within the DRC where monkeypox was known to be circulating. A suspected case of human monkeypox was defined as a patient with a fever accompanied by a vesicular-pustular rash. Cases were considered confirmed if monkeypox virus was detected within scab or vesicular fluid when tested by polymerase chain reaction (PCR).

From 2005-07, 760 confirmed cases of monkeypox were detected in nine health zones in the central DRC, where the annual crude incidence rate was 5.5 cases per 10,000. The mean age of case-patients was 12 years, 62% were male, and cases were more commonly found in forest than savannah regions. In one representative health zone with relatively comparable disease surveillance activity in the 1980s and 2000s, the annual monkeypox incidence increased from 0.7 to 14.4 per 10,000, representing a 20-fold increase.

Overall, the risk of human monkeypox was inversely associated with age and smallpox vaccination. More than 92% of case-patients were born after 1980, and only 4% of case-patients had evidence of prior smallpox vaccination, compared with 26% of the general population. Vaccinated persons who were born before 1980 had a five-fold lower risk of monkeypox compared with unvaccinated persons (0.8 vs. 4.1 per 10,000). In this group, vaccine efficacy was estimated to be 81% (95% CI 68–88%).


Human monkeypox is a zoonosis that occurs primarily in remote villages of Central and West Africa in proximity to tropical rainforests where there is far more frequent contact with infected animals. The use of reservoir animals as food may be an important source of transmission to humans, since contact with sick animals has resulted in transmission through respiratory droplets.

The incubation period for monkeypox is about seven to 17 days, and the illness begins with fever, headache, and myalgias. Lymphadenopathy is prominent and is the principal distinguishing characteristic from smallpox; it occurs coincidentally with prodromal fever prior to the rash. Laboratory diagnosis includes identification through PCR, culture, or blood serology. Currently, there is no proven, safe treatment for monkeypox, and the Centers for Disease Control and Prevention (CDC) recommends that persons investigating monkeypox outbreaks and involved in the care of infected individuals receive smallpox vaccination to protect against monkeypox. Persons who have had close contact with individuals or animals that have monkeypox should also be vaccinated up to 14 days after exposure. CDC does not recommend pre-exposure vaccination for veterinarians, veterinary staff, or animal control officers unless such persons are involved in field investigations. No data are available on the effectiveness of cidofovir in treatment of human monkeypox. However, cidofovir has proven anti-monkeypox activity both in vitro and in animal studies.4

Three decades after the eradication of smallpox, waning population immunity as a result of the elimination of natural disease and the cessation of smallpox vaccination programs caused the unintended effect of reducing immunity to related monkeypox virus. This study demonstrates this effect dramatically through the recent increase in the incidence of monkeypox in the DRC, the preponderance of the infection in the young and unvaccinated, and the less dramatic increase among populations with higher rates of smallpox vaccination. Even 30 years after vaccination, cross-protection for monkeypox appears to be significant.

It is also possible that behavioral factors have driven some of the epidemiological changes seen in this study. As the authors indicate, contact with animal reservoir species is an important factor in many human monkeypox virus infections. In the DRC, contact of local populations with reservoir species harboring monkeypox virus has probably intensified since 1980, increasing the chances of animal-to-human infection. Monkeypox continues to occur almost exclusively in rural villages in proximity to tropical rainforests. Continued deforestation may favor an increase in human exposure to squirrels and other suspected reservoir species. Additionally, war and resultant widespread poverty have forced residents to rely increasingly on monkeys, squirrels, and other rodents for sustenance, all potential sources of monkeypox infection. Additionally, human-to-human transmission also may have increased, as entire households are now vaccine-naïve. Given the high attack rate and secondary transmission rates for this virus, intra-household transmission is now much more likely to occur, particularly between parents and children.

These findings have important implications. Monkeypox is a serious disease, with mortality rates as high as 10% in some series.1 Although the eradication of smallpox represents a public heath triumph, the re-emergence of monkeypox serves as a reminder that unanticipated consequences can result — even from the best of intentions. If monkeypox were to establish itself in a new area, the lack of natural immunity in animals and humans, particularly among the young, could predispose to large outbreaks and a public health threat. Already, within endemic foci of Africa, the disease has largely gone unmonitored, possibly causing increased morbidity and mortality in recent years. Improved surveillance and epidemiological analysis are sorely needed to better assess the public health burden of this infection, and to develop strategies for reducing the spread of infection.


  1. Damon IK. Orthopoxviruses. In: Principles and Practice of Infectious Diseases. 7th ed. Philadelphia, PA: Churchill Livingstone, 2010.
  2. Reed KD, et al. The detection of monkeypox in humans in the Western Hemisphere. N Engl J Med 2004;350:342–350.
  3. Hutin YJ, et al. Outbreak of human monkeypox, Democratic Republic of Congo, 1996 to 1997. Emerg Infect Dis 2001;7:434–8.
  4. De Clercq E. Cidofovir in the treatment of poxvirus infections. Antiviral Res 2002;55:1-13.