Orthopoxviruses: Variola, Vaccinia, Cowpox, and Monkeypox

Abstract

Orthopoxviruses are large, complex DNA viruses within the family Poxviridae. Four orthopoxvirus species are known to cause human disease: variola virus (smallpox), vaccinia virus (smallpox vaccine), cowpox virus, and monkeypox virus. Variola virus is likely the best known member of the orthopoxvirus genus (Mandell GL, Bennett JE, Dolin R. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 7th ed. Philadelphia: Churchill Livingstone/Elsevier; 2010). As the causative agent of smallpox, this virus caused untold human suffering and loss of life until its eradication in 1980 following the successful completion of a global eradication campaign (Fenner F. Smallpox and its eradication. Geneva: World Health Organization; 1988). Ordinary smallpox presented with fever and flu-like symptoms after an incubation period of 10–14 days. Rash generally followed within 2–3 days and was characterized by a centrifugal distribution and stepwise progression through macular, papular, vesicular, and pustular stages. Mortality rates were estimated as high as 30 %. Edward Jenner was the first person to recognize the ability of orthopoxviruses to induce cross-reactive antibodies that protect against infection from other orthopoxvirus species and pioneer the use of vaccination to prevent disease. Vaccinia virus is still in use today as a vaccine as well as a subject and tool for biomedical research. Human vaccinia infections generally cause self-limited, localized lesions though severe and life-threatening complications can occur, particularly in high-risk populations such as immunocompromised individuals and those with atopic dermatitis. In addition, vaccinia infections present a risk of inadvertent inoculation from infectious virus present in vaccinial lesions. Most vaccinia infections are related to vaccination. However, both vaccinia virus and cowpox virus cause sporadic zoonotic infections as well. Cowpox virus is classically associated with occupational exposure to cattle though other sources include rats, cats, and zoo and circus elephants. In contrast, vaccinia virus is only known to occur naturally in cattle and buffalo in Brazil and select regions of the Middle East and Southeast Asia. Monkeypox virus is also transmitted zoonotically; one or more species of squirrels or other rodents is believed to be the natural reservoir of monkeypox virus. The incidence of monkeypox appears to be increasing since the cessation of routine smallpox vaccination following eradication. The presentation of monkeypox is similar to that of ordinary smallpox with lymphadenopathy being the distinguishing clinical features of monkeypox. Overall, monkeypox is less severe compared to smallpox with an estimated mortality rate of ~10 %. An outbreak of human monkeypox occurred in the United States in 2003 demonstrating the capacity for spread of the disease outside of the previously observed geographic boundaries. Prevention of human orthopoxvirus infections is largely accomplished through vaccination. Few treatment options are available for orthopoxvirus infections after the onset of symptoms. Vaccinia immune globulin (VIG) has been used successfully in treating certain severe adverse events from smallpox vaccine. Other drugs with antiviral activity against orthopoxviruses are in development, but none are currently licensed for this indication. Orthopoxviruses pose a threat to public health based on their ability to cause zoonotic outbreaks and potential to be used as a biological weapon or agent of bioterrorism. These concerns continue to drive poxvirus research and efforts to develop preparedness and response plans, improved vaccines, antivirals, and other medical countermeasures.