Orthopoxviruses are a genus of viruses belonging to the family Poxviridae, known for causing significant, often blister-forming diseases in both humans and animals. These pathogens played a dramatic role in human history, most notably as the cause of smallpox, once one of the deadliest infectious diseases globally. Although smallpox has been eradicated, the genus remains a public health concern due to the emergence of related diseases, such as Mpox, which continues to cause outbreaks worldwide. Understanding the characteristics of this genus is important for developing effective countermeasures against current and future viral threats.
The Biology of Orthopoxviruses
Orthopoxviruses are distinguished by their large size and complex structure. They possess a linear, double-stranded DNA genome, typically measuring between 170 and 250 kilobase pairs, allowing them to encode hundreds of different proteins. The virion, or individual virus particle, has a characteristic brick-shaped or ovoid morphology and is surrounded by a complex membrane structure.
A unique feature of orthopoxviruses is their replication cycle, which occurs entirely within the cytoplasm of the host cell, unlike most DNA viruses that require the nucleus. This independence is possible because the virus carries its own machinery for gene expression, including a DNA-dependent RNA polymerase. The virus creates a specialized “factory” within the cytoplasm to synthesize its own DNA and proteins, minimizing reliance on the host cell’s nuclear processes.
The mature virus particle is assembled within this factory, resulting in two infectious forms: the Intracellular Mature Virion and the Extracellular Enveloped Virion. This life cycle, coupled with the large genome, enables the virus to encode proteins that interfere with the host’s immune response. The particle size, approximately 200 by 250 nanometers, makes these viruses among the largest known.
Major Orthopoxviruses Affecting Humans
The genus Orthopoxvirus includes several species capable of infecting humans, the most historically significant being the Variola virus, the causative agent of smallpox. This virus caused devastating epidemics characterized by high fever followed by a rash that progressed into deep, fluid-filled pustules, often leaving permanent scarring. The World Health Organization officially declared smallpox eradicated in 1980 following a successful global vaccination campaign.
Despite its eradication, the Variola virus still exists in two maximum-containment facilities: one at the Centers for Disease Control and Prevention (CDC) in the United States and the other at the State Research Centre of Virology and Biotechnology (VECTOR) in Russia. These official stocks are strictly controlled for research purposes, primarily to develop new vaccines and antiviral treatments.
Another significant member is the Mpox virus, which gained global attention for outbreaks in non-endemic countries beginning in 2022. Mpox infection typically presents with fever, headache, and swollen lymph nodes, followed by a widespread rash of lesions resembling those of smallpox. While less severe than smallpox, Mpox infections are a focus of current public health efforts due to their increasing global spread.
The Vaccinia virus is the most medically beneficial member of the genus, as it served as the live-virus basis for the original smallpox vaccine. It causes a localized, mild infection in humans, providing immunity against other orthopoxviruses due to strong antigenic cross-reactivity. Cowpox virus, originally transmitted from infected cattle and rodents, also causes localized skin lesions and was the agent used by Edward Jenner in the late 18th century to pioneer vaccination.
Transmission and Natural Reservoirs
Orthopoxviruses are primarily transmitted through close contact with an infected animal or person, though specific routes vary by species. Transmission often occurs through direct contact with skin lesions, bodily fluids, or scabs. For Variola virus, prolonged face-to-face contact, involving the inhalation of respiratory droplets, was the main route for person-to-person spread.
Indirect transmission can also occur through contact with contaminated materials, known as fomites, such as bedding or clothing. Mpox has demonstrated the ability to spread through respiratory secretions during prolonged, close encounters, and through intimate physical contact.
The epidemiology of orthopoxviruses is defined by natural reservoirs, the animal populations that maintain the virus in nature. For Mpox, the suspected natural reservoirs are various species of African rodents, including tree and rope squirrels. The virus is maintained in these populations, occasionally jumping to non-human primates and then to humans through zoonotic spillover. The Variola virus is unique because it is strictly a human pathogen with no known animal reservoir, which facilitated its complete eradication.
Vaccines and Antiviral Treatments
The most effective countermeasure against orthopoxviruses is vaccination, which capitalizes on the cross-protective immunity shared across the genus. The original smallpox vaccine utilized the live Vaccinia virus, providing robust protection but carrying a risk of side effects, particularly in immunocompromised individuals. This older generation vaccine is no longer routinely administered to the general public.
Newer, safer vaccines have been developed, such as JYNNEOS, a third-generation vaccine approved for both smallpox and Mpox prevention. This vaccine uses a highly modified, non-replicating form of the Vaccinia virus, meaning it cannot reproduce in human cells and is safer for individuals with underlying health conditions. Vaccination is currently recommended for those at high risk of occupational exposure or during an active outbreak.
For treating severe orthopoxvirus infections, specific antiviral medications are available, with Tecovirimat (TPOXX) being a primary option. Tecovirimat works by targeting the viral protein p37, which is essential for the formation of the extracellular enveloped virion required for efficient cell-to-cell spread. By inhibiting this protein, Tecovirimat limits the virus’s ability to spread throughout the host. Another drug, Cidofovir, is also effective but its use is complicated by the risk of kidney toxicity.