Orthopoxvirus is a genus of large, brick-shaped viruses containing a double-stranded DNA genome. As part of the Poxviridae family, these viruses replicate within the cytoplasm of host cells, a distinct process from many other DNA viruses. This group includes viruses that have caused some of the most well-known diseases in humans and other mammals.
The genetic material of orthopoxviruses is a single, linear molecule of DNA that is large enough to code for approximately 200 proteins. This genetic complexity allows the viruses to produce their own enzymes for replication, making them less dependent on the host cell’s machinery. Viruses within this genus share significant genetic similarities and often induce cross-reactive immunity, meaning infection or vaccination with one can provide protection against others.
Notable Orthopoxvirus Diseases
Variola Virus
The variola virus is the agent responsible for smallpox, a devastating disease that caused millions of deaths. Smallpox was highly contagious and characterized by high fever, vomiting, and a distinctive skin rash that progressed into fluid-filled blisters. The blisters would eventually scab over, often leaving deep scars or causing blindness.
There were two main forms: variola major, the more severe form with a mortality rate of about 30%, and variola minor, with a fatality rate of 1% or less. A successful global vaccination campaign by the World Health Organization (WHO) led to smallpox being declared eradicated in 1980. This achievement is the only time a human disease has been completely wiped out.
Mpox Virus
Mpox virus causes a disease with symptoms similar to, but generally milder than, smallpox. Symptoms include fever, headache, muscle aches, fatigue, and swollen lymph nodes, followed by a characteristic rash. The rash develops into lesions that can appear on the face, hands, feet, and genital regions.
The severity of mpox can vary depending on the viral clade, or genetic branch. Clade I has been associated with a higher case fatality rate of up to 10%, whereas Clade II is less severe. Unlike smallpox, mpox is a zoonotic disease, meaning it circulates in animal populations. The discontinuation of routine smallpox vaccination has left a growing population susceptible to mpox infection.
Cowpox Virus
Cowpox virus is historically significant for its role in the development of the first vaccine. In 1796, physician Edward Jenner observed that milkmaids who contracted cowpox were subsequently immune to smallpox. This discovery led him to create an inoculation method using material from cowpox lesions, which became the foundation of modern vaccination. The word “vaccination” is derived from vacca, the Latin word for cow.
Cowpox is a zoonotic disease that causes localized, painful skin lesions in humans, usually on the hands or face after direct contact with an infected animal. While cattle were the original source, the virus is now more commonly found in rodents, which act as a reservoir. It can be transmitted to humans through intermediate hosts like domestic cats. The infection is self-limiting in healthy individuals but can be more severe in those with compromised immune systems.
Vaccinia Virus
Vaccinia virus is the live virus used in the smallpox vaccine. While its exact origin is unknown, it is genetically distinct from cowpox virus but shares enough similarities with variola virus to confer cross-protective immunity. Its use in the global eradication campaign was instrumental in eliminating smallpox.
Following the eradication of smallpox, vaccinia virus has found a new purpose in scientific research as a viral vector. Its large genome can be genetically engineered to carry and express foreign genes from other pathogens. This makes it a tool for developing new recombinant vaccines and for use in cancer therapy research.
Transmission and Zoonotic Potential
Many orthopoxviruses originate in animal populations, which serve as a natural reservoir. Rodents are a common reservoir for several of these viruses, including cowpox and mpox. The transmission from animals to humans, known as zoonotic spillover, occurs through direct contact with an infected animal’s blood, bodily fluids, or skin lesions. This can happen through bites, scratches, or during the handling of wild game.
Once an orthopoxvirus infects a human, it can spread from person to person. The most common transmission mode is direct contact with the infectious rash, scabs, or body fluids of an infected individual. This includes intimate contact, such as kissing or sexual contact.
Prolonged face-to-face contact can also lead to transmission through respiratory secretions. Additionally, the virus can spread through contact with contaminated materials, known as fomites, like bedding, clothing, or towels used by an infected person.
Vaccination and Treatment Strategies
A primary strategy against orthopoxviruses is vaccination, which relies on cross-protection. The smallpox vaccine, containing the live vaccinia virus, stimulates an immune response that is effective against related viruses, including mpox. Historic data suggests the smallpox vaccine was about 85% effective in preventing mpox, but newer and safer vaccines have since been developed.
One modern vaccine is JYNNEOS, a live, non-replicating vaccinia virus vaccine approved for preventing both smallpox and mpox in high-risk adults. Because it is non-replicating, it has a more favorable safety profile than older vaccines like ACAM2000, which is replication-competent and carries a risk of more serious side effects. The JYNNEOS vaccine has demonstrated 66% to 89% effectiveness in preventing mpox during recent outbreaks.
For individuals who are already infected, antiviral medications are available. The primary treatment is tecovirimat (TPOXX), which was developed for smallpox but is also effective against other orthopoxvirus infections. The medication works by inhibiting a viral protein necessary for the virus to spread from cell to cell, preventing its dissemination throughout the body and reducing the severity of the illness.