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Biological warfare
In 1763, Pontiac's War broke out as a Native American confederacy led by Pontiac attempted to counter British control over the Great Lakes region. A group of Native American warriors laid siege to British-held Fort Pitt on June 22. In response, Henry Bouquet, the commander of the fort, ordered his subordinate Simeon Ecuyer to give smallpox-infested blankets from the infirmary to a Delaware delegation outside the fort. Bouquet had discussed this with his superior, Sir Jeffrey Amherst, who wrote to Bouquet stating: "Could it not be contrived to send the small pox among the disaffected tribes of Indians? We must on this occasion use every stratagem in our power to reduce them." Bouquet agreed with the proposal, writing back that "I will try to inocculate [sic] the Indians by means of Blankets that may fall in their hands". On 24 June 1763, William Trent, a local trader and commander of the Fort Pitt militia, wrote, "Out of our regard for them, we gave them two Blankets and an Handkerchief out of the Small Pox Hospital. I hope it will have the desired effect." The effectiveness of this effort to broadcast the disease is unknown. There are also accounts that smallpox was used as a weapon during the American Revolutionary War (1775–1783).

According to a theory put forward in Journal of Australian Studies (JAS) by independent researcher Christopher Warren, Royal Marines used smallpox in 1789 against indigenous tribes in New South Wales. This theory was also considered earlier in Bulletin of the History of Medicine and by David Day. However it is disputed by some medical academics, including Professor Jack Carmody, who in 2010 claimed that the rapid spread of the outbreak in question was more likely indicative of chickenpox—a more infectious disease which, at the time, was often confused, even by surgeons, with smallpox, and may have been comparably deadly to Aborigines and other peoples without natural immunity to it. Carmody noted that in the 8-month voyage of the First Fleet and the following 14 months there were no reports of smallpox amongst the colonists and that, since smallpox has an incubation period of 10–12 days, it is unlikely it was present in the First Fleet; however, Warren argued in the JAS article that the likely source was bottles of smallpox virus possessed by First Fleet surgeons. Ian and Jennifer Glynn, in The life and death of smallpox, confirm that bottles of "variolous matter" were carried to Australia for use as a vaccine, but think it unlikely the virus could have survived till 1789. In 2007, Christopher Warren offered evidence that the British smallpox may have been still viable. However, the only non-Aborigine reported to have died in this outbreak was a seaman called Joseph Jeffries, who was recorded as being of "American Indian" origin.

W. S. Carus, an expert in biological weapons, has written that there is circumstantial evidence that smallpox was deliberately introduced to the Aboriginal population. However Carmody and the Australian National University's Boyd Hunter continue to support the chickenpox hypothesis. In a 2013 lecture at the Australian National University, Carmody pointed out that chickenpox, unlike smallpox, was known to be present in the Sydney Cove colony. He also suggested that all c. 18th century (and earlier) identifications of smallpox outbreaks were dubious because: "surgeons … would have been unaware of the distinction between smallpox and chickenpox – the latter having traditionally been considered a milder form of smallpox."

Biological warfare
There is no historical evidence that smallpox has ever effectively been used as a bioweapon. Colonial historical accounts have revealed that settlers in both North and South America discussed and even planned to infect indigenous populations, and that on one occasion blankets from a smallpox hospital were recorded as having been given to Delaware tribesmen, but it is implausible that any such efforts were successful or epidemiologically significant.

In 1763, Pontiac's War broke out as a Native American confederacy led by Pontiac attempted to counter British control over the Great Lakes region. A group of Native American warriors laid siege to British-held Fort Pitt on June 22. In response, Colonel Henry Bouquet wrote a letter to Captain Simeon Ecuyer, the commanding officer at Fort Pitt, to give smallpox-infested blankets from the infirmary to a Delaware delegation outside the fort. Bouquet had discussed this with his superior, General Sir Jeffrey Amherst, who wrote to Bouquet stating: "Could it not be contrived to send the small pox among the disaffected tribes of Indians? We must on this occasion use every stratagem in our power to reduce them." Bouquet agreed with the proposal, writing back that "I will try to inocculate [sic] the Indians by means of Blankets that may fall in their hands". However, there is no evidence that he ever followed through on the plan. On 24 June 1763, William Trent, a local trader and commander of the Fort Pitt militia, wrote, "Out of our regard for them, we gave them two Blankets and an Handkerchief out of the Small Pox Hospital. I hope it will have the desired effect." The effectiveness of this effort to broadcast the disease is unknown, as smallpox had been endemic

There are also accounts that smallpox was used as a weapon during the American Revolutionary War (1775–1783).

Outbreak characteristics
Monkeypox is endemic to West and Central Africa. Prior to the 2022 outbreak, the United Kingdom had recorded only seven previous cases of monkeypox, all of which were imported cases from Africa or healthcare workers involved in their treatment. The first three such cases were in 2018, followed by a further case in 2019 and three more in 2021. The only major monkeypox outbreak to be recorded in a Western country prior to 2022 was the 2003 Midwest monkeypox outbreak in the United States, which did not feature community transmission.

This outbreak is of the West African clade, which has a reported case fatality rate of 1% according to the World Health Organization. The genomic sequence of the virus associated with this outbreak was first published on 19 May by Portuguese researchers. They confirmed that the monkeypox virus was of the West African clade, related to other previous international outbreaks in 2018–19. Genetic evidence suggest the 2022 outbreak likely started in Nigeria,

The 2022 outbreak spread differently compared to prior monkeypox outbreaks outside Africa.

The New England Journal of Medicine published the first detailed description and case study of the outbreak on July 21, 2022, based on 528 infections diagnosed at 43 sites in 16 countries during a 2-month period between that April and June. All cases were men, and 98% men who have sex with men (MSM), statistics similar to those seen in New York City and the United Kingdom. Age ranged from 18-68, with a median of 38; three-quarters were white; 41% were infected with HIV; and 29% were infected with another STI. Skin lesions were present in 95% of cases, most frequently on the anogenital region (73%); trunk, arms, or legs (55%); and face (25%). anogenital area (73%); the trunk, arms, or legs (55%); the face (25%). The location of lesions, along with the fact that more than 90% of semen samples tested were PCR positive, strongly suggested sexual transmission, and researchers believe that 95% of cases were spread via close contact during sex between men.

Given the unusually high frequency of human-to-human transmission observed in this event, and the probable community transmission without history of traveling to endemic areas, spread of the virus through close contact is more likely, with transmission during sexual activities being the most common route. The first detailed description and case study of the outbreak found that 98% of the of cases are in men who have sex with men (MSM), notably in Canada, Spain, and the UK, with many cases diagnosed in sexual health clinics. Cases are mostly in young and middle-aged men. This points to transmission due to close contact during sex as being one route of transmission. The European Centre for Disease Prevention and Control (ECDC) considers the monkeypox virus to be moderately transmissible among humans. According to the centre, among MSM who contracted the virus, the most common means of transmission is likely through sexual activity due to intimate contact with infectious skin lesions. The ECDC rates likelihood of transmission due to close contact, including sexual contact, as "high", but, without close contact, the likelihood of transmission between individuals is considered to be low. In Nature, Anne Rimoin and Raina MacIntyre speculate that the higher percentage of MSM affected is a result of coincidental introduction to the community and then sexual activity constituting "close contact" rather than the virus itself becoming sexually transmitted. Monkeypox is not primarily a sexually transmitted disease.

On 23 May, David Heymann, an advisor for the World Health Organization, said that the likely theory of how the outbreak started is transmission during sexual intercourse of gay and bisexual men at two raves in Belgium and Spain. On 25 May, The Guardian stated that many scientists suspect the disease was circulating in the UK and Europe before reaching the MSM community, possibly misdiagnosed or detected only in isolated cases; four cases were diagnosed in 2018 and 2019, all in individuals recently arrived from Nigeria.

The UK Human Animal Infections and Risk Surveillance (HAIRS) group warned that the virus could reach wildlife and become endemic as a result.