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I just stumbled across an interesting story (in a book about water of all things). During the Great Plague of London in 1665, goods sold by a plague victim reached the small town of Eyam. Apparently fleas on some of the clothing managed to jump to the population and plague began spreading through the town.

However, something most remarkable happened: rather than try to save themselves, the city officials imposed a quarantine.

The pestilence swept through the community. Between September and December 1665, 42 villagers died and by the spring of 1666, many were on the verge of fleeing their homes and livelihoods to save themselves.

It was at this point that the newly appointed rector, William Mompesson, intervened. Believing it his duty to prevent the plague spreading to the nearby towns of Sheffield and Bakewell, he decided the village should be quarantined...

...Mompesson said if they agreed to stay - effectively choosing death - he would do everything in his power to alleviate their suffering and remain with them, telling them he was willing to sacrifice his own life rather than see nearby communities desolated.

The plague raged through the town for the next few months.

August 1666 saw the highest number of victims, reaching a peak of five or six deaths a day. The weather was remarkably hot that summer, which meant the fleas were more active, and the pestilence spread unchecked throughout the village...However, the worst of the pestilence was over. The number of cases fell in September and October, and by 1 November the disease had gone. The cordon had worked.

The thing that's interesting about this is that the plague was still going on in August and September 1666. How so? Look what was going on in London:

By late autumn [1665], the death toll in London and the suburbs began to slow until, in February 1666, it was considered safe enough for the King and his entourage to come back to the city. With the return of the monarch, others began to return: The gentry returned in their carriages accompanied by carts piled high with their belongings. The judges moved back from Windsor to sit in Westminster Hall, although Parliament, which had been prorogued in April 1665, did not reconvene until September 1666. Trade recommenced and businesses and workshops opened up. London was the goal of a new wave of people who flocked to the city in expectation of making their fortunes. Writing at the end of March 1666, Lord Clarendon, the Lord Chancellor, stated "... the streets were as full, the Exchange as much crowded, the people in all places as numerous as they had ever been seen ...".

So, consider the following WI. Someone leaving food for the plague victims in Eyam (there were drop-off points where the deliverers were less likely to be infected) manages to get sick in August 1666 somewhere near Eyam. The plague starts back up again and reaches London a few days later, where everyone is just milling around thinking they're clear. IOTL, London was having cases here and there during the summer but it was more or less out of the way. However, ITTL with plague victims arriving from everywhere they do what they can to keep things under control but it doesn't work very well. By September 1st quarantines are back in effect and you've got a lot of sick people in London. Everything is fine as long as no one leaves their houses. However, leaving your house proves to be a good idea a day later, when the Great Fire starts as IOTL.

Suddenly you've got large numbers of people scattering all over the place trying to find places to live, spreading the plague further. Places which thought they were out of the woods suddenly have to deal with the plague again, and there are more fatalities.

Continue on from there. I'm guessing this new outbreak affects maybe half as many people in London as the original outbreak (some have recovered, others have died, and more strict countermeasures are in place). But in this case they think the worst is over so it comes completely out of nowhere. And you can't quarantine victims in a burning house.

If you really want a nasty butterfly, say the King contracts the plague during one of his tours of the city in late August ("hey, I'm out here. Trust me, it's OK."). Conceivably several Parliament members also succumb. Note that the victim is Charles II, having just retaken the throne after the Interregnum. Somebody might think God is saying "I like Cromwell and his government. I DON'T like kings."

https://en.wikipedia.org/wiki/Great_Fire_of_London
https://en.wikipedia.org/wiki/Great_Plague_of_London
https://www.bbc.com/news/uk-england-35064071
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