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Timucua and Calusa archers repelled all three attempts of Juan Ponce de León's well-equipped fleet attempting to land in Florida in 1513, and drove off other Spanish fleets in 15.

The Guale, in what eventually became Georgia, initially welcomed 1,100 Spanish colonists who arrived in 1528; most of these died of malaria, leaving a remnant whose dependence on the Guale for food led to conflict and the evacuation of the surviving Spanish.

Spain was anxious to keep other Europeans well away from the Florida coasts, past which treasure fleets from the Caribbean sailed homeward to Spain.

However, the Timucua allowed one French expedition to stay, in return for support in a local war.

The next time the French returned, in 1541, they numbered 1,500 and intended to settle.

Initial Iroquois curiosity turned to suspicion and then hostility; in 1543 the harrassed French evacuated, becoming the second nation of Europeans to be driven from North American beachheads.

Some decimated societies made room for European strangers in places such as Québec (1608), Plymouth (1620), and Massachusetts (1630); the Iroquois Confederacy reacted to epidemics with a series of successful wars to replace their dead with captives.Endemic malaria plagued European immigrants to the southeast, but "virgin land" infections of smallpox, measles, influenza, cholera, and yellow fever could kill the majority in an American Indian society.Indigenous medicine proved helpless—and lost credibility—against these infectious killers that often hit hardest at more densely-peopled farming societies like the Massachusetts, Huron, and Iroquois, and gave a relative advantage to the more remote and to scattered hunter-gatherers.The human intruders did not arrive or multiply fast enough to match the devastation of Indian North America, and the total population of the continent continued to decline until at least 1700.Natural immunities to new diseases take generations to develop and interaction between migrating peoples from three continents initially proved deadly, and particularly so for American Indians.

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