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During the 1863/1864 winter, smallpox broke out in runaway slave encampments at New Bern and Beaufort. While soldiers in the nearby Union camps had been vaccinated against the disease, approximately 10% of the 2,500 black refugees at Beaufort were diagnosed with the infection. Union soldiers near New Bern were fortunately able to vaccinate the encampment before the virus spread. Soldiers at the Beaufort camp instead chose to isolate smallpox cases and the outbreak eventually died out.
In 19th-century armies, disease often claimed more casualties than the battlefield. Johnston uses the Fifteenth Connecticut Volunteer Infantry, which was the Provost Guard in New Bern in 1864, to show how disease can decimate a military unit. In this instance a rare outbreak of yellow fever killed 60 members of the regiment. In all, 303 Union soldiers died; the Fifteenth Connecticut accounted for 20 percent of them.