<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background.</div><span style="font-style:italic;">Cryptosporidium</span> is a leading cause of moderate to severe childhood diarrhea in resource-poor settings. Understanding the natural history of cryptosporidiosis and the correlates of protection are essential to develop effective and sustainable approaches to disease control and prevention.<div class="boxTitle">Methods.</div>Children (N = 497) were recruited at birth in semiurban slums in Vellore, India, and followed for 3 years with twice-weekly home visits. Stool samples were collected every 2 weeks and during diarrheal episodes were tested for <span style="font-style:italic;">Cryptosporidium</span> species by polymerase chain reaction (PCR). Serum samples obtained every 6 months were evaluated for seroconversion, defined as a 4-fold increase in immunoglobulin G directed against <span style="font-style:italic;">Cryptosporidium</span> gp15 and/or Cp23 antigens between consecutive sera.<div class="boxTitle">Results.</div>Of 410 children completing follow-up, 397 (97%) acquired cryptosporidiosis by 3 years of age. PCR identified 1053 episodes of cryptosporidiosis, with an overall incidence of 0.86 infections per child-year by stool and serology. The median age for the first infection was 9 (interquartile range, 4–17) months, indicating early exposure. Although infections were mainly asymptomatic (693 [66%]), <span style="font-style:italic;">Cryptosporidium</span> was identified in 9.4% of diarrheal episodes. The proportion of reinfected children was high (81%) and there was clustering of asymptomatic and symptomatic infections (<span style="font-style:italic;">P</span> < .0001 for both). Protection against infection increased with the order of infection but was only 69% after 4 infections. <span style="font-style:italic;">Cryptosporidium hominis</span> (73.3%) was the predominant <span style="font-style:italic;">Cryptosporidium</span> species, and there was no species-specific protection.<div class="boxTitle">Conclusions.</div>There is a high burden of endemic cryptosporidiosis in southern India. Clustering of infection is suggestive of host susceptibility. Multiple reinfections conferred some protection against subsequent infection.</span>
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