| Summary: | Background: Endemic Burkitt lymphoma (eBL) is the most common childhood cancer in Africa and is linked to <i>Plasmodium falciparum</i> (<i>Pf</i>) malaria infection, one of the most common and deadly childhood infections in Africa; however, the role of <i>Pf</i> genetic diversity is unclear. A potential role of <i>Pf</i> genetic diversity in eBL has been suggested by a correlation of age-specific patterns of eBL with the complexity of <i>Pf</i> infection in Ghana, Uganda, and Tanzania, as well as a finding of significantly higher <i>Pf</i> genetic diversity, based on a sensitive molecular barcode assay, in eBL cases than matched controls in Malawi. We examined this hypothesis by measuring diversity in <i>Pf-</i>serine repeat antigen-5 (<i>Pfsera5</i>), an antigenic target of blood-stage immunity to malaria, among 200 eBL cases and 140 controls, all <i>Pf</i> polymerase chain reaction (PCR)-positive, in Malawi. Methods: We performed <i>Pfsera5</i> PCR and sequencing (~3.3 kb over exons II–IV) to determine single or mixed <i>Pf</i>SERA5 infection status. The patterns of <i>Pfsera5</i> PCR positivity, mixed infection, sequence variants, and haplotypes among eBL cases, controls, and combined/pooled were analyzed using frequency tables. The association of mixed <i>Pfsera5</i> infection with eBL was evaluated using logistic regression, controlling for age, sex, and previously measured <i>Pf</i> genetic diversity. Results: <i>Pfsera5</i> PCR was positive in 108 eBL cases and 70 controls. Mixed <i>Pf</i>SERA5 infection was detected in 41.7% of eBL cases versus 24.3% of controls; the odds ratio (OR) was 2.18, and the 95% confidence interval (CI) was 1.12–4.26, which remained significant in adjusted results (adjusted odds ratio [aOR] of 2.40, 95% CI of 1.11–5.17). A total of 29 nucleotide variations and 96 haplotypes were identified, but these were unrelated to eBL. Conclusions: Our results increase the evidence supporting the hypothesis that infection with mixed <i>Pf</i> infection is increased with eBL and suggest that measuring <i>Pf</i> genetic diversity may provide new insights into the role of <i>Pf</i> infection in eBL.
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