Genetic Characterization of Plasmodium falciparum Histidine-Rich Protein 2 Deletions and Their Impact on Malaria Interventions in Odisha, India.

Diagnostic escape via Plasmodium falciparum (P. falciparum) histidine-rich protein 2 (pfhrp2) gene deletions is a major potential hurdle for global malaria elimination efforts. We investigated the prevalence of pfhrp2 gene deletions in 15 malaria-endemic villages in the state of Odisha, India, and modeled their impact on an ongoing in-country malaria intervention program. We found that 61.6% of subpatent P. falciparum infections (i.e., rapid diagnostic test [RDT]-negative and positive by polymerase chain reaction [PCR]) had pfhrp2 gene deletions, which were predominantly located in the exon 2 region (96.2%) and largely identified in samples from febrile individuals (82.6%). DNA sequencing and protein diversity features were characterized in a subset of samples from individuals with subpatent infections carrying intact pfhrp2 exon 2 loci. Our analyses revealed novel amino acid repeat motifs (231-293 amino acids), and these variant repeat sequences differed from those of RDT+/PCR+ samples. We also evaluated the state-sponsored mass screening and treatment intervention in the context of pfhrp2 gene deletions. We found that mass screening and treatment conducted alongside additional interventions (e.g., long-lasting insecticidal net distribution, indoor residual spraying) reduced the relative risk of infection for both P. falciparum parasites harboring a pfhrp2 deletion (adjusted relative risk ratio [aRRR] = 0.3; 95% CI = 0.1-1.0) and P. falciparum parasites with intact pfhrp2 genes (aRRR = 0.4; 95% CI = 0.2-1.1) when compared with the use of mass screening and treatment by RDT alone. Combined, our findings highlight the need for alternative diagnostic targets and tools as India moves toward its goal of malaria elimination by 2030.