Global risk of selection and spread of Plasmodium falciparum histidine-rich protein 2 and 3 gene deletions

Since their first detection in 2010, Plasmodium falciparum malaria parasites lacking the P. falciparum histidine-rich protein 2 gene (pfhrp2) have been observed in 40 of 47 surveyed countries, as documented by the World Health Organization. These genetic deletions reduce detection by the most widely used rapid diagnostic tests, prompting three countries to switch to alternative diagnostics. However, manufacturing of alternative rapid diagnostic tests has not been scaled up and there are no World Health Organization-prequalified combination tests that use P. falciparum Plasmodium lactate dehydrogenase. The continuing spread of pfhrp2 and/or pfhrp3 (pfhrp2/3) deletions threatens malaria control, creating an emerging public health crisis. Here we use mathematical modeling informed by current pfhrp2/3 deletion prevalence and a literature review to assess the global risk of pfhrp2/3 deletions. We identify ten priority countries for surveillance and predict that the primary spread in Africa will move southward from the Horn of Africa through East Africa within 20 years. Despite variation in modeled timelines due to uncertainty in model parameters, four countries yet to switch rapid diagnostic tests are consistently classified as high risk under a range of model assumptions. This updated model offers refined predictions to guide pfhrp2/3 policy and prioritize future surveillance efforts and innovation.