Malaria's global footprint and evolutionary history
Malaria remains one of humanity's most persistent pathogenic adversaries, with Plasmodium vivax the most geographically widespread of the human malaria parasites. While P. falciparum causes the majority of malaria deaths worldwide, P. vivax presents unique challenges for disease elimination due to its ability to form dormant liver stages called hypnozoites. These dormant forms can reactivate weeks, or months, after the initial infection, causing relapses and maintaining transmission cycles even in regions with sparse, seasonal mosquito activity.
In Latin America, P. vivax dominates the malaria landscape, responsible for over 70% of all cases. Three countries, Venezuela, Brazil, and Colombia, shoulder the heaviest burden, accounting for 79% of all malaria cases in the region. This considerable public health impact makes understanding the parasite's origins, spread and evolution particularly important.
The evolutionary history of malaria parasites is intimately tied to human migration patterns, with current evidence suggesting that P. vivax likely originated in Africa and shares an ancestor with the chimpanzee parasite P. schwetzi. This understanding was complicated by the high prevalence of the Duffy-negative blood type in many African populations, which was traditionally thought to prevent P. vivax infection. However, recent discoveries that P. vivax can infect Duffy-negative individuals in some African populations suggest the parasite has evolved mechanisms to overcome this barrier.
The global spread of P. vivax has been attributed to multiple migration events throughout human history. Ancient DNA studies confirm its presence in medieval Europe, where it remained endemic until the mid-20th century. The parasite's journey to the Americas, however, has been subject to much debate, with various competing hypotheses purportedly explaining the spread and evolution of P. vivax in Central and Southern America. These include pre-Columbian origins dating back 600-3,000 years ago, pre-Columbian transoceanic voyages from Asia or the Pacific islands, a European origin coinciding with 15th century colonial expansion, and introductions from Africa during the transatlantic slave trade.
The authors note that previous studies addressing the question of how and when P. vivax spread to the Americas have several limitations—particularly the lack of samples from West Africa, which has been previously shown as the origin of American P. falciparum lineages. This recent study by Lefebvre and colleagues, published in PLOS Pathogens, aimed to overcome these limitations with an extensive sampling effort and broad genomic analysis incorporating available genetic data from nearly all potential source populations, spanning all P. vivax-endemic continents.
Sampling, sequencing, and population genomics
The researchers compiled a non-redundant dataset of 620 P. vivax genomes across 36 countries worldwide, representing the nearly all sequenced and available P. vivax isolates to date. This dataset included 107 newly sequenced samples from six Central and Southern American countries (Brazil, Ecuador, French Guiana, Guyana, Honduras, and Venezuela), five African countries (Central Africa, Comoros, Ethiopia, Mauritania, and Sudan), three Middle Eastern countries, two South Asian countries, and one Oceanian country. The dataset also incorporated the historical "Ebro" sample from 1940s Spain and two P. vivax-like genomes from Cameroonian chimpanzees as outgroups.
Distribution of P. vivax samples collected and analysed by Lefebvre et al (2025).
The researchers then used several complementary approaches to analyse parasite population structure, estimate divergence and admixture, infer demographic history, and testing of 12 competing colonisation/invasion scenarios using Approximate Bayesian Computation ABC-RF. The use of multiple lines of genomic evidence allowed the researchers to broadly explore the genetic relationships of P. vivax populations and suggest the parasite’s most likely evolutionary history in Central and Southern America.
Global population structure, admixture, and evolution
The analyses applied to study the global population structure of P. vivax (PCA, ancestry plots and phylogenetic tree) collectively showed worldwide P. vivax populations to cluster into four distinct, well separated genetic groups, (1) Oceania, East and Southeast Asia, (2) Africa, (3) Middle East and South Asia, and (4) Central and Southern America.
Within each of these, finer substructuring could be seen, such as clustering of West and Central African isolates from East African ones, and Malaysian isolates from other Asian populations (reportedly due to a genetic bottleneck resulting from a large decline in P. vivax prevalence in Malaysia).
Global population structure, ancestry and admixture of P. vivax isolates analysed by Lefebvre et al (2025).
This substructuring was also observed in the Central and Southern American cluster, with two genetic groupings evident – a Central American group (Mexico, Honduras, and Colombia), and an Amazonian group (French Guiana, Guyana, and Venezuela). Brazilian, Peruvian, and Ecuadorian populations, however, exhibited admixed ancestry between these sub-clusters, indicative of gene across the continent.
The population branching analysis supported the genetic relationships between P. vivax populations, revealing that American populations formed a highly supported monophyletic cluster, suggesting either a single ancestral source or multiple introductions from similar, possibly admixed populations.
Genetic relationships and admixture between P. vivax geographical isolates, modified from Lefebvre et al (2025).
The Spanish "Ebro" sample showed closest genetic affinity to Latin American populations, supporting a European connection. However, both Ebro and some Latin American populations shared genetic ancestry with West African and Middle Eastern/South Asian populations, revealing a more complex evolutionary history. Geographic diversity patterns—lower genetic diversity in Pacific coastal versus Amazonian populations—likely reflect different transmission dynamics between regions with periodic versus year-round malaria transmission.
A complex origin
The coalescent-based methods and ABC-RF analyses similarly supported the most likely colonisation history and timelines, indicating the genetic divergence between American and European populations at ~100-300 years ago, with a major admixture event occurring approximately 200 years ago. These analyses support a scenario where Central and Southern American P. vivax populations descended from now-extinct European lineages, with contributions from an unsampled population possibly of West African ancestry.
This timeline aligns well with historical human migrations and suggests P. vivax arrived in the Americas in at least two waves – A first wave prior to the 17th century, most likely during early European colonisation, and a second wave from Europe during the 19th century when over 10 million Europeans settled in Central and Southern America. The genetic contribution from West African lineages further corresponds with the transatlantic slave trade that forcibly relocated millions of people from West and Central Africa to the Americas between the 16th and 19th centuries.
This complex pattern of multiple introductions over several centuries parallels the established colonisation history of P. falciparum, which entered the Americas through multiple introductions from West/Central Africa during the slave trade period. Together, these findings reveal a far more intricate evolutionary history for American P. vivax than previously hypothesised, providing evidence to challenge earlier assumptions of a single-source introduction.
Human migrations shape Plasmodium vivax evolution
The findings from this research refine our understanding of how human migration has fundamentally shaped P. vivax evolution and provides context for the origins, introduction, and evolution of the most cosmopolitan malaria species across the region.
As we face ongoing challenges with malaria control and potential range expansions due to climate change, understanding the evolutionary history of malaria parasites provides valuable context for anticipating and addressing future adaptations and spread. The journey of P. vivax to Central and Southern America serves as a powerful example of how human history and pathogen evolution are deeply intertwined, with lasting consequences for global health.
The genetic structure observed suggests that different control strategies may be needed for the Central American versus Amazonian parasite populations.
The shared ancestry and gene flow between regions highlights the importance of multi-national control efforts, particularly in the Amazon basin.
The relatively recent introduction and expansion of European vivax lineages in the late 19th century suggests that major changes in parasite populations can occur rapidly following human migration events – a pertinent consideration in our current era of climate change and increased human mobility.