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Plasmodium vivax is a single-celled parasite of the phylum Apicomplexa and the most geographically widespread cause of human malaria. It is transmitted between people by the bite of infected female Anopheles mosquitoes, of which many species are competent vectors across a wide range of climates, including Anopheles stephensi, An. culicifacies, An. dirus, An. minimus, An. darlingi, An. albimanus, and, historically, the European An. atroparvus. Outside Sub-Saharan Africa, P. vivax is the dominant malaria parasite. It accounts for most clinical malaria in the Americas and roughly half of cases across South and Southeast Asia, the western Pacific, and the Horn of Africa.

Four features distinguish P. vivax from Plasmodium falciparum and make it particularly difficult to eliminate:

1. Dormant liver stages. Some of the parasites that invade the liver do not develop immediately but remain dormant as hypnozoites for weeks, months, or years before reactivating and causing a relapse without any new mosquito bite.
2. Restriction to young red cells. The blood stages invade only immature red blood cells (reticulocytes), and most of the parasite mass resides not in circulating blood but in the spleen and bone marrow.
3. Early production of transmissible stages. Infectious gametocytes appear in the blood within a few days, often before the patient has any fever and seeks treatment.
4. Development at lower temperatures. Inside the mosquito, P. vivax develops at cooler temperatures and more quickly than P. falciparum, allowing transmission at temperate latitudes, at high elevations, and in cooler seasons.

African Ape Origins and Selection of the Duffy-Negative Allele

Plasmodium vivax belongs to a group of parasites that also infect macaques in South and Southeast Asia, including P. knowlesi and P. cynomolgi. For much of the twentieth century it was therefore assumed that the human parasite had arisen in Asia from a macaque parasite. This left a puzzle: the Duffy-negative blood group, which prevents the parasite from entering red cells, is close to universal across West and Central Africa, where P. vivax was thought to be absent, yet is rare in Asia.

From 2014, sequencing of parasite DNA recovered from the faeces of wild African apes, by Weimin Liu, Paul Sharp, Beatrice Hahn, Franck Prugnolle, and colleagues, resolved the question. Wild chimpanzees, bonobos, and gorillas carry a diverse and ancient lineage of P. vivax. All human strains worldwide fall within the diversity of these ape parasites, while the Asian macaque parasites branch off earlier. Human P. vivax therefore originated in Africa and passed from apes to humans.

The usual interpretation is that the parasite then drove the Duffy-negative variant to near-fixation in Africa, after which a small founding population spread out of Africa with Duffy-positive human migrants to Asia, Europe, and eventually the Americas. The selective role of P. vivax in spreading Duffy negativity is inferred rather than demonstrated, and other explanations have been suggested.

Isochore-Like GC-Rich Cores and Subtelomeric vir Multigene Families

The genome comprises about 27 to 29 million base pairs on 14 chromosomes, encoding roughly 5,500 to 6,500 protein-coding genes, alongside small genomes in the mitochondrion and the apicoplast.

It differs strikingly from that of P. falciparum, which is uniformly rich in adenine and thymine. The P. vivax genome has an overall GC content of about 42% and a two-part structure:

• GC-rich chromosome cores contain the genes needed for normal cellular function and for invading host cells, with balanced codon usage and few of the repetitive low-complexity stretches found throughout P. falciparum proteins.
• AT-rich chromosome ends house large families of variable genes that recombine frequently:

1. The vir family, the largest in the parasite, with estimates ranging from a few hundred to over a thousand genes depending on the strain and the method of counting. Unlike the var genes of P. falciparum, vir genes are small, several are expressed at once rather than one at a time, and their products are exported to the surface of the infected cell, where they appear to mediate adhesion within the spleen and bone marrow.
2. Invasion protein families, including eleven reticulocyte-binding protein genes, several msp3 genes, a family of tryptophan-rich antigens, and two erythrocyte-binding proteins, PvDBP1 and PvEBP.

Hepatic Hypnozoite Dormancy and Regional Relapse Periodicity

An infected mosquito injects sporozoites coated with circumsporozoite protein, which occurs in three variant forms worldwide, designated VK210, VK247, and a _P. vivax_-like type. The sporozoites travel to the liver and invade hepatocytes using the host proteins SR-BI and CD81.

Inside the liver cell, the parasites take one of two paths:

• Immediate development. Some begin dividing at once, producing over six to eight days a large schizont that releases tens of thousands of merozoites into the blood, starting the clinical infection.
• Dormancy. The rest arrest as small, single-nucleus forms called hypnozoites, observed microscopically by Wojciech Krotoski, P. C. C. Garnham, and colleagues in the early 1980s.
• How dormancy is maintained. The hypnozoite retains its apicoplast and mitochondrion but greatly reduces its metabolism and stops replicating its DNA. Dormancy appears to be maintained by changes to chromatin that silence most genes, by particular transcription factors, and by a block on protein synthesis. Because the parasite neither divides nor digests haemoglobin, it is unaffected by every drug that acts on blood stages, including chloroquine and the artemisinins, and cannot be detected by blood films, rapid tests, or PCR.
• Regional patterns of relapse. How many hypnozoites form, and how long they wait, differs between regions in a way that matches the local seasons in which mosquitoes are active. Whether these differences are genetically encoded is not established.

Regional relapse patterns

Hypnozoites can also be reactivated by illness. A bout of P. falciparum malaria is followed by a P. vivax relapse in a substantial proportion of patients in regions where both occur, and other infections can have the same effect. In high-transmission tropical settings, relapses rather than new mosquito bites account for the majority of clinical episodes, though the proportion varies widely between regions.

Two-Step Reticulocyte Invasion: PvRBP2b–CD71 Selection and PvDBP1–Duffy Commitment

Unlike P. falciparum, which invades red cells of any age, P. vivax invades only reticulocytes: cells that have recently lost their nucleus in the bone marrow and still retain some ribosomes and other remnants. These make up only about 1% of circulating red cells, which is why parasite densities in the blood rarely exceed 1 to 2%.

Invasion proceeds in two stages, the first selecting the right kind of cell and the second committing to entry:

1. Selecting a young cell. Work by Wai-Hong Tham and colleagues showed that the Duffy receptor cannot explain the parasite's preference, since it occurs on red cells of all ages. Instead, the parasite protein PvRBP2b binds transferrin receptor 1 (also called CD71), and PvRBP2a binds CD98. Both host proteins are abundant on young reticulocytes but are shed within a day or two as the cell matures, so their presence marks a suitable target.
2. Committing to entry. The parasite then releases PvDBP1, which binds the Duffy receptor on the cell surface. This triggers the formation of a junction between the two cells through which the parasite enters.

In much of Africa, a single change in the control region of the Duffy gene prevents the receptor from being produced on red cells, while leaving it intact elsewhere in the body. This was long regarded as giving complete protection against P. vivax.

Surveys in Madagascar, Ethiopia, Sudan, Mauritania, Mali, Cameroon, Kenya, and India have since found P. vivax infections in people who lack the receptor entirely, though generally at low parasite densities. Three explanations have been proposed, which may act together:

1. Extra copies of PvDBP1. Parasites in several of these regions carry multiple copies of the gene, greatly increasing the amount of protein produced, which may allow binding to the small amounts of receptor present on very immature cells in the bone marrow.
2. Use of a related protein. A second erythrocyte-binding protein, PvEBP, is amplified in these lineages and binds young reticulocytes without requiring the Duffy receptor.
3. Entry without the Duffy receptor. In the bone marrow, where newly formed reticulocytes carry very high levels of CD71 and CD98, binding to these may suffice.

Schüffner's Dots, Cryptic Splenic Biomass, and Early Gametocyte Maturation

Inside the cell, the parasite grows with a characteristically restless, amoeba-like shape, from which the species takes its name, and digests haemoglobin, leaving fine pigment granules. It divides into 12 to 24 merozoites over 48 hours.

Where P. falciparum makes the infected cell smaller and much stiffer and covers it with knobs, P. vivax does the opposite: the cell enlarges to one and a half or twice its original size and becomes more flexible. Instead of knobs, the parasite forms thousands of small pits in the cell membrane. On a stained blood film these appear as fine red dots scattered across the enlarged cell, known as Schüffner's dots.

Because every stage of the parasite can be seen in a blood film, P. vivax was long assumed not to hide in deep organs as P. falciparum does. Studies of spleens removed surgically and of bone marrow samples, by Steven Kho, Nicholas Anstey, Hernando del Portillo, and colleagues, have overturned this. The great majority of the parasite mass in an infected person is not in circulating blood at all, but in the spleen and bone marrow, where the young red cells it requires are concentrated. These findings come from a small number of patients and the exact proportion is uncertain, but the conclusion that the circulating parasites are a small fraction of the total is now widely accepted.

Plasmodium falciparum gametocytes take ten to twelve days to mature, hidden in the bone marrow, and appear in the blood about a week after the patient becomes ill. Plasmodium vivax is quite different:

• Parasites commit to sexual development from the first blood cycle onward.
• The gametocytes are large and round rather than crescent-shaped, and mature within a day or two.
• They therefore appear in the blood within a few days, usually before the patient has a fever or seeks treatment.

Once in the blood they survive only a few days and are readily killed by standard treatment. But because transmission has often already occurred before treatment begins, and because relapses repeatedly re-seed the blood with new gametocytes, the parasite continues to spread even where case management is good.

Plasmodium vivax was long called "benign tertian malaria" to distinguish it from the "malignant" P. falciparum. Clinical studies across Asia, Oceania, and the Americas have shown that it can cause severe and fatal illness.

1. Fever at low parasite densities. Fever begins at a parasite density roughly ten times lower than for P. falciparum, and the material released when infected cells rupture provokes a strong inflammatory response, producing severe rigors and high fevers. The exact thresholds vary considerably with the patient's previous exposure.
2. Severe anaemia. Despite low densities in the blood, repeated and relapsing infection can cause severe anaemia, particularly in young children and pregnant women. Modelling of red cell turnover suggests that many uninfected red cells are destroyed for each infected one, perhaps thirty or more, through removal by the spleen, damage to the cell membrane, and suppression of red cell production in the bone marrow.
3. Enlarged spleen and splenic rupture. Because so much of the parasite mass is in the spleen, the organ enlarges rapidly and can rupture, occasionally fatally.
4. Lung injury and effects in pregnancy. Breathing difficulty and fluid in the lungs sometimes appear a day or two after treatment begins, which has been attributed to an inflammatory response as sequestered parasites die, though the mechanism is not established. In pregnancy, P. vivax causes anaemia, miscarriage, and low birth weight, even though it does not accumulate in the placenta as P. falciparum does.

Because P. vivax spread across temperate Eurasia as well as the tropics, it develops inside the mosquito at lower temperatures than P. falciparum. Under the classical degree-day model, the time required is approximately:

The parameters vary between sources, but the difference in threshold is consistent. Its consequences are considerable:

Comparison of development in the mosquito

The combination of a low temperature threshold and a dormant reservoir in people produces distinctive dynamics:

1. A parasite already in place. For P. falciparum to establish in a newly warmed highland valley, infected people and mosquitoes must arrive together during the warm season. Plasmodium vivax faces no such requirement, because people in and around endemic areas already carry dormant parasites. When warming extends the mosquito season by even a few weeks, a relapse can immediately infect the newly emerged mosquitoes. Outbreaks of this kind have occurred in the Ethiopian and Andean highlands, the Himalayan foothills, and the Korean peninsula, with occasional reintroductions around the Mediterranean and in the southern United States.
2. Floods and climate cycles. Incidence in South America, South Asia, and Oceania follows El Niño and related cycles closely. After the Pakistan floods of 2022, which inundated much of the country, reported malaria cases rose several-fold, with P. vivax predominating in much of the surge. Displacement, malnutrition, and other infections are likely to have triggered relapses at the same time as the receding water created breeding sites.
3. Urban mosquitoes in the Horn of Africa. East African P. vivax was historically confined largely to the Ethiopian highlands and Madagascar. The spread of Anopheles stephensi across Djibouti, Ethiopia, Sudan, Somalia, and Kenya since 2012 has raised concern about urban transmission, since this mosquito is a competent vector of P. vivax and breeds in stored water through dry seasons.

Why P. vivax Resists Standard Vector Control and Case Management

Across Latin America, Southeast Asia, China, and the Horn of Africa, the same pattern recurs: as nets, indoor spraying, and effective treatment are scaled up, P. falciparum falls rapidly while P. vivax declines more slowly and comes to dominate. Four reasons account for this:

• Mosquito behaviour. The main vectors outside Africa tend to bite outdoors and in the early evening, before people are under nets, and rest outdoors afterwards. Indoor measures therefore reach them less effectively.
• Transmission before symptoms. Because gametocytes appear within days, treating patients when they present at a clinic comes too late to prevent transmission.
• Low-density and hidden infections. Because the parasite is restricted to young red cells and most of it lies in the spleen and marrow, many infected people have too few parasites in the blood to be detected by rapid tests.
• The untreated liver reservoir. Standard treatment clears the blood but leaves hypnozoites untouched, so the patient relapses weeks later.

Curing P. vivax completely requires clearing both the blood stages and the dormant liver stages, a combination known as radical cure.

1. Blood-stage treatment. Plasmodium vivax remains sensitive to chloroquine across much of South Asia, the Americas, and the Middle East, and chloroquine's slow elimination also suppresses the first relapse. Resistance emerged in Papua New Guinea and Indonesian Papua around 1989 and has spread in Southeast Asia and parts of East Africa; the responsible genetic changes have not been firmly established, with several candidates proposed. Where resistance is established, artemisinin-based combinations are used for all species.
2. Clearing the liver. Only one class of drug, the 8-aminoquinolines, kills hypnozoites.

• Primaquine, available since 1950, is cleared from the body within hours and must be taken daily for fourteen days, or seven days at a higher dose. Because the fever resolves within two days of starting treatment, adherence to an unsupervised fourteen-day course is often poor, and relapses follow.
• Tafenoquine, approved in 2018, is chemically modified to resist breakdown and remains in the body for about two weeks. A single dose taken alongside chloroquine achieves radical cure, avoiding the adherence problem. Its efficacy has been lower in trials when given with some artemisinin combinations, for reasons that are not understood.

The 8-Aminoquinoline Pharmacogenetic Triad: G6PD Hemolysis and CYP2D6 Activation

Both drugs cause destruction of red cells in people with glucose-6-phosphate dehydrogenase deficiency, an inherited condition carried by several hundred million people, and common in malarious regions because it also gives some protection against malaria.

The enzyme supplies the reducing power that protects red cells from oxidative damage. The breakdown products of 8-aminoquinolines generate such damage; in deficient cells it is unopposed, and haemoglobin is denatured, the cell membrane damaged, and the cell destroyed.

Because the gene lies on the X chromosome and one copy is randomly switched off in each cell, women with one affected copy have a mixture of normal and deficient red cells and intermediate overall activity. Simple yes-or-no tests reliably identify deficient men but classify many such women as normal. Since a single dose of tafenoquine cannot be withdrawn once given, WHO guidance requires a quantitative measurement of enzyme activity before it is used. The thresholds used are:

• 70% of normal activity or above: tafenoquine or primaquine may be given.
• 30% to 70%: tafenoquine is contraindicated; daily primaquine may be given with monitoring.
• Below 30%: both are contraindicated as normally given. Weekly primaquine over eight weeks has been used under supervision, allowing the marrow to replace destroyed cells between doses.
• Pregnancy and early infancy: both drugs are contraindicated, because the infant's enzyme status cannot be established.

Work by Jason Bennett, Walter Taylor, Kevin Baird, and colleagues showed that primaquine is inactive as given. It must be converted by a liver enzyme, CYP2D6, into the products that actually kill the hypnozoite.

The gene for this enzyme varies greatly between individuals. People carrying two copies of a non-functional or weakly functional variant cannot activate the drug properly and relapse even when they take the full course under supervision. Reduced-function variants are common in East and Southeast Asia, so this is a substantial obstacle in precisely the regions where relapse rates are highest.

Because dormant parasites cannot be detected directly, an alternative is to identify people who have recently had a blood-stage infection and are therefore likely to be carrying them. This approach, developed by Ivo Mueller, Michael White, Rhea Longley, and colleagues, measures antibodies against parasite proteins whose levels decline over several months. In the settings tested it identified most people infected within the previous nine months, allowing treatment to be targeted rather than given to a whole community. Performance depends on the antigens used and on local transmission intensity.

Vaccine development has been slowed by the inability to grow P. vivax continuously in the laboratory, since it requires a constant supply of young red cells. Researchers have used the related P. knowlesi, modified to carry P. vivax genes, as a substitute, alongside trials in which volunteers are deliberately infected. Three approaches are being pursued:

• Vaccines against sporozoites, based on the circumsporozoite protein. These must combine all three variant forms to avoid being evaded.
• Vaccines against blood stages, principally targeting the binding region of PvDBP1, which has reduced parasite multiplication by around half in volunteer trials, and PvRBP2b, which varies less between strains and acts at the earlier step of selecting a cell.
• Vaccines to block transmission, targeting proteins on the sexual stages so that antibodies taken up by a mosquito prevent development within it.

Plasmodium vivax and Plasmodium falciparum compared

What is a hypnozoite and why does it make Plasmodium vivax so hard to eliminate?

A hypnozoite is a dormant, non-dividing unicellular stage of *Plasmodium vivax* (and *P. ovale*) that persists quietly inside human liver hepatocytes for weeks to over a year after a mosquito bite. Because hypnozoites are metabolically quiescent, they are invisible to blood tests and completely unaffected by standard blood-stage antimalarials (like chloroquine or ACTs), reactivating later to seed relapses that account for up to 70%–80% of all *P. vivax* clinical episodes.

Why does P. vivax only infect young red blood cells (reticulocytes)?

To invade a red blood cell, *P. vivax* first uses its adhesin PvRBP2b to bind the host iron-import protein transferrin receptor 1 (CD71) and PvRBP2a to bind CD98, before engaging the Duffy antigen (ACKR1) via PvDBP1. Because CD71 and CD98 are present on immature reticulocytes (~1% of circulating red cells) and shed within 24–48 hours as erythrocytes mature, *P. vivax* is strictly restricted to reticulocytes and accumulates heavily inside the reticulocyte-rich spleen and bone marrow.

Why must patients be tested for G6PD deficiency before taking primaquine or tafenoquine?

Primaquine and tafenoquine (8-aminoquinolines) are the only drugs that kill dormant liver hypnozoites, but their reactive metabolites generate intense intracellular oxidative stress. In patients with X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency, mature red blood cells cannot regenerate NADPH to detoxify free radicals, causing acute, potentially fatal drug-induced intravascular hemolysis.

• Malaria
• Plasmodium falciparum
• Hypnozoite
• Primaquine
• Duffy antigen system