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Why vivax?

Recognizable descriptions of malaria were recorded in Chinese, Indian, Egyptian and Mesopotamian texts as early as 5,000 years ago. Evidence from human DNA sequences shows the effects of malaria to be far older still, influencing human evolution across tens of thousands of years. It is no exaggeration to say that malaria has played a crucial role in human history, determining the fates of armies and empires. Malaria brought down Alexander the Great and saved Rome from Attila's hordes. Dubbed the 'King of Diseases' in the Vedas, its modern name comes from the Italian peninsula, where mal'aria or 'bad air' was thought to cause the debilitating paroxysmal tertian or quartan (three- or four-day) fevers and febrile deaths that ravaged the populace every year for millennia.

We now know that the infectious agent of malaria is not fetid swamp gas but an apicomplexan protist of the genus Plasmodium whose complex life cycle shuttles between human and mosquito hosts without any free-living stages. Four species of the parasite are known to commonly cause malaria in humans: P. falciparum, P. malariae, P. ovale, and P. vivax. Of the four, P. falciparum is the most deadly; vivax malaria was known historically as 'benign tertian' fever. However, vivax malaria is 'benign' only in that the misery the disease causes rarely ends in death. In fact P. vivax has several characteristics which make it a compelling object of study:

  1. Distribution & population at risk : P.vivax is the most widely distributed human malaria, and the most common species observed in temperate regions of the world, representing the major cause of malaria outside Africa. More people were at risk from vivax malaria in 2005 than from any other species.
  2. Economic impact: Malaria transmission rates are low in most regions where P.vivax is prevalent, thus protective immunity is infrequent and all ages can succumb to the disease. Men of working age, i.e., individuals whose economic productivity is among the most important, are particularly at risk.
  3. Morbidity: P. vivax malaria is acute and excruciating, involving repeated episodes of high fever preceded by violent headache and chills and profuse sweating, and often accompanied by vomiting, diarrhea, and enlargement of the spleen. Uncomplicated falciparum malaria is much less intense with less pronounced paroxysms.
  4. Anemia: Although parasitemias are lower than those seen with P. falciparum infections due to the preference of P.vivax to infect reticulocytes, anemia caused by chronic destruction and depletion of immature red blood cells is the most common pathological consequence.
  5. Selectivity: P.vivax parasites appear limited to invasion of Duffy antigen-positive red blood cells only, which may explain the absence of the species in West Africa where Duffy negativity predominates.
  6. Relapse: The hypnozoite stage of P.vivax can lie dormant in infected liver cells for months or years, providing a mechanism for the parasite to hibernate during less optimal transmission periods.

Reference:
Mendis K, Sina BJ, Marchesini P, Carter R.
The neglected burden of Plasmodium vivax malaria.
Am J Trop Med Hyg. (2001) 64(1-2 Suppl):97-106.


Life cycle

This figure and legend were adapted from the CDC website.
Click on the image to see a full-size version.



The P.vivax life cycle involves two hosts. During a blood meal, a malaria-infected female Anopheles mosquito inoculates sporozoites into the human host (1). Sporozoites infect liver cells (2) and either enter a dormant hypnozoite state or mature into schizonts (3), which rupture and release merozoites (4). After this initial replication in the liver (exo-erythrocytic schizogony A), the parasites undergo asexual multiplication in the erythrocytes (erythrocytic schizogony B). Merozoites infect red blood cells (5). The ring stage trophozoites mature into schizonts, which rupture releasing merozoites (6). Some parasites differentiate into sexual erythrocytic stages (gametocytes) (7). Blood stage parasites are responsible for the clinical manifestations of the disease.

The gametocytes, male (microgametocytes) and female (macrogametocytes), are ingested by an Anopheles mosquito during a blood meal (8). The parasites' multiplication in the mosquito is known as the sporogonic cycle (C). While in the mosquito's stomach, the microgametes penetrate the macrogametes generating zygotes (9). The zygotes in turn become motile and elongated (ookinetes) (10) which invade the midgut wall of the mosquito where they develop into oocysts (11). The oocysts grow, rupture, and release sporozoites (12), which make their way to the mosquito's salivary glands. Inoculation of the sporozoites (1) into a new human host perpetuates the malaria life cycle.

The hypnozoite

Although the existence of a cryptic tissue stage was proposed just six years after Laveran's discovery of the parasite, considerable mystery still surrounds the hypnozoite, the dormant liver stage responsible for relapsing P. vivax and P. ovale malaria in humans. Relapse, characterized by an asymptomatic latency period measured in months or years, was first formally reported in 1897 in a patient who re-developed malaria two years after being 'cured', without new infection. (By contrast, recrudescence is a recurrence of malaria within days or weeks of apparent cure, without new infection, and is caused by inadequate clearing of parasites from the bloodstream.) Thirty years passed before scientists began to make progress in determining the cause of relapse. In the interim, malaria research travelled on what has been called a 'meandering detour' in pursuit of confirmation of a report by the protozoologist Schaudinn, who in 1902 claimed to have observed direct invasion of erythrocytes by sporozoites -- which he hypothesized to be derived from parthenogenesis of gametocytes in the blood. The pursuit proved fruitless, and when Garnham in 1930 definitively failed to induce malaria in subjects infected only with gametocytes, the way was finally cleared for new ideas about the etiology of relapse. In 1946, Shute proposed the existence of the x-body, a post-sporozoite stage with delayed maturation, to explain both the initial attack and relapses. Liver cell schizonts were actually identified in 1948 by Shortt et al., but debate raged for approximately two more decades over whether these schizonts remained continually active, waxing and waning in morbidity under the control of the host immune system, or whether a 'latent' stage was the cause of relapse. By the 1970s the tide of expert opinion had begun to turn in favor of the existence of a latent form. Garnham (1967), abandoning the cyclic model he had co-developed with Shortt, and Coatney et al. (in The Primate Malarias, 1971) mustered observations and logic contradicting the cyclic model, including (1) the susceptibility of the host to new infection during the latency period, when immunity is supposedly high (Cooper et al. 1947); (2) the inability of transfused blood drawn during the latency period to induce infection in susceptible recipients (Cooper et al. 1949); (3) display of characteristic relapse patterns by various strains of P. vivax malaria regardless of the host's immune response (e.g., Coatney et al. 1950); (4) the ineffectiveness of anti-blood stage drugs against preventing relapse, even though liver merozoites are presumed to move from cell to cell via the blood; (5) the paradox of a proposed gradual decline of the host immune system during the cycle, despite continuous re-exposure of the system to merozoites; and (6) the absence of observable 'nests' of maturing liver schizonts predicted to arise from local release and re-infection. Finally, just one year before the centennial of Laveran's discovery of the malaria parasite, Krotoski et al. (1980) published a preliminary report identifying a putative latent form of P. cynomolgi, visualized by antibody immunofluorescence and Giemsa staining of infected rhesus monkey liver cells. Krotoski et al. at first tentatively equated these forms with Shute's x-bodies, but in a 1982 follow-up report, they adopted the term hypnozoite ('sleeping animalcule') suggested by Garnham in 1977. The same group soon demonstrated the existence of P. vivax hypnozoites in liver cells of infected chimpanzees. Hypnozoites were later observed in cultured human hepatoma cells after in vitro infection with P. vivax sporozoites (Hollingdale et al., 1985). That group also confirmed that frequently-relapsing strains of P. vivax deposit more hypnozoites in liver tissue than rarely-relapsing strains do, consistent with the latency model.

The hypnozoite stage presents in liver cells as round, intracytoplasmic, nondividing, uninucleate bodies approximately 5 um in diameter, with staining characteristics similar to those of multinucleate schizonts (see also the light microscope and EM images in Cogswell [1992]). They are first detectable by immunfluorescence in liver 36-40 hours after sporozoite inoculation, and remained essentially unchanged in appearance and number across 226 subsequent days of experimental tissue sampling by Bray et al. (1985). Hypnozoites are vulnerable to primaquine treatment, and are found only in association with relapsing malarias. Beyond these basic facts -- all of which were known by 1992, the date of the most recent review of literature on the latent stage -- little more has been gleaned about the hypnozoite. In particular, we still don't know what triggers its re-activation -- a fundamental question that must be answered if we are ever to understand relapse.


Distribution, prevalence and population at risk (PAR) of P. vivax malaria

Prevalence is the number of people who have the disease in the time period examined. This is distinct from incidence, the number of newly diagnosed cases during a time period (including re-infections of the same patient).
The estimated population at risk (PAR) for malaria is derived from estimations of its geographic extent (distribution) and the human population within that extent, incorporating considerations of altitude, climate, population density, and other environmental factors affecting transmission. Malaria is said to be endemic in regions where it remains more or less constantly present, e.g., parts of Africa and Southern/Eastern Asia.

In brief, it has been estimated that:

  • ~2.6 billion people per year are at risk of vivax malaria
  • ~56% of all malaria cases outside of Africa are due to P. vivax
  • ~70-80 million malaria cases per year worldwide are due to P. vivax

Annual prevalence and PAR of malaria by region, estimated from 1993-1997 data1

(adapted from Mendis et. al [2001].)

Region2 Population at risk
for malaria
Total malaria
cases
Total cases of malaria
due to P. falciparum
or minor species3
Total cases of malaria
due to P. vivax
  -South and East Asia & Western Pacific 1,284,000,000 86,461,294 44,400,333 42,060,961
  -Eastern Mediterranean 64,600,000 14,539,081 2,883,333 11,655,748
  -South America 23,500,000 11,324,643 3,347,010 7,977,633
  -Central America & Caribbean 64,200,000 3,676,288 579,867 3,096,421
  -Central Asia & Caucasus 8,480,000 166,506 0 166,506
Non-African endemic regions total 1,444,780,000 116,334,318 51,210,543 65,123,775
Africa 550,000,000 200-300,000,000 185-294,000,000 6-15,000,000
Nonendemic regions (imported malaria) 1,590,000,000 33,036 11,043 21,993
World total 3,584,780,000 316-416,000,000 236-345,000,000 71-80,000,000

1Calculated for each region from reported number of deaths attributed to malaria, reported number of microscopically or clinically diagnosed cases of malaria, proportion of microscopically diagnosed cases of P. falciparum malaria, and the human population reported by each national government to be at moderate-to-high risk of malaria transmission, with correction factors applied. See Appendix I in Mendis et. al (2001) for details.

2Countries included in the regions designated here as South and East Asia and Western Pacific, Eastern Mediterranean, and Central Asia and Caucasus are as given in the legend of Figure 1 of Mendis et. al (2001). Malaria-endemic countries in Latin America listed in Figure 1 have been further classified here as being in South America, and Central America and the Caribbean, with Mexico being included in the latter. Africa refers to sub-Saharan Africa, Sudan, Ethiopia, and the countries of the Horn of Africa.

3In sub-Saharan Africa and in Papua New Guinea, a variable proportion of cases, usually <20%, can be due to P. malariae, P. ovale, or both. In other parts of the world, these species are much less frequent or are absent altogether.

PAR and distribution of P. falciparum and P. vivax in 2005

The following figures and captions were compiled by the Malaria Atlas Project and published in:

Guerra CA, RW Snow, and SI Hay
Mapping the global extent of malaria in 2005
Trends in Parasitology, 22:353-359
Copyright (2006), adapted with permission from Elsevier.

 

WHO region P. falciparum PARa P. vivax PARa
SEARO 1.252 1.347
AFRO 0.525 0.050
WPRO 0.438 0.890
EMRO 0.245 0.211
AMRO 0.050 0.078
EURO 0.000 0.020
Total 2.510 2.596
aThe risk is given in billion (1,000,000,000) persons. Abbreviations: WHO, World Health Organization; SEARO, South East Asian Regional Office; AFRO, African Regional Office; WPRO, Western Pacific Regional Office; EMRO, Eastern Mediterranean Regional Office; AMRO, American Regional Office; EURO, European Regional Office.


Click on an image to see a full-size version.

  

LEFT
Global distribution of P. falciparum and P. vivax in 2005.
(a) Distribution of P. falciparum. (b) Distribution of P. vivax. Several sources of information on malaria risk (notably ITHGs [International Travel Health Guidelines] on malaria chemoprophylaxis, altitude limits for dominant vectors, climate limits for malaria transmission and human population density thresholds) have been combined in a geographic information system to generate these maps. See the step-by-step guide in Guerra et. al (2006) for a full description of the methods used to derive these limits.

RIGHT
Cartograms of the PAR of malaria from P. falciparum and P. vivax in 2005.
(a) P. falciparum risk. (b) P. vivax risk. In these cartograms, the area is distorted in proportion to the national population at risk (PAR) of malaria, defined as the number of people inhabiting malarious regions in that nation. These maps are useful global indicators and represent broad spatial patterns, but it should be noted that the risk of developing disease, disability or death from malaria infection is specific to parasite and region.


Non-endemic vivax malaria

Approximately 22,000 people per year suffer from vivax malaria in regions where the disease is non-endemic (rare). This is about twice the number suffering from non-endemic falciparum malaria. Such infections are 'imported', that is, they stem from travel to regions where vivax malaria is endemic, or from an encounter with a stray vivax-infected mosquito far from its home. Vivax malaria was formerly endemic in many regions where today it is rare, such as Western Europe. It has been estimated (Hay et al., 2004) that in 1900, before worldwide intervention efforts against the disease began, the probable maximum distribution of malaria spanned 64° north to 32° south latitudes, limits corresponding to the northern and southern 15°C (59°F) summer isotherms supporting P. vivax transmission. Thus malaria, and vivax malaria in particular, formerly prevailed northward into subarctic Siberia and Canada and southward to the upper third of Australia, regions where today it is all but unheard of.

Vivax malaria in the U.S.A.

Malaria was unknown in pre-Columbian America, but became endemic from the Atlantic to the Pacific and from Canada to Argentina by the 1600s. Vivax malaria remained endemic in the southeastern United States into the 1950s, when a combination of improved socioeconomic conditions, vector-control efforts and case managment effectively eradicated it as a serious public health problem. Today the Centers for Disease Control (CDC) maintain a National Malaria Surveillance System (NMSS) to collect epidemiological and clinical information on malaria cases diagnosed in the United States. Between 1,000-1,500 cases of malaria in the US are reported annually, the vast majority of which are acquired in other countries. Local infection is rare enough that even a small outbreak can be national news, as happened in August 2002, when two cases of P. vivax malaria were reported in northern Virginia. In 2004, the most recent year for which NMSS data are available, 1,324 cases of malaria were reported, of which 315 (23.8%) resulted from P. vivax infections and 655 (49.5%) were caused by P. falciparum. Only four cases of malaria were locally acquired, three of which were vivax malaria. Of these, two were acquired locally only in a technical sense: they developed in babies born to immigrant mothers who had been infected overseas but became pregnant in the US. The third was in an employee in a laboratory that worked with vivax-infected mosquitos.

History

This chronology focuses especially on vivax malaria, though of necessity it includes some discoveries involving other Plasmodium species. The evolution and history of malaria were recently reviewed by Carter and Mendis (2002). Detailed histories of malaria are available online at the CDC and Malaria Site.

1880
Laveran announces his discovery of the malaria parasite in the blood of a malarious young soldier in Algeria. During 1880-1881 Laveran observes what in fact are multiple species, though he believes them to be all one organism that he names Oscillaria malariae. His discovery remains controversial for much of the decade, becoming widely accepted only after the invention of the oil-immersion microscope lens (1884) and better staining methods (1890-91).
1885
Marchiafava and Celli propose the genus name Plasmodium for the malaria parasite.
1886
Pel proposes the first theory of the existence of a tissue (extraerythrocytic) stage of the malaria parasite.
Golgi describes the morphological differences that can be used to distinguish two malaria parasite species, those responsible for benign tertian (P. vivax) and quartan (P. malariae) fevers. However, he does not name the two species, and is unable to develop a similar diagnostic for malignant late-summer (P. falciparum) fever. He abandons malaria research for the neurophysiological work that will win him a Nobel Prize in 1906.
1889-90
Sakharov (1889) and Marchiafava & Celli (1890) independently identify P. falciparum as a species distinct from P. vivax and P. malaria.
1890
Grassi and Felleti name the human tertian malaria parasite Haemamoeba vivax, soon revising it to Plasmodium vivax.
1892
Marchiafava and Bignami prove that the multiple forms seen by Laveran are a single species, which ultimately comes to be called P. falciparum.
1897
Thayer publishes the first formal description of relapse, quoting a physician who had a recurrence of symptoms 21 months after the first attack, without new infection. Thayer concludes that there must be a latent intracellular form of the parasite
Ross, working in Secunderabad, India, makes his first observation of malarial cysts on the stomachs of anopheline mosquitoes which four days previously had fed on malarious human blood. Ross believed these cysts would contain passively-transmitted 'spores' of malaria. Soon afterwards he is transferred to Calcutta, where human subjects were harder to obtain, forcing him henceforth to use bird models in his malaria research.
1898
Bignami (using a human volunteer and Anopheles mosquitoes carrying P. falciparum) and Ross (using a bird model system and Culex mosquitoes most likely carrying P. relictum) separately make the first observations of mosquito transmission of malaria. Formal announcement of Ross' discovery is greeted by a standing ovation at a meeting of the British Medical Association in Edinburgh, Scotland. Bitter priority conflicts arise between the Italian and British schools of malariology, because while Bignami's report appeared first, Ross and Manson claim that the Italian work derived from unpublished reports of Ross's work.
1899
Bastianelli & Bignami make the first observation of the complete P. vivax transmission cycle from mosquito to human and back.
1901
Manson's son, P. Thurburn Manson, documents the first experimental evidence of relapse after serving as a voluntary meal for vivax-infected Anopheles. Relapse occurs nine months later.
1903
The eminent protozoologist Schaudinn erroneously reports direct infection of erythrocytes by sporozoites, which he suggests originate by parthenogenesis of gametocytes. This leads researchers into the cause of relapse on a 'meandering detour' that lasts for more than 40 years, as they struggle to replicate his observation.
1920
Mesnil & Roubaud achieve the first experimental infection of chimpanzees with P. vivax.
1926
Marchoux proposes three possible models to account for relapse: 1) parthenogenesis of macrogametocytes; 2) persistence of small numbers of schizonts in the blood, which proliferate as host immunity wanes; and 3) reactivation of a dormant blood stage.
1930
Garnham disproves the parthenogenetic model of relapse, when subjects injected with blood containing only gametocytes fail to develop malaria.
1931
After observing that quinine had no effect when administered before the appearance of clinical symptoms, James proposes that sporozoites are carried by the blood to internal organs, where they enter extraerythrocytic cells and are thus protected from quinine.
1945
Fairley et al report that P. vivax sporozoites disappear from circulating blood within an hour after introduction, and do not reappear in circulation until eight days later, providing strong evidence for an extraerythrocytic stage in vivax malaria.
1946
Shute proposes the existence of post-sporozoite 'x-body' or 'resting parasite' to explain his observation that even when mosquitoes are heavily infected with P. vivax, there is sometimes a long delay before malaria develops in humans they feed on.
1948
Shortt et al. report the discovery of liver cell schizonts, first in monkeys experimentally infected with P. cynomolgi, and then in a liver biopsy from a mentally ill human 'volunteer' injected with a massive dose of P. vivax sporozoites. Short and Garnham also report observing schizonts in the liver of a monkey 3.5 months after inoculation -- a possible source of persistent parasites for relapse. For several decades afterwards, two models of relapse compete: (1) the 'cyclic' model involving more or less continuous maturation of liver schizonts and reinfection of liver cells by locally-released merozoites, whose ability to invade erythrocytes is regulated by the host immune response, and (2) the 'latent stage' model involving a quiescent (dormant) liver stage.
1967, 1971
Two influential reviews argue for the superiority of the latency model.
1977
Garnham proposes the name 'hypnozoite' (sleeping animalcule) for the as-yet-undiscovered latent stage responsible for relapse.
1980
Discovery that P. vivax can only infect Duffy antigen-positive humans
Krotoski et al. report discovery of hypnozoites - small, quiescent, mononucleate bodies persisting months after infection - in immunofluorescence-stained liver cells of monkeys infected with P. cynomolgi.
1982
Krotoski et al. report identification of P. vivax hypnozoites in liver cells of infected chimpanzees.
1984
Mazier et. al report in vitro cultivation of P. vivax liver stage using human hepatocytes
1989
First report of chloroquine resistant P. vivax malaria, from Papua New Guinea.
2002
The genome sequences of P. falciparum and the rodent model malaria P. yoelii yoelii are published.
The P. vivax genome sequencing project begins.
2008
Completion and publication of the P. vivax genome.