What is Malaria?

Malaria is a parasitic disease that is transmitted by infected mosquitoes. The non-specific nature of the symptoms of uncomplicated malaria, including fever, chills, sweating, body aches, nausea, headache, vomiting, and diarrhea, make clinical diagnosis challenging. In contrast, severe disease rapidly leads to anemia, dehydration, respiratory distress, seizures, and coma. Although severe malaria is easier to identify clinically, the symptoms are difficult to manage in resource poor settings, contributing to a high mortality rate in these patients. When left untreated, uncomplicated malaria can rapidly progress to severe disease, especially in young children.

Global Burden

Malaria

Malaria is widespread in the tropical and subtropical regions of Africa, Asia, and Central and South America. There are 108 countries with endemic malaria and an estimated at risk population in high burden countries of close to 670 million.1

Malaria affects 250 million people per year and results in more than 800,000 deaths.Approximately 89% of all malaria deaths occur in Africa, primarily in children under the age of five. In high transmission regions of Africa, malaria accounts for up to 40% of all health expenditures and 30-50% of all hospital admissions.2

The impact of malaria goes beyond health. In Africa, malaria has been estimated to result in more than US$12 billion in lost annual gross domestic profit. It is estimated that in high transmission areas, malaria can decrease GDP by up to 1.3% per year.

Causative Agent

exampleHuman malaria is caused by protozoan parasites of the genus Plasmodium. There are five species of Plasmodium known to affect humans: P. falciparumP. vivaxP. ovaleP. malariae, and P. knowlesi.

 
life-cycleThe parasites are transmitted through the bite of an infected female mosquito of the genus Anopheles. Upon taking a blood meal, an infected mosquito injects sporozoite (pre-erythrocytic) stage parasites into the blood stream of the human host. These parasites travel through the body to the liver where they replicate without causing symptoms. After 7-14 days, the P. falciparum parasites burst out of the infected liver cell and enter the bloodstream where they infect red blood cells (erythrocytic stage). The parasites are then able to continuously replicate inside, burst, and reinvade red blood cells.
 
A mosquito becomes infected with malaria upon taking a blood meal from an infected person. Under certain stress conditions in the human host, the malaria parasites replicating in the blood differentiate into a sexual stage known as the gametocyte. The gametocyte stage parasites are taken up by the feeding mosquito with a blood meal, undergo sexual replication in the mosquito midgut, and the newly produced sporozoite stage parasites are then transmitted to the next human host when the mosquito takes another blood meal.

Pathogenesis

The classical periodic fevers and severe anemia associated with malaria are the result of lysis of infected red blood cells caused by the replication of the parasite in the erythrocytic stage.

P. falciparum causes the majority of severe disease and mortality associated with malaria (~80%). The severity of P. falciparum malaria is primarily attributed to an unusual physical change that occurs in human red blood cells infected with P. falciparum; the parasite exports its own proteins to the surface of the infected cell causing clumping with nearby uninfected red blood cellsasa well as the walls of blood vessels. In the brain, this leads to seizures and coma, and in the placenta of a pregnant woman this leads to low birth weight babies or even death of the fetus.

P. vivax is less deadly, but worldwide is the most prevalent Plasmodium species. P. vivax is associated with fewer malaria deaths, in part because it can only infect immature red blood cells (reticulocytes). However, P. vivax is in some ways the more challenging species of malaria to control as this species is able to lay dormant in the liver of the human host and reemerge years later. This dormant stage, known as the hypnozoite, is difficult to detect and also difficult to treat.

The precise burden of disease for P. ovaleP. malariae, and P. knowlesi has not been fully described. P. malariae and P. ovale are found at a low prevalence in all malaria endemic areas.3 P. knowlesi is a zoonotic species that primarily infects monkeys and was only recently realized as a human pathogen. Research is ongoing to determine the significance of P. knowlesi for human health.

Current Control Strategy

The Roll Back Malaria Partnership has set a goal of eliminating malaria in eight to ten countries by 2015.1 Of the 108 malaria endemic countries, 39 are now taking action to move towards elimination.4 As of 2009, nine countries seeking elimination have interrupted transmission.1

As there is no vaccine for malaria, control efforts primarily focus on prevention and treatment in the form of four major activities:

  1. Insecticide-treated nets (ITN)
  2. Indoor residual spraying (IRS)
  3. Accurate diagnosis and treatment with artemisinin combination therapies (ACTs)
  4. Intermittent preventive therapy (IPT) during pregnancy

Financial support has increased substantially for malaria control programs, rising from US$0.3 billion in 2003 to US$1.7 billion in 2009. However, it is estimated that malaria spending will need to increase to US$5 billion by 2015 in order to sustain current control efforts.1

Existing Products

Drugs

Since 2002, the World Health Organization (WHO) has recommended the use of artemisinin combination therapies (ACTs) for first-line treatment of uncomplicated malaria. This recommendation came as the result of widespread drug resistance to inexpensive monotherapies such as chloroquine and sulfadoxine-pyrimethamine. By combining at least two antimalarials, ACTs reduce the risk for new drug resistance. There are currently five ACTs in use and in late stage development:5

  • Artesunate-amodiaquine (Launched Q4 2008)
  • Artemether-lumefantrine (Launched Q1 2001)
  • Artesunate-mefloquine (Launched Q2 2008)
  • Dihydroartemisinin-piperaquine (Launched Q4 2011)
  • Pyronaridine-artesunate (Launched Q3 2011)

WHO recommends treatment of severe malaria with IV artesunate. However, intramuscular artesunate, artemether, or quinine, and rectal artesunate are recommended for use in settings where IV treatment is not possible.

The one exception to the recommended use of ACTs is in pregnancy. Although there are no reports of adverse events due to use of ACTs during the first trimester of pregnancy, quinine is recommended during the first three months pending more detailed studies of the risks of ACT use. ACTs are still recommended for first line treatment during the second and third trimesters.

Because of the severe effects malaria can have on the developing fetus, it is also recommended that women receive intermittent preventative therapy with sulfadoxine-pyrimethamine (SP) during their second and third trimesters.

Vaccines

There is currently no vaccine approved for the prevention of malaria.

Diagnostics

The high cost of ACTs and the potential for drug resistance has motivated efforts to ensure that ACTs are used correctly. WHO now recommends the use of confirmatory diagnosis for all suspected cases of malaria prior to treatment with ACTs. Unfortunately, malaria diagnosis by microscopy, the gold standard for malaria diagnosis, is not possible in low resource settings. As an alternative, numerous rapid diagnostic tests (RDTs) have been developed to allow minimally trained health workers to administer tests at the point of care. Available RDTs are now being systematically evaluated by WHO/TDR in order to determine which tests are most reliable. 

References

  1. WHO (2009) World Malaria Report 2009
  2. WHO, Malaria Fact Sheet.
  3. Mueller I et al. (2007) “Plasmodium malariae and Plasmodium ovale – the ‘bashful’ malaria parasites.”  TRENDS in Parasitology23:  278-283.
  4. The Malaria Elimination Group (2009) Shrinking the Malaria Map:  A prospectus on elimination.
  5. Wells TNC et al. (2009) “New medicines to improve control and contribute to the eradication of malaria.”  Nature Reviews Drug Discovery 8:  879-891.

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Drugs

Analysis

Despite having numerous products in clinical development, including new chemical entities, the majority of the clinical stage antimalarials are highly related to drugs that are already on market.

Earlier stage drug development projects are exploring more diverse targets including:

  • Lipid biosynthesis inhibitors 
  • Nucleic acid synthesis inhibitors 
  • Protein synthesis inhibitors
  • Compounds with unknown mechanisms of action from cell-based screening projects

The majority of safe medications for malaria target the blood stage of the parasite. However, there is increasing interest in targeting other stages of the parasite lifecycle including the gametocyte stage that is transmitted to the mosquito and the hypnozoite stage of P. vivax that persists in the liver. The persistence of the gametocyte stage following treatment allows infected individuals to transmit malaria to mosquitoes even after receiving treatment, while failure to target the hypnozoite stage can allow parasites to re-emerge from the liver and re-infect the host years after treatment. While these stages of the parasite lifecycle do not cause disease directly, they do pose challenges for malaria control and elimination programs. The 8-aminoquinolines, such as primaquine, are able to kill gametocytes and hypnozoites, but safety concerns in patients with G6PD mutations1 have limited their widespread use. As the target of the 8-aminoquinolines remains unknown, there is a great need to explore new potential targets as well as diverse small molecules to target the gametocytes and hypnozoites.

 StrengthsWeaknessesOpportunitiesRisks
Synthetic endoperoxides (Artemisinin-related)
Most advanced program: OZ439, Phase IIBased on proven drugs with good potency and safety profilesInability to easily evaluate effects on artemisinin resistant parasitesPotentially can overcome artemisinin resistanceUnknown if drug candidate will overcome emerging artemisinin resistance
Aretmisinin derivatives (Artemisinin-related)
Most advanced program: On market (Most advanced NCE artemisone, Phase II)Based on proven drugs with good potency and safety profilesACT market potentially saturated  Susceptible to same resistance mechanisms as artemisininMore extensive safety trials in pregnant women Simplified dosingEmergence of artemisinin resistant parasites in Southeast Asia
4-aminoquinolines (Chloroquine-related)
Most advanced program:  On market (Most advanced NCE ferroquine, Phase II)Based on proven drugs with good efficacy and safety profilesParasites resistant to many on market products from this class suggesting high risk for resistance to new moleculesPrimary value will be in combination therapies with other new drugsExisting extensive drug resistance to related molecules
8-aminoquinolines (Target unknown)
Most advanced program:  On market (Most advanced NCE tafenoquine, Phase I)Targets P. vivaxhypnozoites and P. falciparum gametocytesPotentially causes hemolysis in patients with G6PD deficiencyIdentify drug target in order to find alternative inhibitor classes with improved safetyNew compounds with improved safety could replace this class
Natural products
Most advanced program:  PR259CTI and Argemone mexicana decoction, Phase IUnknown, but potential novel mechanisms of actionsLittle information available on these productsPotential for use as adjuncts to more traditional therapiesPotential cost relative to ACTs unknown 
DNA damage
Most advanced program: Tinidazole, Phase IIIn development for radical cure of P. vivax Novel mechanisms of action relative to on market antimalarialsDNA damage mechanism has potential for off target effects in host May work in patients with G6PD deficiency Potential for use in combination with other antimalarialsClinical efficacy data not yet available

Vaccines

Analysis

Malaria vaccine development is challenging because the parasite has thousands of potential antigens from which to down-select, and malaria has co-evolved to thrive despite immunologic pressure. A diverse portfolio of technologies and antigens is being advanced to account for the differential expression of antigens across the life-cycle and differences in the immununological response arms that are thought to play a protective role with different antigens,. Some technologies (eg DNA and viral vectored vaccines) are better suited for stimulating cellular immunity while other technologies (ie recombinant proteins) are suited for inducing an antibody response. Therefore, malaria vaccines present the opportunity to validate a wide variety of new technologies which may in turn help drive forward the vaccine pipeline for other diseases of the developing world.

GlaxoSmithKline (GSK) and the Malaria Vaccine Initiative (MVI) are currently conducting a large phase III clinical trial for a recombinant protein-based malaria vaccine called RTS,S, the most advanced malaria vaccine in development. While this vaccine has only a moderate effect on malaria prevention (~30-50% protection), the real value of the vaccine is most likely in reducing the severity of disease and likelihood of death. The current phase III trial includes 16,000 patients in seven African countries and evaluates effects of vaccination on disease severity as well as prevention of illness. RTS,S is estimated to be available in 2015.

The moderate efficacy RTS,S has caused an evolution in development strategy. Moving forward, combinations of antigens/vaccines are being explored to 1) increase the breadth of the antigenic targets (i.e. adding additional antigens or antigens from different stages of the life-cycle), 2) increase the magnitude/breadth of the immune response (i.e. using more potent adjutants, new technologies, or heterogonous prime-boost approaches), or both. The benefits of combining vaccines include:

  1. Combined activation of both humoral and cellular immune responses
  2. Ability to target multiple lifecycle stages (i.e. pre-erythrocytic, erythrocytic, or transmission blocking)
 StrengthsWeaknessesOpportunitiesRisks
Recombinant protein
Species targeted: P. falciparum and P. vivax  Stages targeted: pre-erythrocytic, erythrocytic, transmission Most advanced program: RTS,S, Phase III Additional programs in all stages of developmentFirst demonstrated clinical efficacy for malaria prevention (~30-50%) and reduced disease severity  Well defined regulatory pathwayManufacture of antigens with native conformation/structure is complex and time consuming Best suited to induce humoral immune responseCombinations with other technologies for prime-boost strategy  Combinations of targets for different stages  Immune response can be augmented with the use of adjuvantsDue to partial efficacy may need to be used in combination with other vaccines
Live attenuated
Species targeted: P. falciparum  Stages targeted: pre-erythrocytic Most advanced program: PfSPZ and p52-/p36- GAP Vaccine, Phase IIMimics natural infection  Preliminary studies using irradiated infected mosquitoes demonstrated sterilizing immunity in small number of patients  Proven vaccine approach for other diseasesWill require cold chain for delivery/cannot integrate into EPI schedule  Preliminary clinical trial evidence from Sanaria not promising  Vaccine production extremely labor intensive  Cannot apply to P. vivax or other life cycle stagesAdditional variations of genetically modified attenuated sporozoites (rather than irradiated sporozoites)Recombinant protein and other technologies with potential EPI integration more advanced and easier to integrate into general health strategies
Viral vector
Species targeted: P. falciparum Stages targeted:pre-erythrocytic, erythrocytic Most advanced program: Numerous programs, Phase II Additional program in phase I developmentAbility to prime potent cellular immune response Potential to induce humoral immune responsePre-existing anti-vector immunity or generation of anti-vector immunity can affect immunogenicity Capacity to carry multiple antigens limited in some vectorsApply to P. vivax Combinations with other technologies for prime-boost strategy  Explore additional viral vectorsThere are no FDA approved viral vector vaccines on market  Termination of adenovirus-based HIV vaccine trial in 2005 raised safety concerns which may lead to increased regulatory scrutiny
DNA
Species targeted: P. falciparum Stages targeted:pre-erythrocytic, erythrocytic Most advanced program: EP1300 polyepitope, Phase IIAbility to prime cellular immune responses Flexibility and speed in generation of new constructs Able to make multi-antigenic constructsAbility to induce humoral immune response has translated poorly to humans Vaccine technology not yet proven for any disease HLA restriction limits population responses to epitope based vaccinesApply to P. vivax Combinations with other technologies for prime-boost strategy  Explore additional DNA vectors and delivery technologiesThere are no FDA approved viral vector vaccines on market
Peptide
Species targeted: P. falciparum Stages targeted:erythrocytic Most advanced program: MSP3-LSP, Phase II Synthetic peptide may be easier/cheaper to produce than other vaccines Manufacture does not require process development for higher order structures Conformation epitopes difficult to recapitulate There are no on market synthetic peptide vaccines Lack of higher older structures limit magnitude of immune response HLA restriction limits population responses to epitope based vaccines Potential for combination with other vaccine technologies Use of adjuvants can increase magnitude and breadth of immune response If RTS,S vaccine obtains approval, may be difficult to progress

Diagnostics

Analysis

Although there are numerous simple lateral flow RDTs for the diagnosis of malaria available, these tests have had variable effects on the correct use of ACTs. A primary problem identified thus far is that when an RDT result for malaria is negative, a minimally trained health worker can do little in terms of identifying alternative diagnoses and courses of treatment. In a few small clinical trials where field performance of RDTs was evaluated, it was observed that treatment regimens were either, 1) unchanged and ACTs were distributed even when tests were negative, or 2) there was increased use of presumptive antibiotic treatment for patients with negative RDTs. More systematic and large scale analyses are needed to determine the true impact of RDTs on correct ACT use but this preliminary evidence suggests an opportunity for developing more comprehensive diagnostics that can diagnose both malaria and other treatable causes of febrile illness. This test should include malaria diagnosis but also other common causes of febrile illness such as tuberculosis, pneumonia, or meningitis. Panel tests that can be used at the point of care in resource poor settings would better empower health workers to correctly treat not just malaria positive patients but also provide alternative treatments for malaria negative patients.

Many diagnostics currently in development for malaria are focusing on finding novel means of detecting the parasites.  One project in preclinical evaluation aims to use a high-resolution lens on a modified smartphone to detect parasites.  Another, being developed by the Institute for Electrical and Electronics Engineers, hopes to use magnetic interactions to detect low levels of parasitemia without needing to take a blood sample. 

References

  1. G6PD deficiency is the most common enzymopathy worldwide affecting more than 330 million people through more than 160 different mutations. This deficiency was first discovered after observation of hemolysis in malaria patients treated with primaquine, an 8-aminoquinoline. Nkhoma ET et al. (2009) “The global prevalence of glucose-6-phosphate dehydrogenase deficiency: A systematic review and meta-analysis.” Blood Cells Mol Dis 42: 267–278.

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The following series of tables describe the availability of tools for research, discovery, and development of novel drugs, vaccines, and diagnostics for malaria. The tools listed in the following tables are not intended to be an all-inclusive list but rather capture the most common tools used for drug, vaccine, and diagnostic development.

Drugs Development Tools

Basic Research: Target IdentificationTarget ValidationScreening: Hit/Lead Identification OptimizationPre-clinical ValidationClinical Validation

Genome:  Sequenced and annotated 

Key databases:  Plasmodium Genomics Resource 

In vitro culture:Possible for P. falciparumbut not P. vivax; mouse models often used for culture of pre-erythrocytic stages

Gene knock-outs: Yes (erythrocytic stages only) 

Conditional gene knock-outs: Two methods published, not yet widely applied 

Transposon mutagenesis:Possible

RNAi: No, parasite missing key biological pathway components 

Other antisense technology:  Yes

Viability assays:  Yes 

Transcription microarrays: Yes

Proteomics: Yes 

Crystal structures:  Not extensive, difficulty producing recombinant proteins

Whole-cell screening assays: Yes, multiple assays for erythrocytic stages; assays in development for pre-erythrocytic stages using mouse models

Enzymatic screening assays:  Yes, but difficulty producing recombinant proteins, is sometimes limiting

Animal models:  Yes; “humanized” mouse model available for P. falciparum (GSK); P. falciparum can also infect new world monkeys; Model for liver stage infection using transgenic mouse with humanized liver (KMT Hepatech); P. bergheimost common mouse model used for drug discovery (also P. yoeliand P. chabaudi but less common)

Monitoring treatment efficacy: Yes, microscopy is the gold standard, RDTs remain positive up to two weeks after treatment completion

Availability of endpoints: Yes, clearance of parasitemia 

Availability of surrogate endpoints: No 

Access to clinical trial patients/sites: Yes

Vaccines Development Tools

Basic Research: Antigen IdentificationImmune Response CharacterizationClinical Validation

See drug development tools above

Predictive animal models:  No, although multiple mouse models available, little correlation with human response 

Detection of endogenous antigen specific response in clinical samples:Yes, not fully characterized 

Natural immunity well characterized:  No, natural immunity minimal, transient, and not well understood

Surrogate markers of protection: No 

Challenge studies possible: Yes  

Diagnostics Development Tools

Basic Research: Biomarker IdentificationBiomarker ValidationClinical Validation

See drug development tools above

Biomarkers known: Yes 

Access to clinical samples: Yes, as part of RDT testing validated clinical sample registry being developed by TDR

Possible sample types: Blood

Access to clinical trial patients/sites: Yes 

Treatment available if diagnosed: Yes

References

Get Involved

To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs.