Malaria therapeutics: are we close enough?

Abstract

Malaria is a vector-borne parasitic disease caused by the apicomplexan protozoan parasite Plasmodium. Malaria is a significant health problem and the leading cause of socioeconomic losses in developing countries. WHO approved several antimalarials in the last 2 decades, but the growing resistance against the available drugs has worsened the scenario. Drug resistance and diversity among Plasmodium strains hinder the path of eradicating malaria leading to the use of new technologies and strategies to develop effective vaccines and drugs. A timely and accurate diagnosis is crucial for any disease, including malaria. The available diagnostic methods for malaria include microscopy, RDT, PCR, and non-invasive diagnosis. Recently, there have been several developments in detecting malaria, with improvements leading to achieving an accurate, quick, cost-effective, and non-invasive diagnostic tool for malaria. Several vaccine candidates with new methods and antigens are under investigation and moving forward to be considered for clinical trials. This article concisely reviews basic malaria biology, the parasite's life cycle, approved drugs, vaccine candidates, and available diagnostic approaches. It emphasizes new avenues of therapeutics for malaria.

Keywords: Diagnostics; Malaria therapeutics; Plasmodium species; RTS,S; Rapid diagnostic test; Vaccine.

Fig. 1

Life cycle of malaria parasite

Fig. 2

List of approved antimalarials

Fig. 3

Antimalarials targeting the parasite’s life cycle

Fig. 4

An overview of malaria vaccines and their mechanism. a Target stage (sporozoite, merozoites or gametocytes and ookinete). b Vaccine type (whole parasite vaccines, subunit vaccines, recombinant DNA/RNA vaccines) and target antigens. c Immune cell and response (cell-mediated or humoral antibody response). d Mode of action (killing of infected cell or cell invasion inhibition) of vaccine. (e) Vaccine name/s. DNA, deoxyribonucleic acid; RNA, ribonucleic acid

Fig. 5

Schematic representation of (a) CSP region I and region II at N-terminal and C-terminal, respectively, and a central repeat region consists of NANP amino acid repeats. The junction region joins central repeat region to N-terminal and a signal sequence and GPI anchor sequence at N-terminal and C-terminal end, respectively. Central repeats (NANP) and junction region induce antibody generation while CD4 and CD8 T-cell epitopes at C-terminal trigger cell-mediated immune response. b RTS,S vaccine consists of B-cell epitopes from central repeat region at N-terminal and T-cell epitopes from region II of CS protein fused with hepatitis surface antigen (HBsAg) at C-terminal along with three copies of HBsAg (not in fusion with CS protein). c Yeast cell producing VLP (RTS,S and R21 vaccines) expressing CSP antigen on surface fused with hepatitis B surface antigen (HBsAg). GPI, glycosylphosphatidylinositol; CD, clusters of differentiation; CSP, circumsporozoite protein; VLP, virus-like particle

Fig. 6

Diagnosis methods for malaria detection using (a) PCR. (b) Use of microscopy in malaria diagnosis: A blood sample is taken by pricking the finger, and two types of smears can be prepared: thick (for the presence of Plasmodium) and thin (for identification of species of Plasmodium). The figure shows how the trophozoite stage is visualized in thick smear and thin smear. c Flow cytometry in malaria diagnosis: Fluorochrome staining and analysis by flow cytometry. d Rapid diagnostic test (RDT) for malaria: Cassette and interpretation of the assay results as positive, negative, or invalid. (e) Diagnosis by RDTs using samples other than blood such as saliva and urine. PCR, polymerase chain reaction

Fig. 7

The range of malaria infection and a comparison of the sensitivity of three diagnostic methods: microscopy, RDT, and PCR. Microscopy and RDTs are sensitive enough to detect symptomatic infections but not those with low parasite density. PCR is more sensitive than the other two techniques (RDT and microscopy) but is unable to detect infections with very low parasitemia. PCR, polymerase chain reaction; RDT, rapid diagnostic test

Fig. 8

Future tools for malaria diagnosis. a Gazelle device and its mechanism based on magneto-optical detection. b TMek: The iRBCs and hemozoin crystals get captured on the cylindrical Ni concentrators of microchip and the healthy RBCs are sedimented. (c) LAMP for malaria diagnosis: Procedure for DNA extraction and LAMP assay. TMek, Tid Mekii; iRBC, infected red blood cell; LAMP, loop-mediated isothermal amplification; DNA, deoxyribonucleic acid