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Malaria puts more than 3 billion people at risk of infection and causes high morbidity and mortality. Plasmodium vivax forms hypnozoites, which may initiate recurrences, even in the absence of reinfection or superinfection. Until recently, the only drug available for eliminating hypnozoites was primaquine (PQ), which, given its short half-life, requires a relatively long course of treatment. Tafenoquine (TQ) is a PQ analog with a longer half-life. This enables radical cure of malaria with a single dose and overcomes adherence issues associated with PQ, thereby increasing effectiveness in real-life settings. Clinical studies have provided sound evidence for TQ's safety and efficacy against malaria, which recently led to its approval by the US FDA. Here, we review aspects of TQ, including how to avoid hemolytic anemia in G6PD deficient patients. We believe that TQ promises to be a major advance toward malaria elimination.

In studying the relationship between genetic abnormalities of red blood cells and malaria endemicity in the Vanuatu archipelago in the southwestern Pacific, we have found that of 1,442 males tested, 98 (6.8%) were G6PD deficient. The prevalence of GdPD deficiency varied widely (0%-39%), both from one island to another and in different parts of the same island, and generally correlated positively with the degree of malaria transmission. The properties of G6PD from GdPD-deficient subjects were analyzed in a subset of 53 samples. In all cases the residual red-blood-cell activity was < 10%. There were three phenotypic patterns. PCR amplification and sequencing of the entire coding region of the G6PD gene showed that the first of these patterns corresponded to G6PD Union (nucleotide 1360C-->T; amino acid 454Arg-->Cys), previously encountered elsewhere. Analysis of samples exhibiting the second pattern revealed two new mutants: G6PD Vanua Lava (nucleotide 383T-->C; amino acid 128Leu-->Pro) and G6PD Namoru (nucleotide 208T-->C; amino acid 70Tyr-->His); in three samples, the underlying mutation has not yet been identified. Analysis of the sample exhibiting the third pattern revealed another new mutant: G6PD Naone (nucleotide 497G-->A; amino acid 166Arg-->His). Of the four mutations, G6PD Union and G6PD Vanua Lava have a polymorphic frequency in more than one island; and G6PD Vanua Lava has also been detected in a sample from Papua New Guinea. G6PD deficiency is of clinical importance in Vanuatu because it is a cause of neonatal jaundice and is responsible for numerous episodes of drug-induced acute hemolytic anemia.

In 702 Nigerian children under 6 years of age the incidence and the severity of malarial infection was studied with respect to haemoglobin types and red cell glucose-6-phosphate dehydrogenase variants. The results suggest that Hb AS as well as the female genotype GdA-/GdB offer selective advantage against the disease. Parasite densities in carriers of these genotypes were significantly lower than in other subjects. Whereas protection by Hb AS was found mainly in children between 2 and 4 years of age, the advantage afforded by GdA-/GdB was similar in all age groups. Possible mechanisms are discussed.

In a clinical study, 702 Nigerian children aged 1-6 years were examined for malaria. Comparison of morbidity rates and parasitemia of patients with different glucose-6-phosphate dehydrogenase (G6PD) status provided evidence that in heterozygous females the gene for G6PD deficiency (GdA-/GdB) confers an advantage against malaria.

In a holoendemic malaria region of Nigeria children of both sexes aged from 9 months to 6 years with an acute febrile illness were examined for malaria. In 461 children with malaria, predominantly P. falciparum, and in 241 children without malaria, haemoglobin levels, haemoglobin types, red cell glucose-6-phosphate dehydrogenase variants and parasite densities were recorded. The G6PD status was determined by a combination of spectrophotometric enzyme quantitation, electrophoresis and the cytochemical methaemoglobin elution technique. Malaria morbidity and parasitaemia decreased with increasing age. Frequencies of haemoglobin types and G6PD variants were not significantly different in the malaria and the non-malaria series. Haemoglobin values were significantly lower in children with malaria to about the same extent in HbAA and HbAS subjects, but no close correlation existed between haemoglobin level and parasite density. Details of the G6PD classification and the effect of malaria on enzyme activity are discussed.

Two recent developments in the field of trypanosomiasis and malaria are presented: 1) A novel mode of gene expression has been discovered in trypanosomes which enables the parasite to change its surface antigenicity with each new wave of parasitaemia, thus making an effective host response impossible. 2) The possibility to cultivate Plasmodium falciparum in vitro allows studies on the interaction of parasites and red cells, on drug resistance and on surface antigens.- Research in tropical diseases has given important contributions to biology and medicine in general. Basic research on the other hand is necessary to fight successfully tropical disease which are still common and often fatal.

Some of the available information on the genetics of Plasmodium is reviewed, and some of its peculiarities are emphasized. Genetic factors in the human host that may affect susceptibility to malaria are critically evaluated. Most of the studies thus far have been concerned with the genetics of host erythrocytes but there is recent evidence that genes affecting immune processes may also be involved. At least two genes affecting red cells confer relative resistance to P. falciparum: the autosomal gene for haemoglobin S (Hb S) and the sex-linked gene for the glucose-6-phosphate dehydrogenase (G6PD) variant known as A(-). Whereas malaria selection can be regarded as established for these genes, it still remains a hypothesis for some other polymorphic traits of red cells. Differential susceptibility to P. falciparum of red cells with different genotypes has been tested by in vitro cultures, in which the invasion of new cells and intracellular development of the parasite can be followed by parasite counts and by (14)C-isoleucine uptake. A model that relates genetic factors in Plasmodium and in man and that may account for certain features of host-parasite interactions is presented.

The Terai region of Nepal has been known to be heavily malarious since remote times, and it has, therefore, been regarded as uninhabitable by most Nepalese people. The Tharu people, who have been living in the Terai for centuries, were reputed to have an innate resistance to malaria. Following successful control of malaria by the Nepal Malaria Eradication Organization (NMEO), a large and heterogeneous non-Tharu population now inhabits the Terai along with Tharus. By analysing NMEO records, we have found that the prevalence of cases of residual malaria is nearly seven times lower among Tharus compared to sympatric non-Tharus. This difference applies to Plasmodium vivax, which is now much more common, and to Plasmodium falciparum. We suggest that the basis for resistance to malaria in the Tharu people is a genetic factor yet to be identified.

The in vitro culture of Plasmodium falciparum, after synchronization, lends itself well to an analysis of the asexual schizogonic cycle. We have found in this system that DNA synthesis and RNA synthesis are associated mainly with the trophozoite stage, with the latter peaking slightly ahead of the former. Distinctive patterns of protein synthesis are seen at serial times along the cycle, with a number of 'stage-specific' bands identifiable on SDS gels. The fate of the infection can be influenced by the genotype of the host cell. Thus, glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes are invaded normally, but maturation of intracellular parasites is delayed and impaired. However, the parasites that do develop will then have a normal behaviour in their next rounds in G6PD-deficient cells, suggesting that an adaptive change has taken place. These results fit well with the relative protection against P. falciparum in vivo of girls heterozygous for G6PD deficiency but not of hemizygous G6PD-deficient boys.

Erythrocyte mosaicism occurs in females heterozygous for glucose-6-phosphate dehydrogenase deficiency. In blood from female children with acute Plasmodium falciparum malaria the parasite rate was 2 to 80 times higher in normal than in deficient erythrocytes. This may be the mechanism whereby the gene for glucose-6-phosphate dehydrogenase deficiency confers selective advantage against malaria to heterozygous females, and thus may have attained the polymorphic frequency occurring in populations living in areas with endemic malaria.