Malaria Journal

Effective anti-malarial drug treatment reduces malaria transmission. This alone can reduce the incidence and prevalence of malaria, although the effects are greater in areas of low transmission where a greater proportion of the infectious reservoir is symptomatic and receives anti-malarial treatment. Effective treatment has greater effects on the transmission of falciparum malaria, where gametocytogenesis is delayed, compared with the other human malarias in which peak gametocytaemia and transmissibility coincides with peak asexual parasite densities. Mature Plasmodium falciparum gametocytes are more drug resistant and affected only by artemisinins and 8-aminoquinolines. The key operational question now is whether primaquine should be added to artemisinin combination treatments for the treatment of falciparum malaria to reduce further the transmissibility of the treated infection. Radical treatment with primaquine plays a key role in the eradication of vivax and ovale malaria. More evidence is needed on the safety of primaquine when administered without screening for G6PD deficiency to inform individual and mass treatment approaches in the context of malaria elimination programmes.

Control of mosquitoes that transmit malaria has been the mainstay in the fight against the disease, but alternative methods are required in view of emerging insecticide resistance. Entomopathogenic fungi are candidate alternatives, but to date, few trials have translated the use of these agents to field-based evaluations of their actual impact on mosquito survival and malaria risk. Mineral oil-formulations of the entomopathogenic fungi Metarhizium anisopliae and Beauveria bassiana were applied using five different techniques that each exploited the behaviour of malaria mosquitoes when entering, host-seeking or resting in experimental huts in a malaria endemic area of rural Tanzania. Survival of mosquitoes was reduced by 39-57% relative to controls after forcing upward house-entry of mosquitoes through fungus treated baffles attached to the eaves or after application of fungus-treated surfaces around an occupied bed net (bed net strip design). Moreover, 68 to 76% of the treatment mosquitoes showed fungal growth and thus had sufficient contact with fungus treated surfaces. A population dynamic model of malaria-mosquito interactions shows that these infection rates reduce malaria transmission by 75-80% due to the effect of fungal infection on adult mortality alone. The model also demonstrated that even if a high proportion of the mosquitoes exhibits outdoor biting behaviour, malaria transmission was still significantly reduced. Entomopathogenic fungi strongly affect mosquito survival and have a high predicted impact on malaria transmission. These entomopathogens represent a viable alternative for malaria control, especially if they are used as part of an integrated vector management strategy.

Most data describing severe malaria (SM) in sub-Saharan Africa (SSA) are from research settings outside disease endemic areas. Using routinely collected data from Apac District Hospital, this study aimed at determining the burden and clinical spectrum of severe malaria. This was a retrospective study that reviewed all paediatric admission records for malaria in the 24 months period from Jan 2019 to Dec 2020 at Apac District Hospital. Data on children aged 60 days to 12 years who at admission tested positive for malaria and fulfilled the World Health Organization clinical criteria for surveillance of severe malaria were abstracted using a customized proforma designed to capture variables on social demographic, clinical presentation, treatment, and outcomes. In addition, the tool included laboratory variables for complete blood counts, haemoglobin, and glucose levels. Data were analysed using STATA V15.0. The study had ethical approval from Mbale Regional Referral Hospital REC, Approval No. MRRH-REC 053/2019. A total of 5631 admission records were retrieved for this study period. Of these, 3649 (64.8%) were malaria admissions and 3422/3649 were children below 12years, with only 1864 (54.5%) of children having complete data. Of the 1864 children, 745 (40.0%) fulfilled the severe malaria inclusion criteria. Of the 745 children, 51.4% (n = 381) were males. The median age at admission was 31 months (IQR = 17–60). The most common clinical presentations among children with severe malaria were fever 722 (97.3%), cough 478 (64.2%), and difficulty in breathing 122 (17.9%). The median length of hospital stay was 2 (IQR; 2–4) days and 133 (17.9%) had prolonged hospital stay (> 4 days). Factors independently associated with prolonged hospital stay were, presenting with difficulty in breathing, aOR 1.83 (95% CI 1.02–3.27, P = 0.042) and prostration aOR 8.47 (95% CI 1.94–36.99, P = 0.004). A majority of admitted children, 735 (98.7%) survived, while 10 (1.3%) died of SM. A high proportion (40.0%) of malaria admissions were due to SM. Prolonged Hospital stay was associated with prostration and difficulty in breathing. Overall mortality was low, 1.3% compared to mortality in the previously reported series. This study was able to use routinely collected data to describe the burden and clinical spectrum of SM. Improvement in the quality of data from such settings would improve disease descriptions for policy, monitoring of epidemics, response to interventions and to inform research.

Malaria presents public health challenge despite extensive intervention campaigns. A 30-year hindcast of the climatic suitability for malaria transmission in India is presented, using meteorological variables from a state of the art seasonal forecast model to drive a process-based, dynamic disease model. The spatial distribution and seasonal cycles of temperature and precipitation from the forecast model are compared to three observationally-based meteorological datasets. These time series are then used to drive the disease model, producing a simulated forecast of malaria and three synthetic malaria time series that are qualitatively compared to contemporary and pre-intervention malaria estimates. The area under the Relative Operator Characteristic (ROC) curve is calculated as a quantitative metric of forecast skill, comparing the forecast to the meteorologically-driven synthetic malaria time series. The forecast shows probabilistic skill in predicting the spatial distribution of Plasmodium falciparum incidence when compared to the simulated meteorologically-driven malaria time series, particularly where modelled incidence shows high seasonal and interannual variability such as in Orissa, West Bengal, and Jharkhand (North-east India), and Gujarat, Rajastan, Madhya Pradesh and Maharashtra (North-west India). Focusing on these two regions, the malaria forecast is able to distinguish between years of “high”, “above average” and “low” malaria incidence in the peak malaria transmission seasons, with more than 70% sensitivity and a statistically significant area under the ROC curve. These results are encouraging given that the three month forecast lead time used is well in excess of the target for early warning systems adopted by the World Health Organization. This approach could form the basis of an operational system to identify the probability of regional malaria epidemics, allowing advanced and targeted allocation of resources for combatting malaria in India.

Members of the Anopheles gambiae species complex are primary vectors of human malaria in Africa. It is known that a large haplotype shared between An. gambiae and Anopheles coluzzii by introgression carries point mutations of the voltage-gated sodium channel gene para, including the L1014F kdr mutation associated with insensitivity to pyrethroid insecticides. Carriage of L1014F kdr is also correlated with higher susceptibility to infection with Plasmodium falciparum. However, the genetic mechanism and causative gene(s) underlying the parasite susceptibility phenotype are not known. Mosquitoes from the wild Burkina Faso population were challenged by feeding on natural P. falciparum gametocytes. Oocyst infection phenotypes were determined and were tested for association with SNP genotypes. Candidate genes in the detected locus were prioritized and RNAi-mediated gene silencing was used to functionally test for gene effects on P. falciparum susceptibility. A genetic locus, Pfin6, was identified that influences infection levels of P. falciparum in mosquitoes. The locus segregates as a ~3 Mb haplotype carrying 65 predicted genes including the para gene. The haplotype carrying the kdr allele of para is linked to increased parasite infection prevalence, but many single nucleotide polymorphisms on the haplotype are also equally linked to the infection phenotype. Candidate genes in the haplotype were prioritized and functionally tested. Silencing of para did not influence P. falciparum infection, while silencing of a predicted immune gene, serine protease ClipC9, allowed development of significantly increased parasite numbers. Genetic variation influencing Plasmodium infection in wild Anopheles is linked to a natural ~3 megabase haplotype on chromosome 2L that carries the kdr allele of the para gene. Evidence suggests that para gene function does not directly influence parasite susceptibility, and the association of kdr with infection may be due to tight linkage of kdr with other gene(s) on the haplotype. Further work will be required to determine if ClipC9 influences the outcome of P. falciparum infection in nature, as well as to confirm the absence of a direct influence by para.

The Malaria Policy Advisory Committee to the World Health Organization held its seventh meeting in Geneva, Switzerland from 5 to 7 March 2015. This article provides a summary of the discussions, conclusions and meeting recommendations. Meeting sessions included: an update on the Greater Mekong Subregion elimination strategy; an update on the RTS,S vaccine; G6PD testing to support the safe use of anti-relapse therapy for Plasmodium vivax; update from the Vector Control Advisory Group; newly proposed evidence reviews or consultations on malaria terminology, malaria in pregnancy, and the feasibility of eradication; as well as updates from the World Health Organization Global Malaria Programme regarding their strategy update and policy setting processes. Policy statements, position statements, and guidelines that arise from the Malaria Policy Advisory Committee meeting conclusions and recommendations will be formally issued and disseminated to World Health Organization Member States by the World Health Organization Global Malaria Programme.

The circumsporozoite protein is the most abundant polypeptide expressed by sporozoites, the malaria parasite stage capable of infecting humans. Sporozoite invasion of mosquito salivary glands prior to transmission is likely mediated by a receptor/ligand-like interaction of the parasites with the target tissues, and the amino (NH2)-terminal portion of CSP is involved in this interaction but not the TSR region on the carboxyl (C)-terminus. Peptides based on the NH2-terminal domain could compete with the parasites for the salivary gland receptors and thus inhibit penetration. Peptides based on the NH2-terminus and TSR domains of the CSP from avian or human malaria parasites, Plasmodium gallinaceum and Plasmodium falciparum, respectively, were expressed endogenously in mosquito haemolymph using a transient (Sindbis virus-mediated) or stable (piggyBac-mediated transgenesis) system. Transient endogenous expression of partial NH2-terminus peptide from P. falciparum CSP in P. gallinaceum-infected Aedes aegypti resulted in a reduced number of sporozoites in the salivary glands. When a transgenic approach was used to express a partial CSP NH2-terminal domain from P. gallinaceum the number of sporozoites in the salivary glands did not show a difference when compared to controls. However, a significant difference could be observed when mosquitoes with a lower infection were analysed. The same result could not be observed with mosquitoes endogenously expressing peptides based on the TSR domain from either P. gallinaceum or P. falciparum. These results support the conclusion that CSP partial NH2-terminal domain can be endogenously expressed to promote a competition for the receptor used by sporozoites to invade salivary glands, and they could be used to block this interaction and reduce parasite transmission. The same effect cannot be obtained with peptides based on the TSR domain.