Plasmodium Falciparum Malaria Transmission Research Articles

Could less be more? Accounting for fractional-dose regimens and different number of vaccine doses when measuring the impact of the RTS, S/AS01E malaria vaccine.

The RTS, S/AS01E malaria vaccine (RTS, S) is recommended for children in moderate-to-high Plasmodium falciparum malaria transmission areas. This phase 2b trial (NCT03276962) evaluates RTS, S fractional- and full-dose regimens in Ghana and Kenya. 1500 children aged 5-17 months were randomised (1:1:1:1:1) to receive RTS, S or rabies control vaccine. RTS, S groups received two full RTS, S doses at month (M)0/M1 followed by either full (groups R012-20, R012-14-26) or fractional (1/5) doses (groups Fx012-14-26, Fx017-20-32). At M32 post-first dose, vaccine efficacy (VE) against clinical malaria (all episodes) ranged from 38% (R012-20; 95%CI: 24-49) to 53% (R012-14-26; 95%CI: 42-62). Vaccine impact estimates (cumulative number of malaria cases averted/1000 children vaccinated) were 1344 (R012-20), 2450 (R012-14-26), 2273 (Fx012-14-26), 2112 (Fx017-20-32). To account for differences in vaccine volume (fractional- versus full-dose), in a post-hoc analysis, we also estimated cases averted/1000 RTS, S full-dose equivalents: 336 (R012-20), 490 (R012-14-26), 874 (Fx012-14-26), 880 (Fx017-20-32). VE against clinical malaria was similar in all RTS, S groups. Vaccine impact accounting for full-dose equivalence suggests that using fractional-dose regimens could be a viable dose-sparing strategy. If borne out through trial end (M50), these observations underscore the means to reduce cost per regimen with a goal of maximising impact and optimising supply.

Factors affecting haemoglobin dynamics in African children with acute uncomplicated Plasmodium falciparum malaria treated with single low-dose primaquine or placebo

BackgroundSingle low-dose primaquine (SLDPQ) effectively blocks the transmission of Plasmodium falciparum malaria, but anxiety remains regarding its haemolytic potential in patients with glucose-6-phopshate dehydrogenase (G6PD) deficiency. We, therefore, examined the independent effects of several factors on haemoglobin (Hb) dynamics in falciparum-infected children with a particular interest in SLDPQ and G6PD status.MethodsThis randomised, double-blind, placebo-controlled, safety trial was conducted in Congolese and Ugandan children aged 6 months–11 years with acute uncomplicated P. falciparum and day (D) 0 Hbs ≥ 6 g/dL who were treated with age-dosed SLDPQ/placebo and weight-dosed artemether lumefantrine (AL) or dihydroartemisinin piperaquine (DHAPP). Genotyping defined G6PD (G6PD c.202T allele), haemoglobin S (HbS), and α-thalassaemia status.Multivariable linear and logistic regression assessed factor independence for continuous Hb parameters and Hb recovery (D42 Hb > D0 Hb), respectively.ResultsOne thousand one hundred thirty-seven children, whose median age was 5 years, were randomised to receive: AL + SLDPQ (n = 286), AL + placebo (286), DHAPP + SLDPQ (283), and DHAPP + placebo (282). By G6PD status, 284 were G6PD deficient (239 hemizygous males, 45 homozygous females), 119 were heterozygous females, 418 and 299 were normal males and females, respectively, and 17 were of unknown status.The mean D0 Hb was 10.6 (SD 1.6) g/dL and was lower in younger children with longer illnesses, lower mid-upper arm circumferences, splenomegaly, and α-thalassaemia trait, who were either G6PDd or heterozygous females. The initial fractional fall in Hb was greater in younger children with higher D0 Hbs and D0 parasitaemias and longer illnesses but less in sickle cell trait. Older G6PDd children with lower starting Hbs and greater factional falls were more likely to achieve Hb recovery, whilst lower D42 Hb concentrations were associated with younger G6PD normal children with lower fractional falls, sickle cell disease, α-thalassaemia silent carrier and trait, and late treatment failures. Ten blood transfusions were given in the first week (5 SLDPQ, 5 placebo).ConclusionsIn these falciparum-infected African children, posttreatment Hb changes were unaffected by SLDPQ, and G6PDd patients had favourable posttreatment Hb changes and a higher probability of Hb recovery. These reassuring findings support SLDPQ deployment without G6PD screening in Africa.Trial registrationThe trial is registered at ISRCTN 11594437.

Views and Suppositions About Malarial Infections in Cancer Development and Progression

Burkitt lymphoma (BL) is an aggressive non-Hodgkin lymphoma. The prevalence of BL is ten-fold higher in areas with stable transmission of Plasmodium falciparum malaria, where it is the most common childhood cancer, and is referred to as endemic BL (eBL). In addition to its association with exposure to P. falciparum infection, eBL is strongly associated with Epstein-Barr virus (EBV) infection (>90%). This is in contrast to BL as it occurs outside P. falciparum-endemic areas (sporadic BL), where only a minority of the tumors are EBV-positive. Although the striking geographical overlap in the distribution of eBL and P. falciparum was noted shortly after the first detailed description of eBL in 1958, the molecular details of the interaction between malaria and eBL remain unresolved. It is furthermore unexplained why exposure to P. falciparum appears to be essentially a prerequisite to the development of eBL, whereas other types of malaria parasites that infect humans have no impact. 1 Researchers have found that the damage to DNA caused by malaria parasite in cells increases the risk of those cells turning into cancerous cells. Burkitt's lymphoma – a B cell cancer – has previously been epidemiologically linked with malaria endemic areas. Burkitt lymphoma (BL) was first described by Denis Burkitt in the 1950s. While working in Uganda, he observed numerous children with large jaw tumors (usually observed in endemic BL), subsequently noting that the geographical distribution of these tumors tended to correspond to that of malaria. BL has been associated with Epstein-Barr virus (EBV) infection; however, given that EBV is found ubiquitously, EBV infection alone does not explain the burden of BL in Africa but rather, is hypothesized to act as a co-factor for BL along with malaria infection. 2 In our article we try to find the correlation between plasmodium falciparum infection and rising rate of endemic Burkitt lymphoma in African countries from the point of view of karyogamic theory. On the basis of experimental data and information in the literature, one possible basis for the initial tumor cell is a hybrid originated by means of the fusion of two normal somatic cells, there can be created perforations of the plasma membrane. Pores of some definite sizes can lead to the fusion of cells. In the first stage of carcinogenesis(initiation), as a result of a fusion of nuclei, a so-called precancerous sinkaryons with a tetraploid set of chromosomes may be created. Such types of cells can exist in the tissue for a long time. At the stage of promotion they can be transformed into full tumor cells under any perfect carcinogens or promoters. 3

Cost of introducing and delivering malaria vaccine (RTS,S/AS01E) in areas of seasonal malaria transmission, Mali and Burkina Faso

BackgroundThe WHO recommends use of the RTS,S/AS01E (RTS,S) malaria vaccine for young children living in areas of moderate to high Plasmodium falciparum malaria transmission and suggests countries consider seasonal vaccination...

Seasonal targeting of the RTS,S/AS01 malaria vaccine: a complementary tool but sustained funding is required

In October 2021, WHO recommended the RTS,S/AS01 (RTS,S) malaria vaccine for widespread use for children living in regions with moderate to high Plasmodium falciparum malaria transmission.1 The recommendation received a positive reception worldwide as, despite being both preventable and treatable, malaria continues to affect the poorest nations, hampering population health, economic growth, and social wellbeing. The vaccine itself is not a silver bullet for malaria burden, offering only a 30% reduction in severe malaria disease when implemented in routine settings.

Ethical considerations for introducing RTS,S/AS01 in countries with moderate to high Plasmodium falciparum malaria transmission

On Oct 6, 2021, WHO recommended the widespread use of the RTS,S/ASO1 malaria vaccine (Mosquirix; GlaxoSmithKline, Brentford, UK) among children in areas with moderate to high Plasmodium falciparum malaria transmission.1 This recommendation was made despite RTS,S showing only a 30% reduction in preventing deadly severe malaria, falling short of the WHO effectiveness threshold of 75%, and in light of promising vaccines—such as the R21/Matrix-M—under clinical development.2–4

Pyronaridine–artesunate or dihydroartemisinin–piperaquine combined with single low-dose primaquine to prevent Plasmodium falciparum malaria transmission in Ouélessébougou, Mali: a four-arm, single-blind, phase 2/3, randomised trial

SummaryBackgroundPyronaridine–artesunate is the most recently licensed artemisinin-based combination therapy. WHO has recommended that a single low dose of primaquine could be added to artemisinin-based combination therapies to reduce Plasmodium falciparum transmission in areas aiming for elimination of malaria or areas facing artemisinin resistance. We aimed to determine the efficacy of pyronaridine–artesunate and dihydroartemisinin–piperaquine with and without single low-dose primaquine for reducing gametocyte density and transmission to mosquitoes.MethodsWe conducted a four-arm, single-blind, phase 2/3, randomised trial at the Ouélessébougou Clinical Research Unit of the Malaria Research and Training Centre of the University of Bamako (Bamako, Mali). Participants were aged 5–50 years, with asymptomatic P falciparum malaria mono-infection and gametocyte carriage on microscopy, haemoglobin density of 9·5 g/dL or higher, bodyweight less than 80 kg, and no use of antimalarial drugs over the past week. Participants were randomly assigned (1:1:1:1) to one of four treatment groups: pyronaridine–artesunate, pyronaridine–artesunate plus primaquine, dihydroartemisinin–piperaquine, or dihydroartemisinin–piperaquine plus primaquine. Treatment allocation was concealed to all study staff other than the trial pharmacist and treating physician. Dihydroartemisinin–piperaquine and pyronaridine–artesunate were administered as per manufacturer guidelines over 3 days; primaquine was administered as a single dose in oral solution according to bodyweight (0·25 mg/kg; in 1 kg bands). The primary endpoint was percentage reduction in mosquito infection rate (percentage of mosquitoes surviving to dissection that were infected with P falciparum) at 48 h after treatment compared with baseline (before treatment) in all treatment groups. Data were analysed per protocol. This trial is now complete, and is registered with ClinicalTrials.gov, NCT04049916.FindingsBetween Sept 10 and Nov 19, 2019, 1044 patients were assessed for eligibility and 100 were enrolled and randomly assigned to one of the four treatment groups (n=25 per group). Before treatment, 66 (66%) of 100 participants were infectious to mosquitoes, with a median of 15·8% (IQR 5·4–31·9) of mosquitoes becoming infected. In individuals who were infectious before treatment, the median percentage reduction in mosquito infection rate 48 h after treatment was 100·0% (IQR 100·0 to 100·0) for individuals treated with pyronaridine–artesunate plus primaquine (n=18; p<0·0001) and dihydroartemisinin–piperaquine plus primaquine (n=15; p=0·0001), compared with −8·7% (−54·8 to 93·2) with pyronaridine–artesunate (n=17; p=0·88) and 50·4% (13·8 to 70·9) with dihydroartemisinin–piperaquine (n=16; p=0·13). There were no serious adverse events, and there were no significant differences between treatment groups at any point in the frequency of any adverse events (Fisher's exact test p=0·96) or adverse events related to study drugs (p=0·64). The most common adverse events were headaches (40 events in 32 [32%] of 100 participants), rhinitis (31 events in 30 [30%]), and respiratory infection (20 events in 20 [20%]).InterpretationThese data support the use of single low-dose primaquine as an effective supplement to dihydroartemisinin–piperaquine and pyronaridine–artesunate for blocking P falciparum transmission. The new pyronaridine–artesunate plus single low-dose primaquine combination is of immediate relevance to regions in which the containment of partial artemisinin and partner-drug resistance is a growing concern and in regions aiming to eliminate malaria.FundingThe Bill & Melinda Gates Foundation.TranslationsFor the French, Spanish and Swahilil translations of the abstract see Supplementary Materials section.

Safety monitoring experience of single-low dose primaquine co-administered with artemether\u2013lumefantrine among providers and patients in routine healthcare practice: a qualitative study in Eastern Tanzania

BackgroundPrimaquine is a gametocytocidal drug recommended by the World Health Organization (WHO) in a single-low dose combined with artemisinin-based combination therapy (ACT) for the treatment and prevention of Plasmodium falciparum malaria transmission. Safety monitoring concerns and the lack of a universal validated and approved primaquine pharmacovigilance tool is a challenge for a national rollout in many countries. This study aimed to explore the acceptance, reliability and perceived effectiveness of the primaquine roll out monitoring pharmacovigilance tool (PROMPT).MethodsThis study was conducted in three dispensaries in the Coastal region of Eastern Tanzania. The study held six in-depth interviews with healthcare providers and six participatory focus group discussions with malaria patients (3) and parents/guardians of sick children (3). Participants were purposively sampled. Thematic analysis was conducted with the aid of NVivo qualitative analysis software.ResultsThe respondents’ general acceptance and perceived effectiveness of the single-low dose primaquine and PROMPT was good. Screening procedure for treatment eligibility and explaining to patients about the possible adverse events was considered very useful for safety reasons. Crushing and dissolving of primaquine tablet to get the appropriate dose, particularly in children, was reported by all providers to be challenging. Transport costs and poor access to the health facility were the main reasons for a patient failing to return to the clinic for a scheduled follow-up visit. Treatment was perceived to be safe by both providers and patients and reported no case of a severe adverse event. Some providers were concerned with the haemoglobin drop observed on day 7.ConclusionSingle-low dose primaquine was perceived to be safe and acceptable among providers and patients. PROMPT demonstrated to be a reliable and user-friendly tool among providers. Further validation of the tool by involving the National Malaria Control Programme is pivotal to addressing key challenges and facilitating primaquine adoption in the national policy.

The association between gold mining and malaria in Guyana: a statistical inference and time-series analysis

SummaryBackgroundGuyana reported a significant rise in malaria between 2008 and 2014. As there was no evidence of impairment of national malaria control strategies, public health authorities attributed the surge to a temporal increase in gold mining activity in forested regions. However, systematic analysis of this association is lacking because of the difficulties associated with collecting reliable data for both malaria and mining. We aimed to investigate the association between the international gold price and Plasmodium falciparum malaria transmission in Guyana between 2007 and 2019. We also aimed to evaluate the association between P falciparum cases and the El Niño-Southern Oscillation pattern, which has previously been suggested as a major driver of malaria.MethodsWe used national malaria surveillance data from Guyana to estimate the correlation over time between the international gold price and reported P falciparum infections in individuals who were likely to be involved in mining activities (ie, men and boys aged between 15 and 50 years who were living in mining regions) for each month between 2007 and 2019. We compared the estimates with those obtained from individuals who were unlikely to be directly involved in mining activities (ie, women, children aged 12 years and younger, and adults aged over 70 years) and estimates obtained from individuals living in non-mining regions. We also evaluated the correlation between P falciparum infections and the El Niño-Southern Oscillation pattern in the same subpopulations and time period. Lastly, we evaluated the performance of a statistical model formulated to estimate P falciparum infections in real time using the international gold price as the predictor variable.FindingsThe proportion of P falciparum malaria cases in temporary residents, which was used as a proxy for circulating individuals involved in gold mining, was highest during the years of peak gold price (ie, between 2008 and 2014). Cases of malaria in all demographic groups showed a strong positive correlation with the gold price, but only in regions with mining camps (0·88 [95% CI 0·84–0·89] for boys and men aged between 15 and 50 years and 0·80 [0·73–0·85] for the aggregated population of women, children aged 12 years and younger, and adults older than 70 years). The highest correlation occurred earlier in men and boys aged between 15 and 50 years, the demographic most likely to be miners, suggesting that transmission in mining camps is followed by infections in the community. On the basis of these findings, we were able to reliably forecast P falciparum malaria trends using only the gold price as the predictor variable. A 1% increase in gold price was associated with a 2·13% increase in P falciparum infections after 1 month in the mining populations, and with a 1·63% increase after 2 months in the non-mining populations. Lastly, La Niña climatic events showed an additional, smaller positive correlation with malaria transmission.InterpretationOur analysis provides evidence that the P falciparum malaria surge observed in Guyana between 2008 and 2014 was likely to have been driven mainly by an increase in gold mining, while climate factors might have contributed synergistically. We propose that the international gold price over time is a useful indicator of malaria trends. We conclude that the feasibility of malaria elimination in Guyana, and in other areas in the Amazon where malaria and gold mining overlap, should be evaluated against the challenges posed by rapidly rising gold prices.FundingRamón Areces Foundation, National Institutes of Health, and National Institute of General Medical Sciences.

Investment case for malaria elimination in South Africa: a financing model for resource mobilization to accelerate regional malaria elimination

BackgroundMalaria continues to be a public health problem in South Africa. While the disease is mainly confined to three of the nine provinces, most local transmissions occur because of importation of cases from neighbouring countries. The government of South Africa has reiterated its commitment to eliminate malaria within its borders. To support the achievement of this goal, this study presents a cost–benefit analysis of malaria elimination in South Africa through simulating different scenarios aimed at achieving malaria elimination within a 10-year period.MethodsA dynamic mathematical transmission model was developed to estimate the costs and benefits of malaria elimination in South Africa between 2018 and 2030. The model simulated a range of malaria interventions and estimated their impact on the transmission of Plasmodium falciparum malaria between 2018 and 2030 in the three endemic provinces of Limpopo, Mpumalanga and KwaZulu-Natal. Local financial, economic, and epidemiological data were used to calibrate the transmission model.ResultsBased on the three primary simulated scenarios: Business as Usual, Accelerate and Source Reduction, the total economic burden was estimated as follows: for the Business as Usual scenario, the total economic burden of malaria in South Africa was R 3.69 billion (USD 223.3 million) over an 11-year period (2018–2029). The economic burden of malaria was estimated at R4.88 billion (USD 295.5 million) and R6.34 billion (~ USD 384 million) for the Accelerate and Source Reduction scenarios, respectively. Costs and benefits are presented in midyear 2020 values. Malaria elimination was predicted to occur in all three provinces if the Source Reduction strategy was adopted to help reduce malaria rates in southern Mozambique. This could be achieved by limiting annual local incidence in South Africa to less than 1 indigenous case with a prediction of this goal being achieved by the year 2026.ConclusionsMalaria elimination in South Africa is feasible and economically worthwhile with a guaranteed positive return on investment (ROI). Findings of this study show that through securing funding for the proposed malaria interventions in the endemic areas of South Africa and neighbouring Mozambique, national elimination could be within reach in an 8-year period.

CRISPR/Cas9-engineered inducible gametocyte producer lines as a valuable tool for Plasmodium falciparum malaria transmission research

The malaria parasite Plasmodium falciparum replicates inside erythrocytes in the blood of infected humans. During each replication cycle, a small proportion of parasites commits to sexual development and differentiates into gametocytes, which are essential for parasite transmission via the mosquito vector. Detailed molecular investigation of gametocyte biology and transmission has been hampered by difficulties in generating large numbers of these highly specialised cells. Here, we engineer P. falciparum NF54 inducible gametocyte producer (iGP) lines for the routine mass production of synchronous gametocytes via conditional overexpression of the sexual commitment factor GDV1. NF54/iGP lines consistently achieve sexual commitment rates of 75% and produce viable gametocytes that are transmissible by mosquitoes. We also demonstrate that further genetic engineering of NF54/iGP parasites is a valuable tool for the targeted exploration of gametocyte biology. In summary, we believe the iGP approach developed here will greatly expedite basic and applied malaria transmission stage research.

Estimating the risk of declining funding for malaria in Ghana: the case for continued investment in the malaria response

BackgroundGhana has made impressive progress against malaria, decreasing mortality and morbidity by over 50% between 2005 and 2015. These gains have been facilitated in part, due to increased financial commitment from government and donors. Total resources for malaria increased from less than USD 25 million in 2006 to over USD 100 million in 2011. However, the country still faces a high burden of disease and is at risk of declining external financing due to its strong economic growth and the consequential donor requirements for increased government contributions. The resulting financial gap will need to be met domestically. The purpose of this study was to provide economic evidence of the potential risks of withdrawing financing to shape an advocacy strategy for resource mobilization.MethodsA compartmental transmission model was developed to estimate the impact of a range of malaria interventions on the transmission of Plasmodium falciparum malaria between 2018 and 2030. The model projected scenarios of common interventions that allowed the attainment of elimination and those that predicted transmission if interventions were withheld. The outputs of this model were used to generate costs and economic benefits of each option.ResultsElimination was predicted using the package of interventions outlined in the national strategy, particularly increased net usage and improved case management. Malaria elimination in Ghana is predicted to cost USD 961 million between 2020 and 2029. Compared to the baseline, elimination is estimated to prevent 85.5 million cases, save 4468 lives, and avert USD 2.2 billion in health system expenditures. The economic gain was estimated at USD 32 billion in reduced health system expenditure, increased household prosperity and productivity gains. Through malaria elimination, Ghana can expect to see a 32-fold return on their investment. Reducing interventions, predicted an additional 38.2 clinical cases, 2500 deaths and additional economic losses of USD 14.1 billion.ConclusionsMalaria elimination provides robust epidemiological and economic benefits, however, sustained financing is need to accelerate the gains in Ghana. Although government financing has increased in the past decade, the amount is less than 25% of the total malaria financing. The evidence generated by this study can be used to develop a robust domestic strategy to overcome the financial barriers to achieving malaria elimination in Ghana.

Endemic Burkitt lymphoma - an aggressive childhood cancer linked to Plasmodium falciparum exposure, but not to exposure to other malaria parasites.

Burkitt lymphoma (BL) is an aggressive non-Hodgkin lymphoma. The prevalence of BL is ten-fold higher in areas with stable transmission of Plasmodium falciparum malaria, where it is the most common childhood cancer, and is referred to as endemic BL (eBL). In addition to its association with exposure to P.falciparum infection, eBL is strongly associated with Epstein-Barr virus (EBV) infection (>90%). This is in contrast to BL as it occurs outside P.falciparum-endemic areas (sporadic BL), where only a minority of the tumours are EBV-positive. Although the striking geographical overlap in the distribution of eBL and P.falciparum was noted shortly after the first detailed description of eBL in 1958, the molecular details of the interaction between malaria and eBL remain unresolved. It is furthermore unexplained why exposure to P.falciparum appears to be essentially a prerequisite to the development of eBL, whereas other types of malaria parasites that infect humans have no impact. In this brief review, we summarize how malaria exposure may precipitate the malignant transformation of a B-cell clone that leads to eBL, and propose an explanation for why P.falciparum uniquely has this capacity.

Optimal timing of primaquine to reduce Plasmodium falciparum gametocyte carriage when co-administered with artemether\u2013lumefantrine

BackgroundPrimaquine is an important gametocytocidal drug that is combined with conventional malaria treatment for prevention of Plasmodium falciparum malaria transmission. Primaquine has been administered together on the first or the last day of conventional treatment but the impact of primaquine timing has never been examined. This study aimed to assess safety, efficacy and optimal timing of single full-dose (0.75 mg/kg) primaquine when added to a standard 6-dose regimen of artemether–lumefantrine (AL).MethodsIn an individual-level randomized controlled trial, enrolled participants who were G6PD normal and had uncomplicated P. falciparum malaria were randomly assigned to receive: AL only; AL and a single 0.75 mg/kg primaquine dose on the first day of AL (day 1); or AL and single 0.75 mg//kg primaquine on the last day of AL (day 3). On days 2, 3, 4, 8, 11 and 15, gametocytes were assessed and quantified by microscope and quantitative nuclear acid sequence based quantification (QT-NASBA).ResultsOverall, 111 participants aged between 3 and 17 years were randomly allocated to receive AL only (36) or combined with primaquine on day 1 (38), or primaquine on day 3 (37). Day 4 gametocyte prevalence in AL + day 1 primaquine was half the level seen in either AL + day 3 primaquine or AL only arm (11% [4/35] vs 26% [8/31] and 27% [8/30], respectively) albeit not statistically significant. A similar trend of lower gametocyte in the AL + day 1 primaquine verses AL + day 3 primaquine or AL only arm was observed in mean gametocyte density. Mean (sd) haemoglobin level in AL + day 3 primaquine arm recovered from -0.42(1.2) g/dl on day 2 to 0.35 (1.5) g/dl on day 15 of follow up. This was not the case in AL only and AL + day 1 primaquine arms during the same follow-up period, although the difference was not statistically significant (p = 318). No serious adverse events reported in the study. Across arms, 23% (26/111) of participants reported a total of 31 mild adverse events and the difference was not statistically significant (p = 0.477).ConclusionPrimaquine administration on the first day of AL is well tolerated and as safe as later administration. Whilst the World Health Organization currently recommends a lower dose of primaquine (0.25 mg/kg), the findings are supportive of early primaquine administration when combined with artemisinin-combination therapy.ClinicalTrials.gov Registration NCT01906788

Malaria risk map for India based on climate, ecology and geographical modelling.

Mapping the malaria risk at various geographical levels is often undertaken considering climate suitability, infection rate and/or malaria vector distribution, while the ecological factors related to topography and vegetation cover are generally neglected. The present study abides a holistic approach to risk mapping by including topographic, climatic and vegetation components into the framework of malaria risk modelling. This work attempts to delineate the areas of Plasmodium falciparum and Plasmodium vivax malaria transmission risk in India using seven geo-ecological indicators: temperature, relative humidity, rainfall, forest cover, soil, slope, altitude and the normalized difference vegetation index using multi-criteria decision analysis based on geographical information system (GIS). The weight of the risk indicators was assigned by an analytical hierarchical process with the climate suitability (temperature and humidity) data generated using fuzzy logic. Model validation was done through both primary and secondary datasets. The spatio-ecological model was based on GIS to classify the country into five zones characterized by various levels of malaria transmission risk (very high; high; moderate; low; and very low. The study found that about 13% of the country is under very high malaria risk, which includes the malaria- endemic districts of the states of Chhattisgarh, Odisha, Jharkhand, Tripura, Assam, Meghalaya and Manipur. The study also showed that the transmission risk suitability for P. vivax is higher than that for P. falciparum in the Himalayan region. The field study corroborates the identified malaria risk zones and highlights that the low to moderate risk zones are outbreak-prone. It is expected that this information will help the National Vector Borne Disease Control Programme in India to undertake improved surveillance and conduct target based interventions.

Shift in Potential Malaria Transmission Areas in India, Using the Fuzzy-Based Climate Suitability Malaria Transmission (FCSMT) Model under Changing Climatic Conditions.

The future implications of climate change on malaria transmission at the global level have already been reported, however such evidences are scarce and limited in India. Here our study aims to assess, identify and map the potential effects of climate change on Plasmodium vivax (Pv) and Plasmodium falciparum (Pf) malaria transmission in India. A Fuzzy-based Climate Suitability Malaria Transmission (FCSMT) model under the GIS environment was generated using Temperature and Relative Humidity data, extracted from CORDEX South Asia for Baseline (1976–2005) and RCP 4.5 scenario for future projection by the 2030s (2021–2040). National malaria data were used at the model analysis stage. Model outcomes suggest that climate change may significantly increase the spatial spread of Pv and Pf malaria with a numerical increase in the transmission window’s (TW) months, and a shift in the months of transmission. Some areas of the western Himalayan states are likely to have new foci of Pv malaria transmission. Interior parts of some southern and eastern states are likely to become more suitable for Pf malaria transmission. Study has also identified the regions with a reduction in transmission months by the 2030s, leading to unstable malaria, and having the potential for malaria outbreaks.

Impact of seasonal variations in Plasmodium falciparum malaria transmission on the surveillance of pfhrp2 gene deletions

Ten countries have reported pfhrp2/pfhrp3 gene deletions since the first observation of pfhrp2-deleted parasites in 2012. In a previous study (Watson et al., 2017), we characterised the drivers selecting for pfhrp2/3 deletions and mapped the regions in Africa with the greatest selection pressure. In February 2018, the World Health Organization issued guidance on investigating suspected false-negative rapid diagnostic tests (RDTs) due to pfhrp2/3 deletions. However, no guidance is provided regarding the timing of investigations. Failure to consider seasonal variation could cause premature decisions to switch to alternative RDTs. In response, we have extended our methods and predict that the prevalence of false-negative RDTs due to pfhrp2/3 deletions is highest when sampling from younger individuals during the beginning of the rainy season. We conclude by producing a map of the regions impacted by seasonal fluctuations in pfhrp2/3 deletions and a database identifying optimum sampling intervals to support malaria control programmes.

Genetic Evidence of Focal Plasmodium falciparum Transmission in a Pre-elimination Setting in Southern Province, Zambia.

Southern Province, Zambia has experienced a dramatic decline in Plasmodium falciparum malaria transmission in the past decade and is targeted for elimination. Zambia's National Malaria Elimination Program recommends reactive case detection (RCD) within 140 m of index households to enhance surveillance and eliminate remaining transmission foci. To evaluate whether RCD captures local transmission, we genotyped 26 microsatellites from 106 samples collected from index (n = 27) and secondary (n = 79) cases detected through RCD in the Macha Hospital catchment area between January 2015 and April 2016. Participants from the same RCD event harbored more genetically related parasites than those from different RCD events, suggesting that RCD captures, at least in part, infections related through local transmission. Related parasites clustered in space and time, up to at least 250 m from index households. Spatial analysis identified a putative focal transmission hotspot. The current RCD strategy detects focal transmission events, although programmatic guidelines to screen within 140 m of index households may fail to capture all secondary cases. This study highlights the utility of parasite genetic data in assessing programmatic interventions, and similar approaches may be useful to malaria elimination programs seeking to tailor intervention strategies to the underlying transmission epidemiology.

Efficacy of Olyset Duo, a bednet containing pyriproxyfen and permethrin, versus a permethrin-only net against clinical malaria in an area with highly pyrethroid-resistant vectors in rural Burkina Faso: a cluster-randomised controlled trial

Substantial reductions in malaria incidence in sub-Saharan Africa have been achieved with massive deployment of long-lasting insecticidal nets (LLINs), but pyrethroid resistance threatens control. Burkina Faso is an area with intense malaria transmission and highly pyrethroid-resistant vectors. We assessed the effectiveness of bednets containing permethrin, a pyrethroid, and pyriproxyfen, an insect growth regulator, versus permethrin-only (standard) LLINs against clinical malaria in children younger than 5 years in Banfora, Burkina Faso. In this two-group, step-wedge, cluster-randomised, controlled, superiority trial, standard LLINs were incrementally replaced with LLINs treated with permethrin plus pyriproxyfen (PPF) in 40 rural clusters in Burkina Faso. In each cluster, 50 children (aged 6 months to 5 years) were followed up by passive case detection for clinical malaria. Cross-sectional surveys were done at the start and the end of the transmission seasons in 2014 and 2015. We did monthly collections from indoor light traps to estimate vector densities. Primary endpoints were the incidence of clinical malaria, measured by passive case detection, and the entomological inoculation rate. Analyses were adjusted for clustering and for month and health centre. This trial is registered as ISRCTN21853394. 1980 children were enrolled in the cohort in 2014 and 2157 in 2015. At the end of the study, more than 99% of children slept under a bednet. The incidence of clinical malaria was 2·0 episodes per child-year in the standard LLIN group and 1·5 episodes per child-year in the PPF-treated LLIN group (incidence rate ratio 0·88 [95% CI 0·77-0·99; p=0·04]). The entomological inoculation rate was 85 (95% CI 63-108) infective bites per transmission season in the standard LLIN group versus 42 (32-52) infective bites per transmission season in the PPF-treated LLIN group (rate ratio 0·49, 95% CI 0·32-0·66; p<0·0001). PPF-treated LLINs provide greater protection against clinical malaria than do standard LLINs and could be used as an alternative to standard LLINs in areas with intense transmission of Plasmodium falciparum malaria and highly pyrethroid-resistant vectors. EU Seventh Framework Programme.

Machine learning prioritizes synthesis of primaquine ureidoamides with high antimalarial activity and attenuated cytotoxicity

Primaquine (PQ) is a commonly used drug that can prevent the transmission of Plasmodium falciparum malaria, however toxicity limits its use. We prepared five groups of PQ derivatives: amides 1a-k, ureas 2a-k, semicarbazides 3a,b, acylsemicarbazides 4a-k and bis-ureas 5a-v, and evaluated them for antimalarial activity in vitro against the erythrocytic stage of P. falciparum NF54. Particular substituents, such as trityl (in 2j and 5r) and methoxybenzhydryl (in 3b and 5v) were associated with a favorable cytotoxicity-to-activity ratio. To systematically link structural features of PQ derivatives to antiplasmodial activity, we performed a quantitative structure-activity relationship (QSAR) study using the Support Vector Machines machine learning method. This yielded a highly accurate statistical model (R2 = 0.776 in cross-validation), which was used to prioritize novel candidate compounds. Seven novel PQ-ureidoamides 10a-g were synthesized and evaluated for activity, highlighting the benzhydryl ureidoamides 10e and 10f derived from p-chlorophenylglycine. Further experiments on human cell lines revealed that 10e and 10f are an order of magnitude less toxic than PQ in vitro while having antimalarial activity indistinguishable from PQ. The toxicity profile of novel compounds 10 toward human cells was particularly favorable when the glucose-6-phosphate dehydrogenase (G6PD) was inhibited, while toxicity of PQ was exacerbated by G6PD inhibition. Our work therefore highlights promising lead compounds for the development of effective antimalarial drugs that may also be safer for G6PD-deficient patients. In addition, we provide computational inferences of antimalarial activity and cytotoxicity for thousands of PQ-like molecular structures.