Impact of malaria control interventions on malaria infection and anaemia in areas with irrigated schemes: a cross-sectional population-based study in Sudan

Background While the overall burden of malaria is still high, the global technical strategy for malaria advocates for two sets of interventions: vector control-based prevention and diagnosis and prompt effective treatment of malaria cases. This study aimed to assess the performance of malaria interventions on malaria infection and anaemia in irrigated areas in Sudan. Methods Based on the Sudan 2016 national malaria indicator survey, data for two states (Gezira and Sennar), characterized by large-irrigated schemes, were analysed. Four community-level malaria interventions were used as contextual variables: utilization of malaria diagnosis, utilization of Artemisinin-based combination therapy (ACT), utilization of long-lasting insecticidal nets (LLINs) and coverage with indoor residual spraying (IRS). Association between these interventions and two outcomes: malaria infection and anaemia, was assessed separately. Malaria infection was assessed in all age groups while anaemia was assessed in children under 5 years. Multilevel multiple logistic regression analysis were conducted. Results Among 4478 individuals involved in this study distributed over 47 clusters, the overall malaria infection rate was 3.0% and 56.5% of the children under 5 years (total = 322) were anaemic. Except for IRS coverage (69.6%), the average utilization of interventions was relatively low: 52.3% for utilization of diagnosis, 33.0% for utilization of ACTs and 18.6% for LLINs utilization. The multi-level multiple logistic regression model showed that only IRS coverage was associated with malaria infection (Odds ratio 0.83 per 10% coverage, 95%Confidence Interval (95%CI) 0.74–0.94, p = 0.003) indicating that a higher level of IRS coverage was associated with less malaria infection. Anaemia was not associated with any intervention (all p values larger than 0.1). Conclusions Malaria transmission in Gezira and Sennar areas is low. IRS, with insecticide to which vectors are susceptible, is an effective malaria control intervention in irrigated schemes. Community utilization of other interventions was not associated with malaria infection in this study. This may be due to the low utilization of these interventions. However, individual use of LLINs provide personal protection. This study failed to establish an association between anaemia and malaria control interventions in low transmission areas. The higher level of malaria infection in urban areas is a cause for concern.

Analysis of the potential for a malaria vaccine to reduce gaps in malaria intervention coverage

Background The RTS,S/AS01 malaria vaccine is currently being evaluated in a cluster-randomized pilot implementation programme in three African countries. This study seeks to identify whether vaccination could reach additional children who are at risk from malaria but do not currently have access to, or use, core malaria interventions. Methods Using data from household surveys, the overlap between malaria intervention coverage and childhood vaccination (diphtheria-tetanus-pertussis dose 3, DTP3) uptake in 20 African countries with at least one first administrative level unit with Plasmodium falciparum parasite prevalence greater than 10% was calculated. Multilevel logistic regression was used to explore patterns of overlap by demographic and socioeconomic variables. The public health impact of delivering RTS,S/AS01 to those children who do not use an insecticide-treated net (ITN), but who received the DTP3 vaccine, was also estimated. Results Uptake of DTP3 was higher than malaria intervention coverage in most countries. Overall, 34% of children did not use ITNs and received DTP3, while 35% of children used ITNs and received DTP3, although this breakdown varied by country. It was estimated that there are 33 million children in these 20 countries who do not use an ITN. Of these, 23 million (70%) received the DTP3 vaccine. Vaccinating those 23 million children who receive DTP3 but do not use an ITN could avert up to an estimated 9.7 million (range 8.5–10.8 million) clinical malaria cases each year, assuming all children who receive DTP3 are administered all four RTS,S doses. An additional 10.8 million (9.5–12.0 million) cases could be averted by vaccinating those 24 million children who receive the DTP3 vaccine and use an ITN. Children who had access to or used an ITN were 9–13% more likely to reside in rural areas compared to those who had neither intervention regardless of vaccination status. Mothers’ education status was a strong predictor of intervention uptake and was positively associated with use of ITNs and vaccination uptake and negatively associated with having access to an ITN but not using it. Wealth was also a strong predictor of intervention coverage. Conclusions Childhood vaccination to prevent malaria has the potential to reduce inequity in access to existing malaria interventions and could substantially reduce the childhood malaria burden in sub-Saharan Africa, even in regions with lower existing DTP3 coverage.

Estimating intervention effectiveness in trials of malaria interventions with contamination

Background In cluster randomized trials (CRTs) or stepped wedge cluster randomized trials (SWCRTs) of malaria interventions, mosquito movement leads to contamination between trial arms unless buffer zones separate the clusters. Contamination can be accounted for in the analysis, yielding an estimate of the contamination range, the distance over which contamination measurably biases the effectiveness. Methods A previously described analysis for CRTs is extended to SWCRTs and estimates of effectiveness are provided as a function of intervention coverage. The methods are applied to two SWCRTs of malaria interventions, the SolarMal trial on the impact of mass trapping of mosquitoes with odor-baited traps and the AvecNet trial on the effect of adding pyriproxyfen to long-lasting insecticidal nets. Results For the SolarMal trial, the contamination range was estimated to be 146 m ($$95\%$$ 95 % credible interval $$[0.052,\,0.923]$$ [ 0.052 , 0.923 ] km), together with a $$31.9\%$$ 31.9 % ($$95\%$$ 95 % credible interval $$[15.3,\,45.8]\%$$ [ 15.3 , 45.8 ] % ) reduction of Plasmodium infection, compared to the $$30.0\%$$ 30.0 % reduction estimated without accounting for contamination. The estimated effectiveness had an approximately linear relationship with coverage. For the AvecNet trial, estimated contamination effects were minimal, with insufficient data from the cluster boundary regions to estimate the effectiveness as a function of coverage. Conclusions The contamination range in these trials of malaria interventions is much less than the distances Anopheles mosquitoes can fly. An appropriate analysis makes buffer zones unnecessary, enabling the design of more cost-efficient trials. Estimation of the contamination range requires information from the cluster boundary regions and trials should be designed to collect this.

A portfolio of geographically distinct laboratory-adapted Plasmodium falciparum clones with consistent infection rates in Anopheles mosquitoes

Background The ability to culture Plasmodium falciparum continuously in vitro has enabled stable access to asexual and sexual parasites for malaria research. The portfolio of isolates has remained limited and research is still largely based on NF54 and its derived clone 3D7. Since 1978, isolates were collected and cryopreserved at Radboudumc from patients presenting at the hospital. Here, procedures are described for culture adaptation of asexual parasites, cloning and production of sexual stage parasites responsible for transmission (gametocytes) and production of oocysts in Anopheles mosquitoes. This study aimed to identify new culture-adapted transmissible P. falciparum isolates, originating from distinct geographical locations. Methods Out of a collection of 121 P. falciparum isolates stored in liquid nitrogen, 21 from different geographical origin were selected for initial testing. Isolates were evaluated for their ability to be asexually cultured in vitro, their gametocyte production capacity, and consistent generation of oocysts. Results Out of 21 isolates tested, twelve were excluded from further analysis due to lack of mature gametocyte production (n = 1) or generation of satisfactory numbers of oocysts in mosquitoes (n = 11). Nine isolates fulfilled selection criteria and were cloned by limiting dilution and retested. After cloning, one isolate was excluded for not showing transmission. The remaining eight isolates transmitted to Anopheles stephensi or Anopheles coluzzii mosquitoes and were categorized into two groups with a reproducible mean oocyst infection intensity above (n = 5) or below five (n = 3). Conclusions These new P. falciparum culture-adapted isolates with reproducible transmission to Anopheles mosquitoes are a valuable addition to the malaria research tool box. They can aid in the development of malaria interventions and will be particularly useful for those studying malaria transmission.

Computational Insights into the Interaction between Cytoadherence Receptor gC1qR and the DBLβ12 Domain of a Plasmodium falciparum PfEMP1 Ligand

Human receptor gC1qR is a 32 kD protein that mediates the cytoadherence of Plasmodium falciparum-infected erythrocytes (IEs) to human brain microvascular endothelial cells (HBMEC) and platelets. The cytoadherence of IEs to gC1qR has been associated with severe malaria symptoms. The cytoadherence to gC1qR is mediated by the Duffy binding-like β12 (DBLβ12) domain of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), PFD0020c. Here, we report the structural insights into the binding of the DBLβ12 domain of PfEMP1 with the human receptor gC1qR using computational methods. A molecular model of the DBLβ12 domain was generated and used for protein–protein docking with the host receptor gC1qR. The protein–protein docking revealed that the DBLβ12 asymmetrically interacts with two subunits of the gC1qR trimer at the solution face of gC1qR. A total of 21 amino acid residues of DBLβ12 interact with 26 amino acid residues in the gC1qR trimer through 99 nonbonding interactions and 4 hydrogen bonds. Comparative analysis of binding sites on the DBL domain fold for the two receptors gC1qR and ICAM1 showed that the two sites are distinct. This is the first study that provides structural insights into DBLβ12 binding with its receptor gC1qR and may help in designing novel antisevere malaria interventions.

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

Background Malaria 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. Methods A 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. Results Based 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. Conclusions Malaria 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.

Maps and metrics of insecticide-treated net access, use, and nets-per-capita in Africa from 2000-2020

Insecticide-treated nets (ITNs) are one of the most widespread and impactful malaria interventions in Africa, yet a spatially-resolved time series of ITN coverage has never been published. Using data from multiple sources, we generate high-resolution maps of ITN access, use, and nets-per-capita annually from 2000 to 2020 across the 40 highest-burden African countries. Our findings support several existing hypotheses: that use is high among those with access, that nets are discarded more quickly than official policy presumes, and that effectively distributing nets grows more difficult as coverage increases. The primary driving factors behind these findings are most likely strong cultural and social messaging around the importance of net use, low physical net durability, and a mixture of inherent commodity distribution challenges and less-than-optimal net allocation policies, respectively. These results can inform both policy decisions and downstream malaria analyses.

A Portfolio of Geographically Distinct Laboratory-adapted Plasmodium Falciparum Clones With Consistent Infection Rates in Anopheles Mosquitoes

BackgroundThe ability to culture P. falciparum continuously in vitro has enabled stable access to asexual and sexual parasites for malaria research. The portfolio of isolates has remained limited and research is still largely based on NF54 and its derived clone 3D7. Since 1978, isolates were collected and cryopreserved at Radboudumc from patients presenting at the hospital. Here, procedures are described for culture adaptation of asexual parasites, cloning and production of sexual stage parasites responsible for transmission (gametocytes) and production of oocysts in Anopheles mosquitoes. This study aimed to identify new culture adapted transmissible P. falciparum isolates, originating from distinct geographical locations.ResultsOut of a collection of 121 P. falciparum isolates stored in liquid nitrogen, 21 from different geographical origin were selected for initial testing. Isolates were evaluated for their ability to be asexually cultured in vitro, their gametocyte production capacity, and consistent generation of oocysts. Out of 21 isolates tested, twelve were excluded from further analysis due to lack of mature gametocyte production (n = 1) or generation of satisfactory numbers of oocysts in mosquitoes (n = 11). Nine isolates fulfilled selection criteria and were cloned by limiting dilution and retested. After cloning, one isolate was excluded for not showing transmission. The remaining eight isolates transmitted to A. stephensi or A. coluzzii mosquitoes and were categorized into two groups with a reproducible mean oocyst infection intensity above (n = 5) or below five (n = 3). ConclusionsThese new P. falciparum culture adapted isolates with reproducible transmission to Anopheles mosquitoes are a valuable addition to the malaria research tool box. They can aid in the development of malaria interventions and will be particularly useful for those studying malaria transmission.

Malaria Elimination in Unguja Island Zanzibar: Individual Risk Factors for Continued Transmission.

Introduction: To achieve malaria elimination, understanding of the individual risk factors for malaria infection is critical to inform strategic planning and implementation. To address this, a community-based individual risk-factor study was conducted in Unguja Island Zanzibar.Methods: A matched case control study with a sample size of 103 cases and 309 controls was conducted in Unguja Island. Malaria cases from health facilities were reported via Unstructured Supplementary Service Data (USSD) mobile phones to a central database, after which an SMS alert was sent to the District Malaria Surveillance Officer’s (DMSO) mobile phone. DMSO followed up index cases up to household level and performed malaria test on all household members using rapid diagnostic tests (mRDT). Family members tested negative were considered as controls. Both cases and controls were interviewed with the same questionnaire. Data were analyzed using Epi-info version 3.5.1 using conditional logistic regression model. Results: The findings revealed that chance of malaria infection was higher among individuals who travelled outside Zanzibar [AOR = 60.47, 95% CI 15.73 - 232.44], who spend their time in outdoor activities during the night [AOR = 8.53, 95% CI 1.96 - 37.11], whose rooms were not sprayed with indoor residual spray (IRS) [AOR= 29.60, 95% CI 2.68 - 326.49] and those who did not have a bed net [AOR=16.25, 95% CI 3.32 - 79.50].Conclusion: Travel outside Zanzibar, outdoors activities during the night, lack of access to malaria interventions (IRS or bed nets) were the risk factors for malaria infection in Unguja. Ministry of Health should set a mechanism of encouraging people who travel to malaria endemic areas to attend the nearby health facility for malaria screening. Sensitizing people on using protective gear during the night and ensuring good coverage of malaria interventions would reduce the risk of malaria in Unguja Zanzibar.