A non-randomized controlled trial to assess the protective effect of SMC in the context of high parasite resistance in Uganda.

BACKGROUND: Until recently, due to widespread prevalence of molecular markers associated with sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) resistance in east and southern Africa, seasonal malaria chemoprevention (SMC) has not been used at scale in this region. This study assessed the protective effectiveness of monthly administration of SP + AQ (SPAQ) to children aged 3-59 months in Karamoja sub-region, Uganda, where parasite resistance is assumed to be high and malaria transmission is seasonal. METHODS: A two-arm quasi-experimental, open-label prospective non-randomized control trial (nRCT) was conducted in three districts. In two intervention districts, 85,000 children aged 3-59 months were targeted to receive monthly courses of SMC using SPAQ during the peak transmission season (May to September) 2021. A third district served as a control, where SMC was not implemented. Communities with comparable malaria attack rates were selected from the three districts, and households with at least one SMC-eligible child were purposively selected. A total cohort of 600 children (200 children per district) were selected and followed using passive surveillance for breakthrough confirmed malaria episodes during the five-month peak transmission season. Malaria incidence rate per person-months and number of malaria episodes among children in the two arms were compared. Kaplan-Meier failure estimates were used to compare the probability of a positive malaria test. Other factors that may influence malaria transmission and infection among children in the two arms were also assessed using multivariable cox proportional hazards regression model. RESULTS: The malaria incidence rate was 3.0 and 38.8 per 100 person-months in the intervention and control groups, respectively. In the intervention areas 90.0% (361/400) of children did not experience any malaria episodes during the study period, compared to 15% (29/200) in the control area. The incidence rate ratio was 0.078 (95% CI 0.063-0.096), which corresponds to a protective effectiveness of 92% (95% CI 90.0-94.0) among children in the intervention area. CONCLUSION: SMC using SPAQ provided high protective effect against malaria during the peak transmission season in children aged 3-59 months in the Karamoja sub-region of Uganda.

Ownership and use of long-lasting insecticidal nets three months after a mass distribution campaign in Uganda, 2021.

BACKGROUND: Uganda conducted its third mass long-lasting insecticidal net (LLIN) distribution campaign in 2021. The target of the campaign was to ensure that 100% of households own at least one LLIN per two persons and to achieve 85% use of distributed LLINs. LLIN ownership, use and associated factors were assessed 3 months after the campaign. METHODS: A cross-sectional household survey was conducted in 14 districts from 13 to 30 April, 2021. Households were selected using multistage sampling. Each was asked about LLIN ownership, use, duration since received to the time of interview, and the presence of LLINs was visually verified. Outcomes were having at least one LLIN per two household members, and individual LLIN use. Modified Poisson regression was used to assess associations between exposures and outcomes. RESULTS: In total, 5529 households with 27,585 residents and 15,426 LLINs were included in the analysis. Overall, 95% of households owned ≥ 1 LLIN, 92% of the households owned ≥ 1 LLIN < 3 months old, 64% of households owned ≥ 1 LLIN per two persons in the household. Eighty-seven per cent could sleep under an LLIN if every LLIN in the household were used by two people, but only 69% slept under an LLIN the night before the survey. Factors associated with LLIN ownership included believing that LLINs are protective against malaria (aPR = 1.13; 95% CI 1.04-1.24). Reported use of mosquito repellents was negatively associated with ownership of LLINs (aPR = 0.96; 95% CI 0.95-0.98). The prevalence of LLIN use was 9% higher among persons who had LLINs 3-12 months old (aPR = 1.09; 95% CI 1.06-1.11) and 10% higher among those who had LLINs 13-24 months old (aPR = 1.10; 95% CI 1.06-1.14) than those who had LLINs < 3 months old. Of 3,859 LLINs identified in the households but not used for sleeping the previous night, 3250 (84%) were < 3 months old. Among these 3250, 41% were not used because owners were using old LLINs; 16% were not used because of lack of space for hanging them; 11% were not used because of fear of chemicals in the net; 5% were not used because of dislike of the smell of the nets; and, 27% were not used for other reasons. CONCLUSION: The substantial difference between the population that had access to LLINs and the population that slept under LLINs indicates that the National Malaria Control Programme (NMCP) may need to focus on addressing the main drivers or barriers to LLIN use. NMCP and/or other stakeholders could consider designing and conducting targeted behaviour change communication during subsequent mass distribution of LLINs after the mass distribution campaign to counter misconceptions about new LLINs.

East Africa International Center of Excellence for Malaria Research: Impact on Malaria Policy in Uganda.

Malaria is the leading cause of disease burden in sub-Saharan Africa. In 2010, the East Africa International Center of Excellence for Malaria Research, also known as the Program for Resistance, Immunology, Surveillance, and Modeling of Malaria (PRISM), was established to provide a comprehensive approach to malaria surveillance in Uganda. We instituted cohort studies and a robust malaria and entomological surveillance network at selected public health facilities that have provided a platform for monitoring trends in malaria morbidity and mortality, tracking the impact of malaria control interventions (indoor residual spraying of insecticide [IRS], use of long-lasting insecticidal nets [LLINs], and case management with artemisinin-based combination therapies [ACTs]), as well as monitoring of antimalarial drug and insecticide resistance. PRISM studies have informed Uganda's malaria treatment policies, guided selection of LLINs for national distribution campaigns, and revealed widespread pyrethroid resistance, which led to changes in insecticides delivered through IRS. Our continuous engagement and interaction with policy makers at the Ugandan Ministry of Health have enabled PRISM to share evidence, best practices, and lessons learned with key malaria stakeholders, participate in malaria control program reviews, and contribute to malaria policy and national guidelines. Here, we present an overview of interactions between PRISM team members and Ugandan policy makers to demonstrate how PRISM's research has influenced malaria policy and control in Uganda.

Incremental cost and cost-effectiveness of the addition of indoor residual spraying with pirimiphos-methyl in sub-Saharan Africa versus standard malaria control: results of data collection and analysis in the Next Generation Indoor Residual Sprays (NgenIRS) project, an economic-evaluation.

BACKGROUND: Malaria is a major cause of morbidity and mortality globally, especially in sub-Saharan Africa. Widespread resistance to pyrethroids threatens the gains achieved by vector control. To counter resistance to pyrethroids, third-generation indoor residual spraying (3GIRS) products have been developed. This study details the results of a multi-country cost and cost-effectiveness analysis of indoor residual spraying (IRS) programmes using Actellic®300CS, a 3GIRS product with pirimiphos-methyl, in sub-Saharan Africa in 2017 added to standard malaria control interventions including insecticide-treated bed nets versus standard malaria control interventions alone. METHODS: An economic evaluation of 3GIRS using Actellic®300CS in a broad range of sub-Saharan African settings was conducted using a variety of primary data collection and evidence synthesis methods. Four IRS programmes in Ghana, Mali, Uganda, and Zambia were included in the effectiveness analysis. Cost data come from six IRS programmes: one in each of the four countries where effect was measured plus Mozambique and a separate programme conducted by AngloGold Ashanti Malaria Control in Ghana. Financial and economic costs were quantified and valued. The main indicator for the cost was cost per person targeted. Country-specific case incidence rate ratios (IRRs), estimated by comparing IRS study districts to adjacent non-IRS study districts or facilities, were used to calculate cases averted in each study area. A deterministic analysis and sensitivity analysis were conducted in each of the four countries for which effectiveness evaluations were available. Probabilistic sensitivity analysis was used to generate plausibility bounds around the incremental cost-effectiveness ratio estimates for adding IRS to other standard interventions in each study setting as well as jointly utilizing data on effect and cost across all settings. RESULTS: Overall, IRRs from each country indicated that adding IRS with Actellic®300CS to the local standard intervention package was protective compared to the standard intervention package alone (IRR 0.67, [95% CI 0.50-0.91]). Results indicate that Actellic®300CS is expected to be a cost-effective (> 60% probability of being cost-effective in all settings) or highly cost-effective intervention across a range of transmission settings in sub-Saharan Africa. DISCUSSION: Variations in the incremental costs and cost-effectiveness likely result from several sources including: variation in the sprayed wall surfaces and house size relative to household population, the underlying malaria burden in the communities sprayed, the effectiveness of 3GIRS in different settings, and insecticide price. Programmes should be aware that current recommendations to rotate can mean variation and uncertainty in budgets; programmes should consider this in their insecticide-resistance management strategies. CONCLUSIONS: The optimal combination of 3GIRS delivery with other malaria control interventions will be highly context specific. 3GIRS using Actellic®300CS is expected to deliver acceptable value for money in a broad range of sub-Saharan African malaria transmission settings.

Malaria outbreak facilitated by engagement in activities near swamps following increased rainfall and limited preventive measures: Oyam District, Uganda.

In April 2019, the District Health Office of Oyam District, Uganda reported an upsurge in malaria cases exceeding expected epidemic thresholds, requiring outbreak response. We investigated the scope of outbreak and identified exposures for transmission to inform control measures. A confirmed case was a positive malaria rapid diagnostic test or malaria microscopy from 1 January-30 June 2019 in a resident or visitor of Acaba Sub-county, Oyam District. We reviewed medical records at health facilities to get case-patients. We conducted entomological and environmental assessments to determine vector density, and identify aquatic Anopheles habitats, conducted a case-control study to determine exposures associated with illness. Of 9,235 case-patients (AR = 33%), females (AR = 38%) were more affected than males (AR = 20%) (p<0.001). Children <18 years were more affected (AR = 37%) than adults (p<0.001). Among 83 case-patients and 83 asymptomatic controls, 65 (78%) case-patients and 33 (40%) controls engaged in activities <500m from a swamp (ORMH = 12, 95%CI 3.6-38); 18 (22%) case-patients and four (5%) controls lived <500m from rice irrigation sites (ORMH = 8.2, 95%CI 1.8-36); and 23 (28%) case-patients and four (5%) controls had water pools <100m from household for 3-5 days after rainfall (ORMH = 7.3, 95%CI 2.2-25). Twenty three (28%) case-patients and four (5%) controls did not sleep under bed nets the previous night (ORMH = 20, 95%CI 2.7-149); 68 (82%) case-patients and 43(52%) controls did not wear long-sleeved clothes during evenings (ORMH = 9.3, 95%CI 2.8-31). Indoor resting vector density was 4.7 female mosquitoes/household/night. All Anopheles aquatic habitats had Anopheles larvae. Weekly rainfall in 2019 was heavier (6.0±7.2mm) than same period in 2018 (1.8±1.8mm) (p = 0.006). This outbreak was facilitated by Anopheles aquatic habitats near homes created by human activities, following increased rainfall compounded by inadequate use of individual preventive measures. We recommended awareness on use of insecticide-treated bed nets, protective clothing, and avoiding creation of Anopheles aquatic habitats.

Resurgence of malaria in Uganda despite sustained indoor residual spraying and repeated long lasting insecticidal net distributions.

Five years of sustained indoor residual spraying (IRS) of insecticide from 2014 to 2019, first using a carbamate followed by an organophosphate, was associated with a marked reduction in the incidence of malaria in five districts of Uganda. We assessed changes in malaria incidence over an additional 21 months, corresponding to a change in IRS formulations using clothianidin with and without deltamethrin. Using enhanced health facility surveillance data, our objectives were to 1) estimate the impact of IRS on monthly malaria case counts at five surveillance sites over a 6.75 year period, and 2) compare monthly case counts at five facilities receiving IRS to ten facilities in neighboring districts not receiving IRS. For both objectives, we specified mixed effects negative binomial regression models with random intercepts for surveillance site adjusting for rainfall, season, care-seeking, and malaria diagnostic. Following the implementation of IRS, cases were 84% lower in years 4-5 (adjusted incidence rate ratio [aIRR] = 0.16, 95% CI 0.12-0.22), 43% lower in year 6 (aIRR = 0.57, 95% CI 0.44-0.74), and 39% higher in the first 9 months of year 7 (aIRR = 1.39, 95% CI 0.97-1.97) compared to pre-IRS levels. Cases were 67% lower in IRS sites than non-IRS sites in year 6 (aIRR = 0.33, 95% CI 0.17-0.63) but 38% higher in the first 9 months of year 7 (aIRR = 1.38, 95% CI 0.90-2.11). We observed a resurgence in malaria to pre-IRS levels despite sustained IRS. The timing of this resurgence corresponded to a change of active ingredient. Further research is needed to determine causality.

Associations between environmental covariates and temporal changes in malaria incidence in high transmission settings of Uganda: a distributed lag nonlinear analysis.

BACKGROUND: Environmental factors such as temperature, rainfall, and vegetation cover play a critical role in malaria transmission. However, quantifying the relationships between environmental factors and measures of disease burden relevant for public health can be complex as effects are often non-linear and subject to temporal lags between when changes in environmental factors lead to changes in malaria incidence. The study investigated the effect of environmental covariates on malaria incidence in high transmission settings of Uganda. METHODS: This study leveraged data from seven malaria reference centres (MRCs) located in high transmission settings of Uganda over a 24-month period. Estimates of monthly malaria incidence (MI) were derived from MRCs' catchment areas. Environmental data including monthly temperature, rainfall, and normalized difference vegetation index (NDVI) were obtained from remote sensing sources. A distributed lag nonlinear model was used to investigate the effect of environmental covariates on malaria incidence. RESULTS: Overall, the median (range) monthly temperature was 30 °C (26-47), rainfall 133.0 mm (3.0-247), NDVI 0.66 (0.24-0.80) and MI was 790 per 1000 person-years (73-3973). Temperature of 35 °C was significantly associated with malaria incidence compared to the median observed temperature (30 °C) at month lag 2 (IRR: 2.00, 95% CI: 1.42-2.83) and the increased cumulative IRR of malaria at month lags 1-4, with the highest cumulative IRR of 8.16 (95% CI: 3.41-20.26) at lag-month 4. Rainfall of 200 mm significantly increased IRR of malaria compared to the median observed rainfall (133 mm) at lag-month 0 (IRR: 1.24, 95% CI: 1.01-1.52) and the increased cumulative IRR of malaria at month lags 1-4, with the highest cumulative IRR of 1.99(95% CI: 1.22-2.27) at lag-month 4. Average NVDI of 0.72 significantly increased the cumulative IRR of malaria compared to the median observed NDVI (0.66) at month lags 2-4, with the highest cumulative IRR of 1.57(95% CI: 1.09-2.25) at lag-month 4. CONCLUSIONS: In high-malaria transmission settings, high values of environmental covariates were associated with increased cumulative IRR of malaria, with IRR peaks at variable lag times. The complex associations identified are valuable for designing strategies for early warning, prevention, and control of seasonal malaria surges and epidemics.

The impact of stopping and starting indoor residual spraying on malaria burden in Uganda.

The scale-up of malaria control efforts has led to marked reductions in malaria burden over the past twenty years, but progress has slowed. Implementation of indoor residual spraying (IRS) of insecticide, a proven vector control intervention, has been limited and difficult to sustain partly because questions remain on its added impact over widely accepted interventions such as bed nets. Using data from 14 enhanced surveillance health facilities in Uganda, a country with high bed net coverage yet high malaria burden, we estimate the impact of starting and stopping IRS on changes in malaria incidence. We show that stopping IRS was associated with a 5-fold increase in malaria incidence within 10 months, but reinstating IRS was associated with an over 5-fold decrease within 8 months. In areas where IRS was initiated and sustained, malaria incidence dropped by 85% after year 4. IRS could play a critical role in achieving global malaria targets, particularly in areas where progress has stalled.

Spatial-temporal patterns of malaria incidence in Uganda using HMIS data from 2015 to 2019.

BACKGROUND: As global progress to reduce malaria transmission continues, it is increasingly important to track changes in malaria incidence rather than prevalence. Risk estimates for Africa have largely underutilized available health management information systems (HMIS) data to monitor trends. This study uses national HMIS data, together with environmental and geographical data, to assess spatial-temporal patterns of malaria incidence at facility catchment level in Uganda, over a recent 5-year period. METHODS: Data reported by 3446 health facilities in Uganda, between July 2015 and September 2019, was analysed. To assess the geographic accessibility of the health facilities network, AccessMod was employed to determine a three-hour cost-distance catchment around each facility. Using confirmed malaria cases and total catchment population by facility, an ecological Bayesian conditional autoregressive spatial-temporal Poisson model was fitted to generate monthly posterior incidence rate estimates, adjusted for caregiver education, rainfall, land surface temperature, night-time light (an indicator of urbanicity), and vegetation index. RESULTS: An estimated 38.8 million (95% Credible Interval [CI]: 37.9-40.9) confirmed cases of malaria occurred over the period, with a national mean monthly incidence rate of 20.4 (95% CI: 19.9-21.5) cases per 1000, ranging from 8.9 (95% CI: 8.7-9.4) to 36.6 (95% CI: 35.7-38.5) across the study period. Strong seasonality was observed, with June-July experiencing highest peaks and February-March the lowest peaks. There was also considerable geographic heterogeneity in incidence, with health facility catchment relative risk during peak transmission months ranging from 0 to 50.5 (95% CI: 49.0-50.8) times higher than national average. Both districts and health facility catchments showed significant positive spatial autocorrelation; health facility catchments had global Moran's I = 0.3 (p < 0.001) and districts Moran's I = 0.4 (p < 0.001). Notably, significant clusters of high-risk health facility catchments were concentrated in Acholi, West Nile, Karamoja, and East Central - Busoga regions. CONCLUSION: Findings showed clear countrywide spatial-temporal patterns with clustering of malaria risk across districts and health facility catchments within high risk regions, which can facilitate targeting of interventions to those areas at highest risk. Moreover, despite high and perennial transmission, seasonality for malaria incidence highlights the potential for optimal and timely implementation of targeted interventions.

Changing malaria fever test positivity among paediatric admissions to Tororo district hospital, Uganda 2012-2019.

BACKGROUND: The World Health Organization (WHO) promotes long-lasting insecticidal nets (LLIN) and indoor residual house-spraying (IRS) for malaria control in endemic countries. However, long-term impact data of vector control interventions is rarely measured empirically. METHODS: Surveillance data was collected from paediatric admissions at Tororo district hospital for the period January 2012 to December 2019, during which LLIN and IRS campaigns were implemented in the district. Malaria test positivity rate (TPR) among febrile admissions aged 1 month to 14 years was aggregated at baseline and three intervention periods (first LLIN campaign; Bendiocarb IRS; and Actellic IRS + second LLIN campaign) and compared using before-and-after analysis. Interrupted time-series analysis (ITSA) was used to determine the effect of IRS (Bendiocarb + Actellic) with the second LLIN campaign on monthly TPR compared to the combined baseline and first LLIN campaign periods controlling for age, rainfall, type of malaria test performed. The mean and median ages were examined between intervention intervals and as trend since January 2012. RESULTS: Among 28,049 febrile admissions between January 2012 and December 2019, TPR decreased from 60% at baseline (January 2012-October 2013) to 31% during the final period of Actellic IRS and LLIN (June 2016-December 2019). Comparing intervention intervals to the baseline TPR (60.3%), TPR was higher during the first LLIN period (67.3%, difference 7.0%; 95% CI 5.2%, 8.8%, p < 0.001), and lower during the Bendiocarb IRS (43.5%, difference - 16.8%; 95% CI - 18.7%, - 14.9%) and Actellic IRS (31.3%, difference - 29.0%; 95% CI - 30.3%, - 27.6%, p < 0.001) periods. ITSA confirmed a significant decrease in the level and trend of TPR during the IRS (Bendicarb + Actellic) with the second LLIN period compared to the pre-IRS (baseline + first LLIN) period. The age of children with positive test results significantly increased with time from a mean of 24 months at baseline to 39 months during the final IRS and LLIN period. CONCLUSION: IRS can have a dramatic impact on hospital paediatric admissions harbouring malaria infection. The sustained expansion of effective vector control leads to an increase in the age of malaria positive febrile paediatric admissions. However, despite large reductions, malaria test-positive admissions continued to be concentrated in children aged under five years. Despite high coverage of IRS and LLIN, these vector control measures failed to interrupt transmission in Tororo district. Using simple, cost-effective hospital surveillance, it is possible to monitor the public health impacts of IRS in combination with LLIN.

Malaria Outbreak Facilitated by Appearance of Vector-Breeding Sites after Heavy Rainfall and Inadequate Preventive Measures: Nwoya District, Northern Uganda, February-May 2018.

Background: Malaria is a leading cause of morbidity and mortality in Uganda. In April 2018, malaria cases surged in Nwoya District, Northern Uganda, exceeding expected limits and thereby requiring epidemic response. We investigated this outbreak to estimate its magnitude, identify exposure factors for transmission, and recommend evidence-based control measures. Methods: We defined a malaria case as onset of fever in a resident of Anaka subcounty, Koch Goma subcounty, and Nwoya Town Council, Nwoya District, with a positive rapid diagnostic test or microscopy for malaria from 1 February to 25 May 2018. We reviewed medical records in all health facilities of affected subcounties to find cases. In a case-control study, we compared exposure factors between case-persons and asymptomatic controls matched by age and village. We also conducted entomological assessments on vector density and behavior. Results: We identified 3,879 case-persons (attack rate [AR] = 6.5%) and two deaths (case-fatality rate = 5.2/10,000). Females (AR = 8.1%) were more affected than males (AR = 4.7%) (p < 0.0001). Of all age groups, 5-18 years (AR = 8.4%) were most affected. Heavy rain started in early March 2018, and a propagated outbreak followed in the first week of April 2018. In the case-control study, 55% (59/107) of case-persons and 18% (19/107) of controls had stagnant water around households for several days following rainfall (ORM-H = 5.6, 95% CI = 3.0-11); 25% (27/107) of case-persons and 51% (55/107) of controls wore full extremity covering clothes during evening hours (ORM-H = 0.30, 95% CI = 0.20-0.60); 71% (76/107) of case-persons and 85% (91/107) of controls slept under a long-lasting insecticide-treated net (LLIN) 14 days before symptom onset (ORM-H = 0.43, 95% CI = 0.22-0.85); 37% (40/107) of case-persons and 52% (56/107) of controls had access to at least one LLIN per 2 household members (ORM-H = 0.54, 95% CI = 0.30-0.97). Entomological assessment indicated active breeding sites in the entire study area; Anopheles gambiae sensu lato species were the predominant vector. Conclusion: Increased vector-breeding sites after heavy rainfall and inadequate malaria preventive measures were found to have contributed to this outbreak. We recommended increasing coverage for LLINs and larviciding breeding sites in the area.

Rapid shifts in the age-specific burden of malaria following successful control interventions in four regions of Uganda.

BACKGROUND: Malaria control using long-lasting insecticidal nets (LLINs) and indoor residual spraying of insecticide (IRS) has been associated with reduced transmission throughout Africa. However, the impact of transmission reduction on the age distribution of malaria cases remains unclear. METHODS: Over a 10-year period (January 2009 to July 2018), outpatient surveillance data from four health facilities in Uganda were used to estimate the impact of control interventions on temporal changes in the age distribution of malaria cases using multinomial regression. Interventions included mass distribution of LLINs at all sites and IRS at two sites. RESULTS: Overall, 896,550 patient visits were included in the study; 211,632 aged < 5 years, 171,166 aged 5-15 years and 513,752 > 15 years. Over time, the age distribution of patients not suspected of malaria and those malaria negative either declined or remained the same across all sites. In contrast, the age distribution of suspected and confirmed malaria cases increased across all four sites. In the two LLINs-only sites, the proportion of malaria cases in < 5 years decreased from 31 to 16% and 35 to 25%, respectively. In the two sites receiving LLINs plus IRS, these proportions decreased from 58 to 30% and 64 to 47%, respectively. Similarly, in the LLINs-only sites, the proportion of malaria cases > 15 years increased from 40 to 61% and 29 to 39%, respectively. In the sites receiving LLINs plus IRS, these proportions increased from 19 to 44% and 18 to 31%, respectively. CONCLUSIONS: These findings demonstrate a shift in the burden of malaria from younger to older individuals following implementation of successful control interventions, which has important implications for malaria prevention, surveillance, case management and control strategies.

The effect of case management and vector-control interventions on space-time patterns of malaria incidence in Uganda.

BACKGROUND: Electronic reporting of routine health facility data in Uganda began with the adoption of the District Health Information Software System version 2 (DHIS2) in 2011. This has improved health facility reporting and overall data quality. In this study, the effects of case management with artemisinin-based combination therapy (ACT) and vector control interventions on space-time patterns of disease incidence were determined using DHIS2 data reported during 2013-2016. METHODS: Bayesian spatio-temporal negative binomial models were fitted on district-aggregated monthly malaria cases, reported by two age groups, defined by a cut-off age of 5 years. The effects of interventions were adjusted for socio-economic and climatic factors. Spatial and temporal correlations were taken into account by assuming a conditional autoregressive and a first-order autoregressive AR(1) process on district and monthly specific random effects, respectively. Fourier trigonometric functions were incorporated in the models to take into account seasonal fluctuations in malaria transmission. RESULTS: The temporal variation in incidence was similar in both age groups and depicted a steady decline up to February 2014, followed by an increase from March 2015 onwards. The trends were characterized by a strong bi-annual seasonal pattern with two peaks during May-July and September-December. Average monthly incidence in children < 5 years declined from 74.7 cases (95% CI 72.4-77.1) in 2013 to 49.4 (95% CI 42.9-55.8) per 1000 in 2015 and followed by an increase in 2016 of up to 51.3 (95% CI 42.9-55.8). In individuals ≥ 5 years, a decline in incidence from 2013 to 2015 was followed by an increase in 2016. A 100% increase in insecticide-treated nets (ITN) coverage was associated with a decline in incidence by 44% (95% BCI 28-59%). Similarly, a 100% increase in ACT coverage reduces incidence by 28% (95% BCI 11-45%) and 25% (95% BCI 20-28%) in children < 5 years and individuals ≥ 5 years, respectively. The ITN effect was not statistically important in older individuals. The space-time patterns of malaria incidence in children < 5 are similar to those of parasitaemia risk predicted from the malaria indicator survey of 2014-15. CONCLUSION: The decline in malaria incidence highlights the effectiveness of vector-control interventions and case management with ACT in Uganda. This calls for optimizing and sustaining interventions to achieve universal coverage and curb reverses in malaria decline.