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Good house construction may reduce the risk of malaria by limiting the entry of mosquito vectors. We assessed how house design may affect mosquito house entry and malaria risk in Uganda. 100 households were enrolled in each of three sub-counties: Walukuba, Jinja district; Kihihi, Kanungu district; and Nagongera, Tororo district. CDC light trap collections of mosquitoes were done monthly in all homes. All children aged six months to ten years (n = 878) were followed prospectively for a total of 24 months to measure parasite prevalence every three months and malaria incidence. Homes were classified as modern (cement, wood or metal walls; and tiled or metal roof; and closed eaves) or traditional (all other homes). A total of 113,618 female Anopheles were collected over 6,765 nights. 6,816 routine blood smears were taken of which 1,061 (15.6%) were malaria parasite positive. 2,582 episodes of uncomplicated malaria were diagnosed after 1,569 person years of follow-up, giving an overall incidence of 1.6 episodes per person year at risk. The human biting rate was lower in modern homes than in traditional homes (adjusted incidence rate ratio (IRR) 0.48, 95% confidence interval (CI) 0.37-0.64, p<0.001). The odds of malaria infection were lower in modern homes across all the sub-counties (adjusted odds ratio 0.44, 95%CI 0.30-0.65, p<0.001), while malaria incidence was lower in modern homes in Kihihi (adjusted IRR 0.61, 95%CI 0.40-0.91, p = 0.02) but not in Walukuba or Nagongera. House design is likely to explain some of the heterogeneity of malaria transmission in Uganda and represents a promising target for future interventions, even in highly endemic areas.

Heterogeneity in transmission is a challenge for infectious disease dynamics and control. An 80-20 “Pareto” rule has been proposed to describe this heterogeneity whereby 80% of transmission is accounted for by 20% of individuals, herein called super-spreaders. It is unclear, however, whether super-spreading can be attributed to certain individuals or whether it is an unpredictable and unavoidable feature of epidemics. Here, we investigate heterogeneous malaria transmission at three sites in Uganda and find that super-spreading is negatively correlated with overall malaria transmission intensity. Mosquito biting among humans is 90-10 at the lowest transmission intensities declining to less than 70-30 at the highest intensities. For super-spreaders, biting ranges from 70-30 down to 60-40. The difference, approximately half the total variance, is due to environmental stochasticity. Super-spreading is thus partly due to super-spreaders, but modest gains are expected from targeting super-spreaders. Investigating malaria transmission at three sites in Uganda, the authors identify super-spreaders and show that super-spreading is more prominent at low-intensity transmission, and that seasonality and environmental stochasticity have a greater influence on super-spreading.

Tororo District, in Eastern Uganda, experienced a dramatic decline in malaria burden starting in 2014 following the implementation of indoor residual spraying of insecticide (IRS) in the setting of repeated long-lasting insecticide treated nets (LLINs) distribution campaigns. However, in 2020 malaria began to resurge in Tororo following a change in the active ingredient used for IRS. In this study, epidemiological measures of malaria were compared shortly after the resurgence between two parishes in Tororo District (Kayoro and Osukuru) and one contiguous parish in Busia District (Buteba), where IRS has never been implemented. A cohort of 483 residents from 80 randomly selected households were followed from August 2020 to January 2021. Mosquitoes were collected every 2 weeks using CDC light traps in rooms where participants slept; parasitemia and gametoctyemia measured every 4 weeks by microscopy and PCR; and symptomatic malaria measured by passive surveillance. The annual entomological inoculation rate was significantly higher in Buteba (108.2 infective bites/person/year), compared to Osukuru (59.0, p = 0.001) and Kayoro (27.4, p<0.001). Overall, parasite prevalence was 19.5% by microscopy and 50.7% by PCR, with no significant differences between the three parishes. Among infected individuals, gametocyte prevalence by PCR was 45.5% and similar between sites. The incidence of malaria was significantly higher in Osukuru (2.46 episodes PPY) compared to Buteba (1.47, p = 0.005) and Kayoro (1.09, p<0.001). For participants over 15 years of age, the risk of symptomatic malaria if microscopic parasitemia was present was higher in Osukuru (relative risk [RR] = 2.99, p = 0.03) compared to Buteba. These findings highlight the complex relationships between measures of malaria transmission, infection, and disease, and the potential for excess disease burden, possibly due to waning immunity, in areas where vector control interventions begin to fail after a sustained period of highly effective control.

Long-lasting insecticidal nets (LLINs) and indoor residual spraying of insecticide (IRS) are the primary vector control interventions used to prevent malaria in Africa. Although both interventions are effective in some settings, high-quality evidence is rarely available to evaluate their effectiveness following deployment by a national malaria control program. In Uganda, we measured changes in key malaria indicators following universal LLIN distribution in three sites, with the addition of IRS at one of these sites. Comprehensive malaria surveillance was conducted from October 1, 2011, to March 31, 2016, in three sub-counties with relatively low (Walukuba), moderate (Kihihi), and high transmission (Nagongera). Between 2013 and 2014, universal LLIN distribution campaigns were conducted in all sites, and in December 2014, IRS with the carbamate bendiocarb was initiated in Nagongera. High-quality surveillance evaluated malaria metrics and mosquito exposure before and after interventions through (a) enhanced health-facility-based surveillance to estimate malaria test positivity rate (TPR), expressed as the number testing positive for malaria/number tested for malaria (number of children tested for malaria: Walukuba = 42,833, Kihihi = 28,790, and Nagongera = 38,690); (b) cohort studies to estimate the incidence of malaria, expressed as the number of episodes per person-year [PPY] at risk (number of children observed: Walukuba = 340, Kihihi = 380, and Nagongera = 361); and (c) entomology surveys to estimate household-level human biting rate (HBR), expressed as the number of female Anopheles mosquitoes collected per house-night of collection (number of households observed: Walukuba = 117, Kihihi = 107, and Nagongera = 107). The LLIN distribution campaign substantially increased LLIN coverage levels at the three sites to between 65.0% and 95.5% of households with at least one LLIN. In Walukuba, over the 28-mo post-intervention period, universal LLIN distribution was associated with no change in the incidence of malaria (0.39 episodes PPY pre-intervention versus 0.20 post-intervention; adjusted rate ratio [aRR] = 1.02, 95% CI 0.36-2.91, p = 0.97) and non-significant reductions in the TPR (26.5% pre-intervention versus 26.2% post-intervention; aRR = 0.70, 95% CI 0.46-1.06, p = 0.09) and HBR (1.07 mosquitoes per house-night pre-intervention versus 0.71 post-intervention; aRR = 0.41, 95% CI 0.14-1.18, p = 0.10). In Kihihi, over the 21-mo post-intervention period, universal LLIN distribution was associated with a reduction in the incidence of malaria (1.77 pre-intervention versus 1.89 post-intervention; aRR = 0.65, 95% CI 0.43-0.98, p = 0.04) but no significant change in the TPR (49.3% pre-intervention versus 45.9% post-intervention; aRR = 0.83, 95% 0.58-1.18, p = 0.30) or HBR (4.06 pre-intervention versus 2.44 post-intervention; aRR = 0.71, 95% CI 0.30-1.64, p = 0.40). In Nagongera, over the 12-mo post-intervention period, universal LLIN distribution was associated with a reduction in the TPR (45.3% pre-intervention versus 36.5% post-intervention; aRR = 0.82, 95% CI 0.76-0.88, p < 0.001) but no significant change in the incidence of malaria (2.82 pre-intervention versus 3.28 post-intervention; aRR = 1.10, 95% 0.76-1.59, p = 0.60) or HBR (41.04 pre-intervention versus 20.15 post-intervention; aRR = 0.87, 95% CI 0.31-2.47, p = 0.80). The addition of three rounds of IRS at ~6-mo intervals in Nagongera was followed by clear decreases in all outcomes: incidence of malaria (3.25 pre-intervention versus 0.63 post-intervention; aRR = 0.13, 95% CI 0.07-0.27, p < 0.001), TPR (37.8% pre-intervention versus 15.0% post-intervention; aRR = 0.54, 95% CI 0.49-0.60, p < 0.001), and HBR (18.71 pre-intervention versus 3.23 post-intervention; aRR = 0.29, 95% CI 0.17-0.50, p < 0.001). High levels of pyrethroid resistance were documented at all three study sites. Limitations of the study included the observational study design, the lack of contemporaneous control groups, and that the interventions were implemented under programmatic conditions. Universal distribution of LLINs at three sites with varying transmission intensity was associated with modest declines in the burden of malaria for some indicators, but the addition of IRS at the highest transmission site was associated with a marked decline in the burden of malaria for all indicators. In highly endemic areas of Africa with widespread pyrethroid resistance, IRS using alternative insecticide formulations may be needed to achieve substantial gains in malaria control.

Long-lasting insecticidal nets (LLINs) are the primary malaria prevention tool, but their effectiveness is threatened by pyrethroid resistance. We embedded a pragmatic cluster-randomised trial into Uganda's national LLIN campaign to compare conventional LLINs with those containing piperonyl butoxide (PBO), a synergist that can partially restore pyrethroid susceptibility in mosquito vectors. 104 health sub-districts, from 48 districts in Uganda, were randomly assigned to LLINs with PBO (PermaNet 3.0 and Olyset Plus) and conventional LLINs (PermaNet 2.0 and Olyset Net) by proportionate randomisation using an iterative process. At baseline 6, 12, and 18 months after LLIN distribution, cross-sectional surveys were done in 50 randomly selected households per cluster (5200 per survey); a subset of ten households per cluster (1040 per survey) were randomly selected for entomological surveys. The primary outcome was parasite prevalence by microscopy in children aged 2–10 years, assessed in the as-treated population at 6, 12, and 18 months. This trial is registered with ISRCTN, ISRCTN17516395. LLINs were delivered to households from March 25, 2017, to March 18, 2018, 32 clusters were randomly assigned to PermaNet 3.0, 20 to Olyset Plus, 37 to PermaNet 2.0, and 15 to Olyset Net. In the as-treated analysis, three clusters were excluded because no dominant LLIN was received, and four clusters were reassigned, resulting in 49 PBO LLIN clusters (31 received PermaNet 3.0 and 18 received Olyset Plus) and 52 non-PBO LLIN clusters (39 received PermaNet 2.0 and 13 received Olyset Net). At 6 months, parasite prevalence was 11% (386/3614) in the PBO group compared with 15% (556/3844) in the non-PBO group (prevalence ratio [PR] adjusted for baseline values 0·74, 95% CI 0·62–0·87; p=0·0003). Parasite prevalence was similar at month 12 (11% vs 13%; PR 0·73, 95% CI 0·63–0·85; p=0·0001) and month 18 (12% vs 14%; PR 0·84, 95% CI 0·72–0·98; p=0·029). In Uganda, where pyrethroid resistance is high, PBO LLINs reduced parasite prevalence more effectively than did conventional LLINs for up to 18 months. This study provides evidence needed to support WHO's final recommendation on use of PBO LLINs. The Against Malaria Foundation, UK Department for International Development, Innovative Vector Control Consortium, and Bill and Melinda Gates Foundation.

As many malaria-endemic countries move towards elimination of Plasmodium falciparum, the most virulent human malaria parasite, effective tools for monitoring malaria epidemiology are urgent priorities. P. falciparum population genetic approaches offer promising tools for understanding transmission and spread of the disease, but a high prevalence of multi-clone or polygenomic infections can render estimation of even the most basic parameters, such as allele frequencies, challenging. A previous method, COIL, was developed to estimate complexity of infection (COI) from single nucleotide polymorphism (SNP) data, but relies on monogenomic infections to estimate allele frequencies or requires external allele frequency data which may not available. Estimates limited to monogenomic infections may not be representative, however, and when the average COI is high, they can be difficult or impossible to obtain. Therefore, we developed THE REAL McCOIL, Turning HEterozygous SNP data into Robust Estimates of ALelle frequency, via Markov chain Monte Carlo, and Complexity Of Infection using Likelihood, to incorporate polygenomic samples and simultaneously estimate allele frequency and COI. This approach was tested via simulations then applied to SNP data from cross-sectional surveys performed in three Ugandan sites with varying malaria transmission. We show that THE REAL McCOIL consistently outperforms COIL on simulated data, particularly when most infections are polygenomic. Using field data we show that, unlike with COIL, we can distinguish epidemiologically relevant differences in COI between and within these sites. Surprisingly, for example, we estimated high average COI in a peri-urban subregion with lower transmission intensity, suggesting that many of these cases were imported from surrounding regions with higher transmission intensity. THE REAL McCOIL therefore provides a robust tool for understanding the molecular epidemiology of malaria across transmission settings.

Indoor residual spraying (IRS) and long-lasting insecticide-treated bednets (LLINs) are common tools for reducing malaria transmission. We studied a cohort in Uganda with universal access to LLINs after 5 years of sustained IRS to explore LLIN adherence when malaria transmission has been greatly reduced. Eighty households and 526 individuals in Nagongera, Uganda were followed from October 2017 –October 2019. Every two weeks, mosquitoes were collected from sleeping rooms and LLIN adherence the prior night assessed. Episodes of malaria were diagnosed using passive surveillance. Risk factors for LLIN non-adherence were evaluated using multi-level mixed logistic regression. An age-matched case-control design was used to measure the association between LLIN non-adherence and malaria. Across all time periods, and particularly in the last 6 months, non-adherence was higher among both children <5 years (OR 3.31, 95% CI: 2.30–4.75; p<0.001) and school-aged children 5–17 years (OR 6.88, 95% CI: 5.01–9.45; p<0.001) compared to adults. In the first 18 months, collection of fewer mosquitoes was associated with non-adherence (OR 3.25, 95% CI: 2.92–3.63; p<0.001), and, in the last 6 months, residents of poorer households were less adherent (OR 5.1, 95% CI: 1.17–22.2; p = 0.03). Any reported non-adherence over the prior two months was associated with a 15-fold increase in the odds of having malaria (OR 15.0, 95% CI: 1.95 to 114.9; p = 0.009). Knowledge about LLIN use was high, and the most frequently reported barriers to use included heat and low perceived risk of malaria. Children, particularly school-aged, participants exposed to fewer mosquitoes, and those from poorer households, were less likely to use LLINs. Non-adherence to LLINs was associated with an increased risk of malaria. Strategies, such as behavior change communications, should be prioritized to ensure consistent LLIN use even when malaria transmission has been greatly reduced.

Symptomatic malaria cases reflect only a small proportion of all Plasmodium spp infections. Many infected individuals are asymptomatic, and persistent asymptomatic Plasmodium falciparum infections are common in endemic settings. We aimed to quantify the contribution of symptomatic and asymptomatic infections to P falciparum transmission in Tororo, Uganda. We did a longitudinal, observational cohort study in Tororo district, Uganda. We recruited participants of all ages from randomly selected households within this district. Participants were eligible if the selected household had no more than nine permanent residents and at least two members younger than 10 years, and the household was their primary residence, and they agreed to come to the study clinic for any fever episode and avoid antimalarial medications outside the study. Participants were followed-up by continuous passive surveillance for the incidence of symptomatic infections; routine assessments (ie, standardised clinical evaluation and blood samples) were done at baseline and at routine visits every 4 weeks for 2 years. P falciparum parasite density, gametocyte density, and genetic composition were determined molecularly using quantitative PCR (qPCR), quantitative reverse transcriptase PCR (qRT-PCR), and amplicon deep sequencing, respectively. Membrane feeding assays were also done to assess infectivity to mosquitoes. The contribution of different populations to the infectious reservoir was estimated for symptomatic infections, asymptomatic but microscopically detected infections, and asymptomatic but qPCR-detected infections; and for age groups younger than 5 years, 5–15 years, and 16 years or older. Between Oct 4, 2017, and Oct 31, 2019, 531 individuals were enrolled from 80 randomly selected households and were followed-up for 2 years. At baseline, P falciparum was detected in 28 (5·3%) of 531 participants by microscopy and an additional 64 (12·1%) by qPCR and declined thereafter. In 538 mosquito feeding experiments on 107 individuals, 446 (1·2%) of 37 404 mosquitoes became infected, with mosquito infection rates being strongly associated with gametocyte densities (β=2·11, 95% CI 1·62–2·67; p<0·0001). Considering both transmissibility of infections and their relative frequency, the estimated human infectious reservoir consisted primarily of asymptomatic microscopy-detected infections (83·8%), followed by asymptomatic submicroscopic infections (15·6%), and symptomatic infections (0·6%). Children aged 5–15 years accounted for more than half of the infectious reservoir (58·7%); individuals younger than 5 years (25·8%) and those 16 years or older (15·6%) contributed less. Samples from four children contribued to 279 (62·6%) of 446 infected mosquitoes after multiple mosquito-feeding assays. Individuals with asymptomatic infections were important drivers of malaria transmission. School-aged children contributed to more than half of all mosquito infections, with a small minority of asymptomatic children being highly infectious. Demographically targeted interventions, aimed at school-aged children, could further reduce transmission in areas under effective vector control. US National Institutes of Health, Bill & Melinda Gates Foundation, and the European Research Council.

The cause of malaria transmission has been known for over a century but it is still unclear whether entomological measures are sufficiently reliable to inform policy decisions in human health. Decision-making on the effectiveness of new insecticide-treated nets (ITNs) and the indoor residual spraying of insecticide (IRS) have been based on epidemiological data, typically collected in cluster-randomised control trials. The number of these trials that can be conducted is limited. Here we use a systematic review to highlight that efficacy estimates of the same intervention may vary substantially between trials. Analyses indicate that mosquito data collected in experimental hut trials can be used to parameterize mechanistic models for Plasmodium falciparum malaria and reliably predict the epidemiological efficacy of quick-acting, neuro-acting ITNs and IRS. Results suggest that for certain types of ITNs and IRS using this framework instead of clinical endpoints could support policy and expedite the widespread use of novel technologies. Estimating the effectiveness of malaria vector control interventions has typically relied on resource-intensive cluster randomised trials. Here, the authors estimate changes in malaria prevalence using entomological data from experimental hut trials, which may provide an alternative route to approval of interventions in some situations.

Background Routine malaria surveillance data in Africa primarily come from public health facilities reporting to national health management information systems. Although information on gender is routinely collected from patients presenting to these health facilities, stratification of malaria surveillance data by gender is rarely done. This study evaluated gender difference among patients diagnosed with parasitological confirmed malaria at public health facilities in Uganda. Methods This study utilized individual level patient data collected from January 2020 through April 2021 at 12 public health facilities in Uganda and cross-sectional surveys conducted in target areas around these facilities in April 2021. Associations between gender and the incidence of malaria and non-malarial visits captured at the health facilities from patients residing within the target areas were estimated using poisson regression models controlling for seasonality. Associations between gender and data on health-seeking behaviour from the cross-sectional surveys were estimated using poisson regression models controlling for seasonality. Results Overall, incidence of malaria diagnosed per 1000 person years was 735 among females and 449 among males (IRR = 1.72, 95% CI 1.68–1.77, p < 0.001), with larger differences among those 15–39 years (IRR = 2.46, 95% CI 2.34–2.58, p < 0.001) and over 39 years (IRR = 2.26, 95% CI 2.05–2.50, p < 0.001) compared to those under 15 years (IRR = 1.46, 95% CI 1.41–1.50, p < 0.001). Female gender was also associated with a higher incidence of visits where malaria was not suspected (IRR = 1.77, 95% CI 1.71–1.83, p < 0.001), with a similar pattern across age strata. These associations were consistent across the 12 individual health centres. From the cross-sectional surveys, females were more likely than males to report fever in the past 2 weeks and seek care at the local health centre (7.5% vs. 4.7%, p = 0.001) with these associations significant for those 15–39 years (RR = 2.49, 95% CI 1.17–5.31, p = 0.018) and over 39 years (RR = 2.56, 95% CI 1.00–6.54, p = 0.049). Conclusions Females disproportionately contribute to the burden of malaria diagnosed at public health facilities in Uganda, especially once they reach childbearing age. Contributing factors included more frequent visits to these facilities independent of malaria and a higher reported risk of seeking care at these facilities for febrile illnesses.