Malaria in pregnancy (MiP) studies assessing the clinical performance of highly sensitive rapid diagnostic tests (HS-RDT) for Plasmodium falciparum detection.

BACKGROUND: Rapid diagnostic tests (RDTs) are effective tools to diagnose and inform the treatment of malaria in adults and children. The recent development of a highly sensitive rapid diagnostic test (HS-RDT) for Plasmodium falciparum has prompted questions over whether it could improve the diagnosis of malaria in pregnancy and pregnancy outcomes in malaria endemic areas. METHODS: This landscape review collates studies addressing the clinical performance of the HS-RDT. Thirteen studies were identified comparing the HS-RDT and conventional RDT (co-RDT) to molecular methods to detect malaria in pregnancy. Using data from five completed studies, the association of epidemiological and pregnancy-related factors on the sensitivity of HS-RDT, and comparisons with co-RDT were investigated. The studies were conducted in 4 countries over a range of transmission intensities in largely asymptomatic women. RESULTS: Sensitivity of both RDTs varied widely (HS-RDT range 19.6 to 85.7%, co-RDT range 22.8 to 82.8% compared to molecular testing) yet HS-RDT detected individuals with similar parasite densities across all the studies including different geographies and transmission areas [geometric mean parasitaemia around 100 parasites per µL (p/µL)]. HS-RDTs were capable of detecting low-density parasitaemias and in one study detected around 30% of infections with parasite densities of 0-2 p/µL compared to the co-RDT in the same study which detected around 15%. CONCLUSION: The HS-RDT has a slightly higher analytical sensitivity to detect malaria infections in pregnancy than co-RDT but this mostly translates to only fractional and not statistically significant improvement in clinical performance by gravidity, trimester, geography or transmission intensity. The analysis presented here highlights the need for larger and more studies to evaluate incremental improvements in RDTs. The HS-RDT could be used in any situation where co-RDT are currently used for P. falciparum diagnosis, if storage conditions can be adhered to.

Evaluating the Impact of Programmatic Mass Drug Administration for Malaria in Zambia Using Routine Incidence Data.

BACKGROUND: In 2016, the Zambian National Malaria Elimination Centre started programmatic mass drug administration (pMDA) campaigns with dihydroartemisinin-piperaquine as a malaria elimination tool in Southern Province. Two rounds were administered, 2 months apart (coverage 70% and 57%, respectively). We evaluated the impact of 1 year of pMDA on malaria incidence using routine data. METHODS: We conducted an interrupted time series with comparison group analysis on monthly incidence data collected at the health facility catchment area (HFCA) level, with a negative binomial model using generalized estimating equations. Programmatic mass drug administration was conducted in HFCAs with greater than 50 cases/1000 people per year. Ten HFCAs with incidence rates marginally above this threshold (pMDA group) were compared with 20 HFCAs marginally below (comparison group). RESULTS: The pMDA HFCAs saw a 46% greater decrease in incidence at the time of intervention than the comparison areas (incidence rate ratio = 0.536; confidence interval = 0.337-0.852); however, incidence increased toward the end of the season. No HFCAs saw a transmission interruption. CONCLUSIONS: Programmatic mass drug administration, implemented during 1 year with imperfect coverage in low transmission areas with suboptimal vector control coverage, significantly reduced incidence. However, elimination will require additional tools. Routine data are important resources for programmatic impact evaluations and should be considered for future analyses.

Evaluating the Performance of Malaria Genetics for Inferring Changes in Transmission Intensity Using Transmission Modeling.

Substantial progress has been made globally to control malaria, however there is a growing need for innovative new tools to ensure continued progress. One approach is to harness genetic sequencing and accompanying methodological approaches as have been used in the control of other infectious diseases. However, to utilize these methodologies for malaria, we first need to extend the methods to capture the complex interactions between parasites, human and vector hosts, and environment, which all impact the level of genetic diversity and relatedness of malaria parasites. We develop an individual-based transmission model to simulate malaria parasite genetics parameterized using estimated relationships between complexity of infection and age from five regions in Uganda and Kenya. We predict that cotransmission and superinfection contribute equally to within-host parasite genetic diversity at 11.5% PCR prevalence, above which superinfections dominate. Finally, we characterize the predictive power of six metrics of parasite genetics for detecting changes in transmission intensity, before grouping them in an ensemble statistical model. The model predicted malaria prevalence with a mean absolute error of 0.055. Different assumptions about the availability of sample metadata were considered, with the most accurate predictions of malaria prevalence made when the clinical status and age of sampled individuals is known. Parasite genetics may provide a novel surveillance tool for estimating the prevalence of malaria in areas in which prevalence surveys are not feasible. However, the findings presented here reinforce the need for patient metadata to be recorded and made available within all future attempts to use parasite genetics for surveillance.

Performance and utility of more highly sensitive malaria rapid diagnostic tests.

BACKGROUND: A new more highly sensitive rapid diagnostic test (HS-RDT) for Plasmodium falciparum malaria (Alere™/Abbott Malaria Ag P.f RDT [05FK140], now called NxTek™ Eliminate Malaria Ag Pf) was launched in 2017. The test has already been used in many research studies in a wide range of geographies and use cases. METHODS: In this study, we collate all published and available unpublished studies that use the HS-RDT and assess its performance in (i) prevalence surveys, (ii) clinical diagnosis, (iii) screening pregnant women, and (iv) active case detection. Two individual-level data sets from asymptomatic populations are used to fit logistic regression models to estimate the probability of HS-RDT positivity based on histidine-rich protein 2 (HRP2) concentration and parasite density. The performance of the HS-RDT in prevalence surveys is estimated by calculating the sensitivity and positive proportion in comparison to polymerase chain reaction (PCR) and conventional malaria RDTs. RESULTS: We find that across 18 studies, in prevalence surveys, the mean sensitivity of the HS-RDT is estimated to be 56.1% (95% confidence interval [CI] 46.9-65.4%) compared to 44.3% (95% CI 32.6-56.0%) for a conventional RDT (co-RDT) when using nucleic acid amplification techniques as the reference standard. In studies where prevalence was estimated using both the HS-RDT and a co-RDT, we found that prevalence was on average 46% higher using a HS-RDT compared to a co-RDT. For use in clinical diagnosis and screening pregnant women, the HS-RDT was not significantly more sensitive than a co-RDT. CONCLUSIONS: Overall, the evidence presented here suggests that the HS-RDT is more sensitive in asymptomatic populations and could provide a marginal improvement in clinical diagnosis and screening pregnant women. Although the HS-RDT has limited temperature stability and shelf-life claims compared to co-RDTs, there is no evidence to suggest, given this test has the same cost as current RDTs, it would have any negative impacts in terms of malaria misdiagnosis if it were widely used in all four population groups explored here.

Assessing the impact of next-generation rapid diagnostic tests on Plasmodium falciparum malaria elimination strategies.

Mass-screen-and-treat and targeted mass-drug-administration strategies are being considered as a means to interrupt transmission of Plasmodium falciparum malaria. However, the effectiveness of such strategies will depend on the extent to which current and future diagnostics are able to detect those individuals who are infectious to mosquitoes. We estimate the relationship between parasite density and onward infectivity using sensitive quantitative parasite diagnostics and mosquito feeding assays from Burkina Faso. We find that a diagnostic with a lower detection limit of 200 parasites per microlitre would detect 55% of the infectious reservoir (the combined infectivity to mosquitoes of the whole population weighted by how often each individual is bitten) whereas a test with a limit of 20 parasites per microlitre would detect 83% and 2 parasites per microlitre would detect 95% of the infectious reservoir. Using mathematical models, we show that increasing the diagnostic sensitivity from 200 parasites per microlitre (equivalent to microscopy or current rapid diagnostic tests) to 2 parasites per microlitre would increase the number of regions where transmission could be interrupted with a mass-screen-and-treat programme from an entomological inoculation rate below 1 to one of up to 4. The higher sensitivity diagnostic could reduce the number of treatment rounds required to interrupt transmission in areas of lower prevalence. We predict that mass-screen-and-treat with a highly sensitive diagnostic is less effective than mass drug administration owing to the prophylactic protection provided to uninfected individuals by the latter approach. In low-transmission settings such as those in Southeast Asia, we find that a diagnostic tool with a sensitivity of 20 parasites per microlitre may be sufficient for targeted mass drug administration because this diagnostic is predicted to identify a similar village population prevalence compared with that currently detected using polymerase chain reaction if treatment levels are high and screening is conducted during the dry season. Along with other factors, such as coverage, choice of drug, timing of the intervention, importation of infections, and seasonality, the sensitivity of the diagnostic can play a part in increasing the chance of interrupting transmission.

Design and analysis of a 2-year parallel follow-up of repeated ivermectin mass drug administrations for control of malaria: Small sample considerations for cluster-randomized trials with count data.

BACKGROUND: Cluster-randomized trials allow for the evaluation of a community-level or group-/cluster-level intervention. For studies that require a cluster-randomized trial design to evaluate cluster-level interventions aimed at controlling vector-borne diseases, it may be difficult to assess a large number of clusters while performing the additional work needed to monitor participants, vectors, and environmental factors associated with the disease. One such example of a cluster-randomized trial with few clusters was the "efficacy and risk of harms of repeated ivermectin mass drug administrations for control of malaria" trial. Although previous work has provided recommendations for analyzing trials like repeated ivermectin mass drug administrations for control of malaria, additional evaluation of the multiple approaches for analysis is needed for study designs with count outcomes. METHODS: Using a simulation study, we applied three analysis frameworks to three cluster-randomized trial designs (single-year, 2-year parallel, and 2-year crossover) in the context of a 2-year parallel follow-up of repeated ivermectin mass drug administrations for control of malaria. Mixed-effects models, generalized estimating equations, and cluster-level analyses were evaluated. Additional 2-year parallel designs with different numbers of clusters and different cluster correlations were also explored. RESULTS: Mixed-effects models with a small sample correction and unweighted cluster-level summaries yielded both high power and control of the Type I error rate. Generalized estimating equation approaches that utilized small sample corrections controlled the Type I error rate but did not confer greater power when compared to a mixed model approach with small sample correction. The crossover design generally yielded higher power relative to the parallel equivalent. Differences in power between analysis methods became less pronounced as the number of clusters increased. The strength of within-cluster correlation impacted the relative differences in power. CONCLUSION: Regardless of study design, cluster-level analyses as well as individual-level analyses like mixed-effects models or generalized estimating equations with small sample size corrections can both provide reliable results in small cluster settings. For 2-year parallel follow-up of repeated ivermectin mass drug administrations for control of malaria, we recommend a mixed-effects model with a pseudo-likelihood approximation method and Kenward-Roger correction. Similarly designed studies with small sample sizes and count outcomes should consider adjustments for small sample sizes when using a mixed-effects model or generalized estimating equation for analysis. Although the 2-year parallel follow-up of repeated ivermectin mass drug administrations for control of malaria is already underway as a parallel trial, applying the simulation parameters to a crossover design yielded improved power, suggesting that crossover designs may be valuable in settings where the number of available clusters is limited. Finally, the sensitivity of the analysis approach to the strength of within-cluster correlation should be carefully considered when selecting the primary analysis for a cluster-randomized trial.

Quantifying Plasmodium falciparum infections clustering within households to inform household-based intervention strategies for malaria control programs: An observational study and meta-analysis from 41 malaria-endemic countries.

BACKGROUND: Reactive malaria strategies are predicated on the assumption that individuals infected with malaria are clustered within households or neighbourhoods. Despite the widespread programmatic implementation of reactive strategies, little empirical evidence exists as to whether such strategies are appropriate and, if so, how they should be most effectively implemented. METHODS AND FINDINGS: We collated 2 different datasets to assess clustering of malaria infections within households: (i) demographic health survey (DHS) data, integrating household information and patent malaria infection, recent fever, and recent treatment status in children; and (ii) data from cross-sectional and reactive detection studies containing information on the household and malaria infection status (patent and subpatent) of all-aged individuals. Both datasets were used to assess the odds of infections clustering within index households, where index households were defined based on whether they contained infections detectable through one of 3 programmatic strategies: (a) Reactive Case Detection (RACD) classifed by confirmed clinical cases, (b) Mass Screen and Treat (MSAT) classifed by febrile, symptomatic infections, and (c) Mass Test and Treat (MTAT) classifed by infections detectable using routine diagnostics. Data included 59,050 infections in 208,140 children under 7 years old (median age = 2 years, minimum = 2, maximum = 7) by microscopy/rapid diagnostic test (RDT) from 57 DHSs conducted between November 2006 and December 2018 from 23 African countries. Data representing 11,349 infections across all ages (median age = 22 years, minimum = 0.5, maximum = 100) detected by molecular tools in 132,590 individuals in 43 studies published between April 2006 and May 2019 in 20 African, American, Asian, and Middle Eastern countries were obtained from the published literature. Extensive clustering was observed-overall, there was a 20.40 greater (95% credible interval [CrI] 0.35-20.45; P < 0.001) odds of patent infections (according to the DHS data) and 5.13 greater odds (95% CI 3.85-6.84; P < 0.001) of molecularly detected infections (from the published literature) detected within households in which a programmatically detectable infection resides. The strongest degree of clustering identified by polymerase chain reaction (PCR)/ loop mediated isothermal amplification (LAMP) was observed using the MTAT strategy (odds ratio [OR] = 6.79, 95% CI 4.42-10.43) but was not significantly different when compared to MSAT (OR = 5.2, 95% CI 3.22-8.37; P-difference = 0.883) and RACD (OR = 4.08, 95% CI 2.55-6.53; P-difference = 0.29). Across both datasets, clustering became more prominent when transmission was low. However, limitations to our analysis include not accounting for any malaria control interventions in place, malaria seasonality, or the likely heterogeneity of transmission within study sites. Clustering may thus have been underestimated. CONCLUSIONS: In areas where malaria transmission is peri-domestic, there are programmatic options for identifying households where residual infections are likely to be found. Combining these detection strategies with presumptively treating residents of index households over a sustained time period could contribute to malaria elimination efforts.

Efficacy and risk of harms of repeat ivermectin mass drug administrations for control of malaria (RIMDAMAL): a cluster-randomised trial.

BACKGROUND: Ivermectin is widely used in mass drug administrations for controlling neglected parasitic diseases, and can be lethal to malaria vectors that bite treated humans. Therefore, it could be a new tool to reduce plasmodium transmission. We tested the hypothesis that frequently repeated mass administrations of ivermectin to village residents would reduce clinical malaria episodes in children and would be well tolerated with minimal harms. METHODS: We invited villages (clusters) in Burkina Faso to participate in a single-blind (outcomes assessor), parallel-assignment, two-arm, cluster-randomised trial over the 2015 rainy season. Villages were assigned (1:1) by random draw to either the intervention group or the control group. In both groups, all eligible participants who consented to the treatment and were at least 90 cm in height received single oral doses of ivermectin (150-200 µg/kg) and albendazole (400 mg), and those in the intervention group received five further doses of ivermectin alone at 3-week intervals thereafter over the 18-week treatment phase. The primary outcome was cumulative incidence of uncomplicated malaria episodes over 18 weeks (analysed on a cluster intention-to-treat basis) in an active case detection cohort of children aged 5 years or younger living in the study villages. This trial is registered with ClinicalTrials.gov, number NCT02509481. FINDINGS: Eight villages agreed to participate, and four were randomly assigned to each group. 2712 participants (1333 [49%] males and 1379 [51%] females; median age 15 years [IQR 6-34]), including 590 children aged 5 years or younger, provided consent and were enrolled between May 22 and July 20, 2015 (except for 77 participants enrolled after these dates because of unavailability before the first mass drug administration, travel into the village during the trial, or birth), with 1447 enrolled into the intervention group and 1265 into the control group. 330 (23%) participants in the intervention group and 233 (18%) in the control group met the exclusion criteria for mass drug administration. Most children in the active case detection cohort were not treated because of height restrictions. 14 (4%) children in the intervention group and 10 (4%) in the control group were lost to follow-up. Cumulative malaria incidence was reduced in the intervention group (648 episodes among 327 children; estimated mean 2·00 episodes per child) compared with the control group (647 episodes among 263 children; 2·49 episodes per child; risk difference -0·49 [95% CI -0·79 to -0·21], p=0·0009, adjusted for sex and clustering). The risk of adverse events among all participants did not differ between groups (45 events [3%] among 1447 participants in the intervention group vs 24 events [2%] among 1265 in the control group; risk ratio 1·63 [1·01 to 2·67]; risk difference 1·21 [0·04 to 2·38], p=0·060), and no adverse reactions were reported. INTERPRETATION: Frequently repeated mass administrations of ivermectin during the malaria transmission season can reduce malaria episodes among children without significantly increasing harms in the populace. FUNDING: Bill & Melinda Gates Foundation.

Ultra-sensitive RDT performance and antigen dynamics in a high-transmission Plasmodium falciparum setting in Mali.

BACKGROUND: The recent expansion of tools designed to accurately quantify malaria parasite-produced antigens has enabled us to evaluate the performance of rapid diagnostic tests (RDTs) as a function of the antigens they detect-typically histidine rich protein 2 (HRP2) or lactate dehydrogenase (LDH). METHODS: For this analysis, whole blood specimens from a longitudinal study in Bancoumana, Mali were used to evaluate the performance of the ultra-sensitive HRP2-based Alere™ Malaria Ag P.f RDT (uRDT). The samples were collected as part of a transmission-blocking vaccine trial in a high transmission region for Plasmodium falciparum malaria. Furthermore, antigen dynamics after successful anti-malarial drug treatment were evaluated in these samples using the Q-Plex Human Malaria Array (4-Plex) to quantify antigen concentrations. RESULTS: The uRDT had a 50% probability of a positive result at 207 pg/mL HRP2 [95% credible interval (CrI) 160-268]. Individuals with symptomatic infection remained positive by uRDT for a median of 33 days [95% confidence interval (CI) 28-47] post anti-malarial drug treatment. Biphasic exponential decay models accurately captured the population level post-treatment dynamics of both HRP2 and Plasmodium LDH (pLDH), with the latter decaying more rapidly. Motivated by these differences in rates of decay, a novel algorithm that used HRP2:pLDH ratios to predict if an individual had active versus recently cleared P. falciparum infection was developed. The algorithm had 77.5% accuracy in correctly classifying antigen-positive individuals as those with and without active infection. CONCLUSIONS: These results characterize the performance of the ultra-sensitive RDT and demonstrate the potential for emerging antigen-quantifying technologies in the field of malaria diagnostics to be helpful tools in distinguishing between active versus recently cleared malaria infections.

The Relative Contribution of Symptomatic and Asymptomatic Plasmodium vivax and Plasmodium falciparum Infections to the Infectious Reservoir in a Low-Endemic Setting in Ethiopia.

Background: The majority of Plasmodium vivax and Plasmodium falciparum infections in low-endemic settings are asymptomatic. The relative contribution to the infectious reservoir of these infections compared to clinical malaria cases is currently unknown. Methods: We assessed infectivity of passively recruited symptomatic malaria patients (n = 41) and community-recruited asymptomatic individuals with microscopy-detected (n = 41) and polymerase chain reaction (PCR)-detected infections (n = 82) using membrane feeding assays with Anopheles arabiensis mosquitoes in Adama, Ethiopia. Malaria incidence and prevalence data were used to estimate the contributions of these populations to the infectious reservoir. Results: Overall, 34.9% (29/83) of P. vivax- and 15.1% (8/53) P. falciparum-infected individuals infected ≥1 mosquitoes. Mosquito infection rates were strongly correlated with asexual parasite density for P. vivax (ρ = 0.63; P < .001) but not for P. falciparum (ρ = 0.06; P = .770). Plasmodium vivax symptomatic infections were more infectious to mosquitoes (infecting 46.5% of mosquitoes, 307/660) compared to asymptomatic microscopy-detected (infecting 12.0% of mosquitoes, 80/667; P = .005) and PCR-detected infections (infecting 0.8% of mosquitoes, 6/744; P < .001). Adjusting for population prevalence, symptomatic, asymptomatic microscopy-detected, and PCR-detected infections were responsible for 8.0%, 76.2%, and 15.8% of the infectious reservoir for P. vivax, respectively. For P. falciparum, mosquito infections were sparser and also predominantly from asymptomatic infections. Conclusions: In this low-endemic setting aiming for malaria elimination, asymptomatic infections were highly prevalent and responsible for the majority of onward mosquito infections. The early identification and treatment of asymptomatic infections might accelerate elimination efforts.

Pfhrp2-Deleted Plasmodium falciparum Parasites in the Democratic Republic of the Congo: A National Cross-sectional Survey.

Background: Rapid diagnostic tests (RDTs) account for more than two-thirds of malaria diagnoses in Africa. Deletions of the Plasmodium falciparum hrp2 (pfhrp2) gene cause false-negative RDT results and have never been investigated on a national level. Spread of pfhrp2-deleted P. falciparum mutants, resistant to detection by HRP2-based RDTs, would represent a serious threat to malaria elimination efforts. Methods: Using a nationally representative cross-sectional study of 7,137 children under five years of age from the Democratic Republic of Congo (DRC), we tested 783 subjects with RDT-/PCR+ results using PCR assays to detect and confirm deletions of the pfhrp2 gene. Spatial and population genetic analyses were employed to examine the distribution and evolution of these parasites. Results: We identified 149 pfhrp2-deleted parasites, representing 6.4% of all P. falciparum infections country-wide (95% confidence interval 5.1-8.0%). Bayesian spatial analyses identified statistically significant clustering of pfhrp2 deletions near Kinshasa and Kivu. Population genetic analysis revealed significant genetic differentiation between wild-type and pfhrp2-deleted parasite populations (GST = .046, p ≤ .00001). Conclusions: Pfhrp2-deleted P. falciparum is a common cause of RDT-/PCR+ malaria among asymptomatic children in the DRC and appears to be clustered within select communities. Surveillance for these deletions is needed, and alternatives to HRP2-specific RDTs may be necessary.

The US President's Malaria Initiative, Plasmodium falciparum transmission and mortality: A modelling study.

BACKGROUND: Although significant progress has been made in reducing malaria transmission globally in recent years, a large number of people remain at risk and hence the gains made are fragile. Funding lags well behind amounts needed to protect all those at risk and ongoing contributions from major donors, such as the President's Malaria Initiative (PMI), are vital to maintain progress and pursue further reductions in burden. We use a mathematical modelling approach to estimate the impact of PMI investments to date in reducing malaria burden and to explore the potential negative impact on malaria burden should a proposed 44% reduction in PMI funding occur. METHODS AND FINDINGS: We combined an established mathematical model of Plasmodium falciparum transmission dynamics with epidemiological, intervention, and PMI-financing data to estimate the contribution PMI has made to malaria control via funding for long-lasting insecticide treated nets (LLINs), indoor residual spraying (IRS), and artemisinin combination therapies (ACTs). We estimate that PMI has prevented 185 million (95% CrI: 138 million, 230 million) malaria cases and saved 940,049 (95% CrI: 545,228, 1.4 million) lives since 2005. If funding is maintained, PMI-funded interventions are estimated to avert a further 162 million (95% CrI: 116 million, 194 million) cases, saving a further 692,589 (95% CrI: 392,694, 955,653) lives between 2017 and 2020. With an estimate of US$94 (95% CrI: US$51, US$166) per Disability Adjusted Life Year (DALY) averted, PMI-funded interventions are highly cost-effective. We also demonstrate the further impact of this investment by reducing caseloads on health systems. If a 44% reduction in PMI funding were to occur, we predict that this loss of direct aid could result in an additional 67 million (95% CrI: 49 million, 82 million) cases and 290,649 (95% CrI: 167,208, 395,263) deaths between 2017 and 2020. We have not modelled indirect impacts of PMI funding (such as health systems strengthening) in this analysis. CONCLUSIONS: Our model estimates that PMI has played a significant role in reducing malaria cases and deaths since its inception. Reductions in funding to PMI could lead to large increases in the number of malaria cases and deaths, damaging global goals of malaria control and elimination.

A novel model fitted to multiple life stages of malaria for assessing efficacy of transmission-blocking interventions.

BACKGROUND: Transmission-blocking interventions (TBIs) aim to eliminate malaria by reducing transmission of the parasite between the host and the invertebrate vector. TBIs include transmission-blocking drugs and vaccines that, when given to humans, are taken up by mosquitoes and inhibit parasitic development within the vector. Accurate methodologies are key to assess TBI efficacy to ensure that only the most potent candidates progress to expensive and time-consuming clinical trials. Measuring intervention efficacy can be problematic because there is substantial variation in the number of parasites in both the host and vector populations, which can impact transmission even in laboratory settings. METHODS: A statistically robust empirical method is introduced for estimating intervention efficacy from standardised population assay experiments. This method will be more reliable than simple summary statistics as it captures changes in parasite density in different life-stages. It also allows efficacy estimates at a finer resolution than previous methods enabling the impact of the intervention over successive generations to be tracked. A major advantage of the new methodology is that it makes no assumptions on the population dynamics of infection. This enables both host-to-vector and vector-to-host transmission to be density-dependent (or other) processes and generates easy-to-understand estimates of intervention efficacy. RESULTS: This method increases the precision of intervention efficacy estimates and demonstrates that relying on changes in infection prevalence (the proportion of infected hosts) alone may be insufficient to capture the impact of TBIs, which also suppress parasite density in secondarily infected hosts. CONCLUSIONS: The method indicates that potentially useful, partially effective TBIs may require multiple infection cycles before substantial reductions in prevalence are observed, despite more rapidly suppressing parasite density. Accurate models to quantify efficacy will have important implications for understanding how TBI candidates might perform in field situations and how they should be evaluated in clinical trials.

Assessing the potential impact of artemisinin and partner drug resistance in sub-Saharan Africa.

BACKGROUND: Artemisinin and partner drug resistant malaria parasites have emerged in Southeast Asia. If resistance were to emerge in Africa it could have a devastating impact on malaria-related morbidity and mortality. This study estimates the potential impact of artemisinin and partner drug resistance on disease burden in Africa if it were to emerge. METHODS: Using data from Asia and Africa, five possible artemisinin and partner drug resistance scenarios are characterized. An individual-based malaria transmission model is used to estimate the impact of each resistance scenario on clinical incidence and parasite prevalence across Africa. Artemisinin resistance is characterized by slow parasite clearance and partner drug resistance is associated with late clinical failure or late parasitological failure. RESULTS: Scenarios with high levels of recrudescent infections resulted in far greater increases in clinical incidence compared to scenarios with high levels of slow parasite clearance. Across Africa, it is estimated that artemisinin and partner drug resistance at levels similar to those observed in Oddar Meanchey province in Cambodia could result in an additional 78 million cases over a 5 year period, a 7% increase in cases compared to a scenario with no resistance. A scenario with high levels of slow clearance but no recrudescence resulted in an additional 10 million additional cases over the same period. CONCLUSION: Artemisinin resistance is potentially a more pressing concern than partner drug resistance due to the lack of viable alternatives. However, it is predicted that a failing partner drug will result in greater increases in malaria cases and morbidity than would be observed from artemisinin resistance only.

Efficacy and safety of the mosquitocidal drug ivermectin to prevent malaria transmission after treatment: a double-blind, randomized, clinical trial.

BACKGROUND: Artemisinin combination therapy effectively clears asexual malaria parasites and immature gametocytes but does not prevent posttreatment malaria transmission. Ivermectin (IVM) may reduce malaria transmission by killing mosquitoes that take blood meals from IVM-treated humans. METHODS: In this double-blind, placebo-controlled trial, 120 asymptomatic Plasmodium falciparum parasite carriers were randomized to receive artemether-lumefantrine (AL) plus placebo or AL plus a single or repeated dose (200 µg/kg) of ivermectin (AL-IVM1 and AL-IVM2, respectively). Mosquito membrane feeding was performed 1, 3, and 7 days after initiation of treatment to determine Anopheles gambiae and Anopheles funestus survival and infection rates. RESULTS: The AL-IVM combination was well tolerated. IVM resulted in a 4- to 7-fold increased mortality in mosquitoes feeding 1 day after IVM (P < .001). Day 7 IVM plasma levels were positively associated with body mass index (r = 0.57, P < .001) and were higher in female participants (P = .003), for whom An. gambiae mosquito mortality was increased until 7 days after a single dose of IVM (hazard rate ratio, 1.34 [95% confidence interval, 1.07-1.69]; P = .012). Although we found no evidence that IVM reduced Plasmodium infection rates among surviving mosquitoes, the mosquitocidal effect of AL-IVM1 and AL-IVM2 resulted in 27% and 35% reductions, respectively, in estimated malaria transmission potential during the first week after initiation of treatment. CONCLUSIONS: We conclude that IVM can be safely given in combination with AL and can reduce the likelihood of malaria transmission by reducing the life span of feeding mosquitoes. CLINICAL TRIALS REGISTRATION: NCT0160325.

The potential impact of adding ivermectin to a mass treatment intervention to reduce malaria transmission: a modelling study.

BACKGROUND: Ivermectin (IVM), used alongside mass treatment strategies with an artemisinin combination therapy, has been suggested as a possible tool for reducing malaria transmission. Mosquitoes ingesting a bloodmeal containing IVM have increased mortality, reducing the probability that the parasite completes sporogony. METHODS: Human pharmacokinetic data and mortality data for mosquitoes taking bloodmeals containing IVM are used to quantify the mosquitocidal effect of IVM. These are incorporated into a transmission model to estimate the impact of IVM in combination with mass treatment strategies with artemether-lumefantrine on transmission metrics. RESULTS: Adding IVM increases the reductions in parasite prevalence achieved and delays the reemergence of parasites compared to mass treatment alone. This transmission effect is obtained through its effect on vector mortality. IVM effectiveness depends on coverage with the highest impact achieved if given to the whole population rather than only those with existing detectable parasites. Our results suggest that including IVM in a mass treatment strategy can reduce the time taken to interrupt transmission as well as help to achieve transmission interruption in transmission settings in which mass treatment strategies alone would be insufficient. CONCLUSIONS: Including IVM in mass treatment strategies could be a useful adjunct to reduce and interrupt malaria transmission.

Modelling co-infection with malaria and lymphatic filariasis.

Malaria and lymphatic filariasis (LF) continue to cause a considerable public health burden globally and are co-endemic in many regions of sub-Saharan Africa. These infections are transmitted by the same mosquito species which raises important questions about optimal vector control strategies in co-endemic regions, as well as the effect of the presence of each infection on endemicity of the other; there is currently little consensus on the latter. The need for comprehensive modelling studies to address such questions is therefore significant, yet very few have been undertaken to date despite the recognised explanatory power of reliable dynamic mathematical models. Here, we develop a malaria-LF co-infection modelling framework that accounts for two key interactions between these infections, namely the increase in vector mortality as LF mosquito prevalence increases and the antagonistic Th1/Th2 immune response that occurs in co-infected hosts. We consider the crucial interplay between these interactions on the resulting endemic prevalence when introducing each infection in regions where the other is already endemic (e.g. due to regional environmental change), and the associated timescale for such changes, as well as effects on the basic reproduction number R0 of each disease. We also highlight potential perverse effects of vector controls on human infection prevalence in co-endemic regions, noting that understanding such effects is critical in designing optimal integrated control programmes. Hence, as well as highlighting where better data are required to more reliably address such questions, we provide an important framework that will form the basis of future scenario analysis tools used to plan and inform policy decisions on intervention measures in different transmission settings.

Analytical Sensitivity Analysis and Clinical Impact Modeling of Rapigen Rapid Diagnostic Tests for Malaria.

Laboratory benchmarking allows objective analysis of the analytical performance of malaria rapid diagnostic tests (RDTs). We present the analytical detection limits of the Rapigen BIOCREDIT Malaria Ag Pf/Pv (pLDH/pLDH), the Rapigen BIOCREDIT Malaria Ag Pf (pLDH/HRPII), and two best-in-class WHO-prequalified comparator RDTs, generated using standardized panels containing recombinant antigen, in vitro cultured parasites, international standards, and clinical samples. Detection limit antigen concentrations of HRP2, PfLDH, and PvLDH were determined for the Rapigen and comparator RDTs. Detection of antigens in international units (IU)/mL was also evaluated. The Rapigen Ag Pf (pLDH/HRPII) detected 3.9 and 3.9 IU/mL for PfLDH and HRP2, respectively, and the Ag Pf/Pv (pLDH/pLDH) detected 3.9 and 5.0 IU/mL for PfLDH and PvLDH, respectively. The comparator HRP2/PfLDH and HRP2/PvLDH detected 15.6 and 31.3 IU/mL for HRP2 and PfLDH and 15.6 and 50.0 IU/mL for HRP2 and PvLDH, respectively. The RDT clinical sensitivity was predicted through application of analytical detection limits to antigen concentration distributions from clinical symptomatic and asymptomatic cases. Febrile cases would be detected in a majority by both standard and Rapigen RDTs, but incremental increases in sensitivity in the Rapigen RDTs may be important for clinical cases currently missed by microscopy. Rapigen RDTs were predicted to have improved detection of asymptomatic cases and infections with parasites carrying hrp2 deletions through more sensitive PfLDH detection. Through the benchmarking and simulation of clinical sensitivity, a method for rapidly assessing the ability of new RDTs to meet clinical needs using high-sensitivity antigen distribution data is presented.

Repeat Ivermectin Mass Drug Administrations for Malaria Control II: Protocol for a Double-blind, Cluster-Randomized, Placebo-Controlled Trial for the Integrated Control of Malaria.

BACKGROUND: The gains made against malaria have stagnated since 2015, threatened further by increasing resistance to insecticides and antimalarials. Improvement in malaria control necessitates a multipronged strategy, which includes the development of novel tools. One such tool is mass drug administration (MDA) with endectocides, primarily ivermectin, which has shown promise in reducing malaria transmission through lethal and sublethal impacts on the mosquito vector. OBJECTIVE: The primary objective of the study is to assess the impact of repeated ivermectin MDA on malaria incidence in children aged ≤10 years. METHODS: Repeat Ivermectin MDA for Malaria Control II is a double-blind, placebo-controlled, cluster-randomized, and parallel-group trial conducted in a setting with intense seasonal malaria transmission in Southwest Burkina Faso. The study included 14 discrete villages: 7 (50%) randomized to receive standard measures (seasonal malaria chemoprevention [SMC] and bed net use for children aged 3 to 59 months) and placebo, and 7 (50%) randomized to receive standard measures and monthly ivermectin MDA at 300 µg/kg for 3 consecutive days, provided under supervision to all eligible village inhabitants, over 2 successive rainy seasons. Nonpregnant individuals >90 cm in height were eligible for ivermectin MDA, and cotreatment with ivermectin and SMC was not permitted. The primary outcome is malaria incidence in children aged ≤10 years, as assessed by active case surveillance. The secondary safety outcome of repeated ivermectin MDA was assessed through active and passive adverse event monitoring. RESULTS: The trial intervention was conducted from July to November in 2019 and 2020, with additional sampling of humans and mosquitoes occurring through February 2022 to assess postintervention changes in transmission patterns. Additional human and entomological assessments were performed over the 2 years in a subset of households from 6 cross-sectional villages. A subset of individuals underwent additional sampling in 2020 to characterize ivermectin pharmacokinetics and pharmacodynamics. Analysis and unblinding will commence once the database has been completed, cleaned, and locked. CONCLUSIONS: Our trial represents the first study to directly assess the impact of a novel approach for malaria control, ivermectin MDA as a mosquitocidal agent, layered into existing standard-of-care interventions. The study was designed to leverage the current SMC deployment infrastructure and will provide evidence regarding the additional benefit of ivermectin MDA in reducing malaria incidence in children. TRIAL REGISTRATIONS: ClinicalTrials.gov NCT03967054; https://clinicaltrials.gov/ct2/show/NCT03967054 and Pan African Clinical Trials Registry PACT201907479787308; https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=8219. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/41197.