Optimising Malaria Control Interventions in Mali Based on Epidemiological Surveillance and Rainfall Data

Background In malaria endemic countries, control interventions are performed during the high malaria transmission season using epidemiological surveillance data. One such intervention, seasonal chemoprevention (SMC), consists of the monthly administration of antimalarial drugs to children under 5 years. This study proposes an anticipating approach for adapting the timing of SMC interventions in Mali and the number of rounds. Our primary objective was to select the best approach for anticipating the onset of the high transmission season in the different health districts of Mali based on epidemiological surveillance and rainfall data. Our secondary objective was to evaluate the number of malaria cases, hospitalisations, and deaths in children under 5 years that could be prevented in Mali using the selected approach and the additional cost associated.Method Confirmed malaria cases and weekly rainfall data were collected for the 75 health districts of Mali for the 2014-2019 period. The onset of the rainy season, the onset of the high transmission season, the lag between these two events and the duration of the high transmission season were determined for each health district. Two approaches for anticipating the onset of the high transmission season in 2019 were evaluated. Results In 2014-2019, the onset of the rainy season ranged from W17 April to W34 August and that of the high transmission season from W25 June to W40 September. The lag between these two events ranged from 5 to 12 weeks. The duration of the high transmission season ranged from 3 to 6 months. The best approach anticipated the onset of the high transmission season 2019 in June in 2 districts, July in 46 districts, August in 21 districts and September in 6 districts. Using this approach over the 2014-2019 period would have led to changing the timing of SMC interventions in 36 health districts and would have prevented 43,819 cases, 1,943 hospitalisations and 70 deaths in children under 5 years. The additional cost of using our proposed approach is less than 5% of the current approach. Conclusion Adapting the timing of SMC interventions using our proposed approach would improve the prevention of malaria cases, hospitalisations, and deaths for a reasonable additional cost.

Evaluating the efficacy, impact, and feasibility of community-based house screening as a complementary malaria control intervention in southern Africa: a study protocol for a household randomized trial

Background Concerted effort to control malaria has had a substantial impact on the transmission of the disease in the past two decades. In areas where reduced malaria transmission is being sustained through insecticide-based vector control interventions, primarily long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS), non-insecticidal complementary tools will likely be needed to push towards malaria elimination. Once interruption in local disease transmission is achieved, insecticide-based measures can be scaled down gradually and eventually phased out, saving on costs of sustaining control programs and mitigating any unintended negative health and environmental impacts posed by insecticides. These non-insecticidal methods could eventually replace insecticidal methods of vector control. House screening, a non-insecticidal method, has a long history in malaria control, but is still not widely adopted in sub-Saharan Africa. This study aims to add to the evidence base for this intervention in low transmission settings by assessing the efficacy, impact, and feasibility of house screening in areas where LLINs are conventionally used for malaria control. Methods A two-armed, household randomized clinical trial will be conducted in Mozambique, Zambia, and Zimbabwe to evaluate whether combined the use of house screens and LLINs affords better protection against clinical malaria in children between 6 months and 13 years compared to the sole use of LLINs. Eight hundred households will be enrolled in each study area, where 400 households will be randomly assigned the intervention, house screening, and LLINs while the control households will be provided with LLINs only. Clinical malaria incidence will be estimated by actively following up one child from each household for 6 months over the malaria transmission season. Cross-sectional parasite prevalence will be estimated by testing all participating children for malaria parasites at the beginning and end of each transmission season using rapid diagnostic tests. CDC light traps and pyrethrum spray catches (PSC) will be used to sample adult mosquitoes and evaluate the impact of house screening on indoor mosquito density, species distribution, and sporozoite rates. Discussion This study will contribute epidemiological data on the impact of house screening on malaria transmission and assess the feasibility of its implementation on a programmatic scale. Trial registration ClinicalTrials.gov PACTR202008524310568. Registered on August 11, 2020.

Emergence of a New Lineage 1C Variant of Porcine Reproductive and Respiratory Syndrome Virus 2 in the United States

We report an ongoing regional outbreak of an emerging porcine reproductive and respiratory syndrome virus (PRRSV2) variant within Lineage 1C affecting 154 breeding and grow-finishing sites in the Midwestern U.S. Transmission seemed to have occurred in two waves, with the first peak of weekly cases occurring between October and December 2020 and the second starting in April 2021. Most of cases occurred within a 120 km radius. Both orf5 and whole genome sequencing results suggest that this represents the emergence of a new variant within Lineage 1C distinct from what has been previously circulating. A case-control study was conducted with 50 cases (sites affected with the newly emerged variant) and 58 controls (sites affected with other PRRSV variants) between October and December 2020. Sites that had a market vehicle that was not exclusive to the production system had 0.04 times the odds of being a case than a control. A spatial cluster (81.42 km radius) with 1.68 times higher the number of cases than controls was found. The average finishing mortality within the first 4 weeks after detection was higher amongst cases (4.50%) than controls (0.01%). The transmission of a highly similar virus between different farms carrying on trough spring rises concerns for the next high transmission season of PRRS.

Infection risk varies within urbanized landscapes: the case of coyotes and heartworm

Background Urbanization can have profound effects on ecological interactions. For host–pathogen interactions, differences have been detected between urban and non-urban landscapes. However, host–pathogen interactions may also differ within highly heterogeneous, urbanized landscapes. Methods We investigated differences in infection risk (i.e., probability of infection) within urbanized landscapes using the coyote (Canis latrans) and mosquito-borne nematode, Dirofilaria immitis (the causative agent for canine heartworm), as a case study. We focused on a coyote population in Chicago for which extensive behavioral and heartworm infection data has been collected between 2001 and 2016. Our objectives were to: (i) determine how onset and duration of the heartworm transmission season varied over the 16-year period and across the urban–suburban gradient; and (ii) investigate how heartworm infection risk in coyotes varied over the years, across the urban–suburban gradient, by coyote characteristics (e.g., age, sex, resident status), and coyote use of the urbanized landscape (e.g., use of urban areas, mosquito habitats). Results While onset of the heartworm transmission season differed neither by year nor across the urban–suburban gradient, it was longer closer to the core of Chicago. Of the 315 coyotes sampled, 31.1% were infected with D. immitis. Older coyotes and coyotes sampled in later years (i.e., 2012–2016) were more likely to have heartworm. While coyote location in the urban–suburban gradient was not a significant predictor of infection, the proportion of urban land in coyote home ranges was. Importantly, the size and direction of this association varied by age class. For adults and pups, infection risk declined with urbanization, whereas for subadults it increased. Further, models had a higher predictive power when focusing on resident coyotes (and excluding transient coyotes). The proportion of mosquito habitat in coyote home ranges was not a significant predictor of infection. Conclusions Our findings suggest that urbanization may affect host exposure to vectors of D. immitis, that risk of infection can vary within urbanized landscapes, and that urbanization–wildlife infection associations may only be detected for animals with certain characteristics (e.g., age class and resident status). Graphical abstract

Malaria Positivity Following a Single Oral Dose of Azithromycin Among Children in Burkina Faso: A Randomized Controlled Trial

Background. Azithromycin is a broad-spectrum antibiotic that has moderate antimalarial activity and has been shown to reduce all-cause mortality when biannually administered to children under five in high mortality settings in sub-Saharan Africa. One potential mechanism for this observed reduction in mortality is via a reduction in malaria transmission.Methods. We evaluated whether a single oral dose of azithromycin reduces malaria positivity by rapid diagnostic test (RDT). We conducted an individually randomized placebo-controlled trial in Burkina Faso during the high malaria transmission season in August 2020. Children aged 8 days to 59 months old were randomized to a single oral dose of azithromycin (20 mg/kg) or matching placebo. At baseline and 14 days following treatment, we administered a rapid diagnostic test (RDT) to detect Plasmodium falciparum and measured tympanic temperature for all children. Caregiver-reported adverse events and clinic visits were recorded at the day 14 visit. Results. We enrolled 449 children with 221 randomized to azithromycin and 228 to placebo. The median age was 32 months and 48% were female. A total of 8% of children had a positive RDT for malaria at baseline and 11% had a fever (tympanic temperature ³37.5°C). In the azithromycin arm, 8% of children had a positive RDT for malaria at 14 days compared to 7% in the placebo arm (P=0.65). Fifteen percent of children in the azithromycin arm had a fever ³37.5°C compared to 21% in the placebo arm (P=0.12). Caregivers of children in the azithromycin group had lower odds of reporting fever as an adverse event compared to children in the placebo group (OR 0.41, 95% CI 0.18-0.96, P=0.04). Caregiver-reported clinic visits were uncommon, and there were no observed differences between arms (P=0.32).Conclusions. We did not find evidence that a single oral dose of azithromycin reduced malaria positivity during the high transmission season. Caregiver-reported fever occurred less often in children receiving azithromycin compared to placebo, indicating that azithromycin may have some effect on non-malarial infections. Trial Registration: NCT03676751

Malian adults maintain serologic responses to virulent PfEMP1s amid seasonal patterns of fluctuation

Plasmodium falciparum erythrocyte membrane protein-1s (PfEMP1s), diverse malaria proteins expressed on the infected erythrocyte surface, play an important role in pathogenesis, mediating adhesion to host vascular endothelium. Antibodies to particular non-CD36-binding PfEMP1s are associated with protection against severe disease. We hypothesized that given lifelong P. falciparum exposure, Malian adults would have broad PfEMP1 serorecognition and high seroreactivity levels during follow-up, particularly to non-CD36-binding PfEMP1s such as those that attach to endothelial protein C receptor (EPCR) and intercellular adhesion molecule-1 (ICAM-1). Using a protein microarray, we determined serologic responses to 166 reference PfEMP1 fragments during a dry and subsequent malaria transmission season in Malian adults. Malian adult sera had PfEMP1 serologic responses throughout the year, with decreased reactivity to a small subset of PfEMP1 fragments during the dry season and increases in reactivity to a different subset of PfEMP1 fragments during the subsequent peak malaria transmission season, especially for intracellular PfEMP1 domains. For some individuals, PfEMP1 serologic responses increased after the dry season, suggesting antigenic switching during asymptomatic infection. Adults were more likely to experience variable serorecognition of CD36-binding PfEMP1s than non-CD36-binding PfEMP1s that bind EPCR or ICAM-1, which remained serorecognized throughout the year. Sustained seroreactivity to non-CD36-binding PfEMP1s throughout adulthood amid seasonal fluctuation patterns may reflect underlying protective severe malaria immunity and merits further investigation.

Model-informed target product profiles of long acting-injectables for use as seasonal malaria prevention

Seasonal malaria chemoprevention (SMC) has proven highly efficacious in reducing malaria incidence. However, the continued success of SMC is threatened by the spread of resistance against one of its main preventive ingredients, Sulfadoxine-Pyrimethamine(SP), operational challenges in delivery, and incomplete adherence to the regimens. Via a simulation study with an individual-based model of malaria dynamics, we provide quantitative evidence to assess long-acting injectables (LAIs) as potential alternatives to SMC. We explored the predicted impact of a range of novel preventive LAIs as a seasonal prevention tool in children aged three months to five years old during late-stage clinical trials and at implementation. LAIs were co-administered with a blood-stage clearing drug once at the beginning of the transmission season. We found the establishment of non-inferiority of LAIs to standard 3 or 4 rounds of SMC with SP-amodiaquine was challenging in clinical trial stages due to high intervention deployment coverage. However, our analysis of implementation settings where the achievable SMC coverage was much lower, LAIs with fewer visits per season are potential suitable replacements to SMC. Suitability as a replacement with higher impact is possible if the duration of protection of LAIs covered the duration of the transmission season. Furthermore, optimizing LAIs coverage and protective efficacy half-life via simulation analysis in settings with an SMC coverage of 60% revealed important trade-offs between protective efficacy decay and deployment coverage. Our analysis additionally highlights that for seasonal deployment for LAIs, it will be necessary to investigate the protective efficacy decay as early as possible during clinical development to ensure a well-informed candidate selection process.

Malaria and dengue in Hodeidah city, Yemen: High proportion of febrile outpatients with dengue or malaria, but low proportion co-infected

Background The emergence of dengue in malaria-endemic countries with limited diagnostic resources, such as Yemen, can be problematic because presumptive treatment of febrile cases as being malaria is a common practice. Co-infections with dengue and malaria are often overlooked and misdiagnosed as being a mono-infection because of clinical similarities. In Hodeidah city, Yemen, the capacity to conduct the diagnosis can be aggravated by the war context. To assess the magnitude of the problem, we determined the proportions of malaria, dengue and co-infection in relation to clinical characteristics among febrile outpatients. Methods This cross-sectional study included 355 febrile outpatients from Hodeidah city during the malaria transmission season (September 2018 –February 2019). Sociodemographic and clinical characteristics were collected using a pre-designed, structured questionnaire. Malaria was confirmed using microscopy and rapid diagnostic tests (RDTs), while dengue was confirmed using RDTs. Results Mono-infection proportions of 32.4% for falciparum malaria and 35.2% for dengue were found, where about two-thirds of dengue patients had a recent probable infection. However, co-infection with falciparum malaria and dengue was detected among 4.8% of cases. There was no statistically significant difference between having co-infection and mono-infection with malaria or dengue in relation to the sociodemographic characteristics. On the other hand, the odds of co-infection were significantly lower than the odds of malaria among patients presenting with sweating (OR = 0.1, 95% CI: 0.05–0.45; p <0.001), while the odds of co-infection were 3.5 times significantly higher than the odds of dengue among patients presenting with vomiting (OR = 3.5, 95% CI: 1.20–10.04; p <0.021). However, there were no statistically significant differences between having co-infection and mono-infection (malaria or dengue) in relation to other clinical characteristics. Conclusions Mono-infection with malaria or dengue can be detected among about one-third of febrile outpatients in Hodeidah, while almost 5.0% of cases can be co-infected. Sociodemographic and clinical characteristics cannot easily distinguish malaria patients from dengue-infected or co-infected ones, reinforcing the necessity of laboratory confirmation and avoidance of treating febrile patients as being presumed malaria cases.