Showing papers by "Immo Kleinschmidt published in 2021"

Assessing the efficacy of two dual-active ingredients long-lasting insecticidal nets for the control of malaria transmitted by pyrethroid-resistant vectors in Benin: study protocol for a three-arm, single-blinded, parallel, cluster-randomized controlled trial.

Abstract: Long-lasting insecticidal nets (LLINs) are currently the primary method of malaria control in sub-Saharan Africa and have contributed to a significant reduction in malaria burden over the past 15 years. However, this progress is threatened by the wide-scale selection of insecticide-resistant malaria vectors. It is, therefore, important to accelerate the generation of evidence for new classes of LLINs. This protocol presents a three-arm superiority, single-blinded, cluster randomized controlled trial to evaluate the impact of 2 novel dual-active ingredient LLINs on epidemiological and entomological outcomes in Benin, a malaria-endemic area with highly pyrethroid-resistant vector populations. The study arms consist of (i) Royal Guard® LLIN, a net combining a pyrethroid (alpha-cypermethrin) plus an insect growth regulator (pyriproxyfen), which in the adult female is known to disrupt reproduction and egg fertility; (ii) Interceptor G2® LLIN, a net incorporating two adulticides (alpha-cypermethrin and chlorfenapyr) with different modes of action; and (iii) the control arm, Interceptor® LLIN, a pyrethroid (alpha-cypermethrin) only LLIN. In all arms, one net for every 2 people will be distributed to each household. Sixty clusters were identified and randomised 1:1:1 to each study arm. The primary outcome is malaria case incidence measured over 24 months through active case detection in a cohort of 25 children aged 6 months to 10 years, randomly selected from each cluster. Secondary outcomes include 1) malaria infection prevalence (all ages) and prevalence of moderate to severe anaemia in children under 5 years old, measured at 6 and 18 months post-intervention; 2) entomological indices measured every 3 months using human landing catches over 24 months. Insecticide resistance intensity will also be monitored over the study period. This study is the second cluster randomised controlled trial to evaluate the efficacy of these next-generation LLINs to control malaria transmitted by insecticide-resistant mosquitoes. The results of this study will form part of the WHO evidence-based review to support potential public health recommendations of these nets and shape malaria control strategies of sub-Saharan Africa for the next decade. ClinicalTrials.gov, NCT03931473 , registered on 30 April 2019.

Protocol for a four parallel-arm, single-blind, cluster-randomised trial to assess the effectiveness of three types of dual active ingredient treated nets compared to pyrethroid-only long-lasting insecticidal nets to prevent malaria transmitted by pyrethroid insecticide-resistant vector mosquitoes in Tanzania

Abstract: Introduction The massive scale-up of long-lasting insecticidal nets (LLINs) has led to major reductions in malaria burden in many sub-Saharan African countries. This progress is threatened by widespread insecticide resistance among malaria vectors. This cluster-randomised controlled trial (c-RCT) compares three of the most promising dual active ingredients LLINs (dual-AI LLINs), which incorporate mixtures of insecticides or insecticide synergists to standard LLINs in an area of pyrethroid insecticide resistance. Methods A four-arm, single-blinded, c-RCT will evaluate the effectiveness of three types of dual-AI LLINs (1) Royal Guard, combining two insecticides, pyriproxyfen and the pyrethroid alpha-cypermethrin; (2) Interceptor G2, combining chlorfenapyr and alpha-cypermethrin; (3) Olyset Plus, an LLIN combining a synergist, piperonyl butoxide and the pyrethroid permethrin, compared with; (4) Interceptor LN, a standard LLIN containing the pyrethroid alpha-cypermethrin as the sole AI. The primary outcomes are malaria infection prevalence in children aged 6 months–14 years and entomological inoculation rate (EIR), as a standard measure of malaria transmission at 24 months postintervention and cost-effectiveness. Ethics and dissemination Ethical approval was received from the institutional review boards of the Tanzanian National Institute for Medical Research, Kilimanjaro Christian Medical University College, London School of Hygiene and Tropical Medicine, and University of Ottawa. Study findings will be actively disseminated via reports and presentations to stakeholders, local community leaders, and relevant national and international policy makers as well as through conferences, and peer-reviewed publications. Trial registration number NCT03554616.

Malaria risk factors in northern Namibia: The importance of occupation, age and mobility in characterizing high-risk populations.

Abstract: In areas of low and unstable transmission, malaria cases occur in populations with lower access to malaria services and interventions, and in groups with specific malaria risk exposures often away from the household. In support of the Namibian National Vector Borne Disease Program's drive to better target interventions based upon risk, we implemented a health facility-based case control study aimed to identify risk factors for symptomatic malaria in Zambezi Region, northern Namibia. A total of 770 febrile individuals reporting to 6 health facilities and testing positive by rapid diagnostic test (RDT) between February 2015 and April 2016 were recruited as cases; 641 febrile individuals testing negative by RDT at the same health facilities through June 2016 were recruited as controls. Data on socio-demographics, housing construction, overnight travel, use of malaria prevention and outdoor behaviors at night were collected through interview and recorded on a tablet-based questionnaire. Remotely-sensed environmental data were extracted for geo-located village residence locations. Multivariable logistic regression was conducted to identify risk factors and latent class analyses (LCA) used to identify and characterize high-risk subgroups. The majority of participants (87% of cases and 69% of controls) were recruited during the 2016 transmission season, an outbreak year in Southern Africa. After adjustment, cases were more likely to be cattle herders (Adjusted Odds Ratio (aOR): 4.46 95%CI 1.05-18.96), members of the police or other security personnel (aOR: 4.60 95%CI: 1.16-18.16), and pensioners/unemployed persons (aOR: 2.25 95%CI 1.24-4.08), compared to agricultural workers (most common category). Children (aOR 2.28 95%CI 1.13-4.59) and self-identified students were at higher risk of malaria (aOR: 4.32 95%CI 2.31-8.10). Other actionable risk factors for malaria included housing and behavioral characteristics, including traditional home construction and sleeping in an open structure (versus modern structure: aOR: 2.01 95%CI 1.45-2.79 and aOR: 4.76 95%CI: 2.14-10.57); cross border travel in the prior 30 days (aOR: 10.55 95%CI 2.94-37.84); and outdoor agricultural work at night (aOR: 2.09 95%CI 1.12-3.87). Malaria preventive activities were all protective and included personal use of an insecticide treated net (ITN) (aOR: 0.61 95%CI 0.42-0.87), adequate household ITN coverage (aOR: 0.63 95%CI 0.42-0.94), and household indoor residual spraying (IRS) in the past year (versus never sprayed: (aOR: 0.63 95%CI 0.44-0.90). A number of environmental factors were associated with increased risk of malaria, including lower temperatures, higher rainfall and increased vegetation for the 30 days prior to diagnosis and residing more than 5 minutes from a health facility. LCA identified six classes of cases, with class membership strongly correlated with occupation, age and select behavioral risk factors. Use of ITNs and IRS coverage was similarly low across classes. For malaria elimination these high-risk groups will need targeted and tailored intervention strategies, for example, by implementing alternative delivery methods of interventions through schools and worksites, as well as the use of specific interventions that address outdoor transmission.

Pre-intervention characteristics of the mosquito species in Benin in preparation for a randomized controlled trial assessing the efficacy of dual active-ingredient long-lasting insecticidal nets for controlling insecticide-resistant malaria vectors.

Abstract: BACKGROUND: This study provides detailed characteristics of vector populations in preparation for a three-arm cluster randomized controlled trial (RCT) aiming to compare the community impact of dual active-ingredient (AI) long-lasting insecticidal nets (LLINs) that combine two novel insecticide classes-chlorfenapyr or pyriproxifen-with alpha-cypermethrin to improve the prevention of malaria transmitted by insecticide-resistant vectors compared to standard pyrethroid LLINs. METHODS: The study was carried out in 60 villages across Cove, Zangnanando and Ouinhi districts, southern Benin. Mosquito collections were performed using human landing catches (HLCs). After morphological identification, a sub-sample of Anopheles gambiae s.l. were dissected for parity, analyzed by PCR for species and presence of L1014F kdr mutation and by ELISA-CSP to identify Plasmodium falciparum sporozoite infection. WHO susceptibility tube tests were performed by exposing adult An. gambiae s.l., collected as larvae from each district, to 0.05% alphacypermethrin, 0.75% permethrin, 0.1% bendiocarb and 0.25% pirimiphos-methyl. Synergist assays were also conducted with exposure first to 4% PBO followed by alpha-cypermethrin. RESULTS: An. gambiae s.l. (n = 10807) was the main malaria vector complex found followed by Anopheles funestus s.l. (n = 397) and Anopheles nili (n = 82). An. gambiae s.l. was comprised of An. coluzzii (53.9%) and An. gambiae s.s. (46.1%), both displaying a frequency of the L1014F kdr mutation >80%. Although more than 80% of people slept under standard LLIN, human biting rate (HBR) in An. gambiae s.l. was higher indoors [26.5 bite/person/night (95% CI: 25.2-27.9)] than outdoors [18.5 b/p/n (95% CI: 17.4-19.6)], as were the trends for sporozoite rate (SR) [2.9% (95% CI: 1.7-4.8) vs 1.8% (95% CI: 0.6-3.8)] and entomological inoculation rate (EIR) [21.6 infected bites/person/month (95% CI: 20.4-22.8) vs 5.4 (95% CI: 4.8-6.0)]. Parous rate was 81.6% (95%CI: 75.4-88.4). An. gambiae s.l. was resistant to alpha-cypermethrin and permethrin but, fully susceptible to bendiocarb and pirimiphos-methyl. PBO pre-exposure followed by alpha-cypermethrin treatment induced a higher 24 hours mortality compared to alphacypermethrin alone but not exceeding 40%. CONCLUSIONS: Despite a high usage of standard pyrethroid LLINs, the study area is characterized by intense malaria transmission. The main vectors An. coluzzii and An. gambiae s.s. were both highly resistant to pyrethroids and displayed multiple resistance mechanisms, L1014F kdr mutation and mixed function oxidases. These conditions of the study area make it an appropriate site to conduct the trial that aims to assess the effect of novel dual-AI LLINs on malaria transmitted by insecticide-resistant vectors.

Community acceptance of reactive focal mass drug administration and reactive focal vector control using indoor residual spraying, a mixed‐methods study in Zambezi region, Namibia

Abstract: In Namibia, as in many malaria elimination settings, reactive case detection (RACD), or malaria testing and treatment around index cases, is a standard intervention Reactive focal mass drug administration (rfMDA), or treatment without testing, and reactive focal vector control (RAVC) in the form of indoor residual spraying, are alternative or adjunctive interventions, but there are limited data regarding their community acceptability A parent trial aimed to compare the effectiveness of rfMDA versus RACD, RAVC versus no RAVC, and rfMDA + RAVC versus RACD only To assess acceptability of these interventions, a mixed-methods study was conducted using key informant interviews (KIIs) and focus group discussions (FGDs) in three rounds (pre-trial and in years 1 and 2 of the trial), and an endline survey In total, 17 KIIs, 49 FGDs were conducted with 449 people over three annual rounds of qualitative data collection Pre-trial, community members more accurately predicted the level of community acceptability than key stakeholders Throughout the trial, key participant motivators included: malaria risk perception, access to free community-based healthcare and IRS, and community education by respectful study teams RACD or rfMDA were offered to 1372 and 8948 individuals in years 1 and 2, respectively, and refusal rates were low (< 2%) RAVC was offered to few households (n = 72) in year 1 In year 2, RAVC was offered to more households (n = 944) and refusals were < 1% In the endline survey, 943% of 2147 respondents said they would participate in the same intervention again Communities found both reactive focal interventions and their combination highly acceptable Engaging communities and centering and incorporating their perspectives and experiences during design, implementation, and evaluation of this community-based intervention was critical for optimizing study engagement

Serological evaluation of a cluster randomised trial on the use of reactive focal mass drug administration and reactive vector control to reduce malaria transmission in Zambezi Region, Namibia

Abstract: Due to challenges in measuring changes in malaria in low transmission settings, serology is increasingly being used to complement clinical and parasitological surveillance. Longitudinal cohort studies have shown serological markers, such as Etramp5.Ag1, to be particularly discriminatory of spatio-temporal differences in malaria transmission. However, these markers have yet to be used as endpoints in intervention trials. This study is an extended analysis of a 2017 cluster randomised trial conducted in Zambezi Region, Namibia, evaluating the effectiveness of reactive focal mass drug administration (rfMDA) and reactive vector control (RAVC). A panel of eight serological markers of Plasmodium falciparum infection - Etramp5.Ag1, GEXP18, HSP40.Ag1, Rh2.2030, EBA175, PfMSP119, PfAMA1, and PfGLURP.R2 - was used on a multiplex immunoassay to measure population antibody responses as trial endpoints. Reductions in sero-prevalence to antigens Etramp.Ag1, PfMSP119, Rh2.2030, and PfAMA1 were observed in study arms combining rfMDA and RAVC, but only effects for Etramp5.Ag1 were statistically significant. Etramp5.Ag1 sero-prevalence was significantly lower in all intervention arms. Compared to the reference arms, adjusted Etramp5.Ag1 prevalence ratio (aPR) was 0.77 (95%CI 0.65 - 0.90, p<0.001) for rfMDA and 0.79 (95%CI 0.67 - 0.92, p=0.001) for RACD. For combined rfMDA plus RAVC, aPR was 0.58 (95%CI 0.45 - 0.75, p<0.001). Significant reductions were also observed based on continuous antibody responses. Sero-prevalence as an endpoint was found to achieve higher study power (99.9% power to detect a 50% reduction in prevalence) compared to quantitative polymerase chain reaction (qPCR) prevalence (72.9% power to detect a 50% reduction in prevalence). The use of serological endpoints to evaluate trial outcomes was comparable to qPCR and measured effect size with improved precision. Serology has clear application in cluster randomised trials, particularly in settings where measuring clinical incidence or infection is less reliable due to seasonal fluctuations, limitations in health care seeking, or incomplete testing and reporting. Key questionsO_ST_ABSWhat is already known?C_ST_ABS{blacksquare} Numerous serological studies across sub-Saharan Africa have found that malaria-specific antibody responses are highly correlated with malaria transmission. {blacksquare}Serology is increasingly being used to complement traditional malaria surveillance data in settings where clinical or parasitological measures of incidence or infection may be less reliable due to fluctuations in parasite densities, limitations in health care seeking, or incomplete testing and reporting. {blacksquare}The identification of new serological markers associated with recent malaria exposure hold promise as measures of malaria incidence. In previous longitudinal cohort studies, Etramp5.Ag1 has been shown to be a discriminatory serological marker capable of detecting spatio-temporal differences in malaria transmission. However, these markers have never been formally used as endpoints in a malaria cluster randomised trial. What are the new findings?{blacksquare} This study is the first application of serological endpoints in a malaria cluster randomised trial. Using a multiplexed immunoassay, a panel of sero-incidence markers of recent malaria exposure were used to evaluate the effectiveness of reactive focal mass drug administration (rfMDA) and reactive focal vector control (RAVC) compared to reactive case detection (standard of care) to reduce malaria transmission. {blacksquare}Cluster-level antibody responses were significantly lower in all intervention arms compared to control, and effect sizes were measured with greater study power than other trial endpoints such as quantitative polymerase chain reaction (qPCR) parasite prevalence. What do the new findings imply?{blacksquare} The findings from this study, together with ongoing innovations in assay design and multi-disease platforms, illustrate the potential application of serological markers as endpoints in cluster randomised trials. The use of serological endpoints can help achieve trial efficiencies, such as reduced sample size, particularly in low transmission settings or multi-intervention trials where measuring differences between study arms may be challenging with clinical or parasitological endpoints alone.

Improving the quality of malaria diagnosis in southern Africa through the development of a regional malaria slide bank.

Abstract: Background A malaria slide bank (MSB) is a useful asset for any malaria microscopy testing laboratory to have access to. However, it is not feasible for every country to have its own MSB. If countries are able to pool their resources, a regional MSB is a viable solution. This paper describes the methodology, costing and lessons learnt of establishing and maintaining an MSB over a 3-year period, for a Southern Africa Development Community region. Methods A national reference laboratory in South Africa was granted funding for setting up the MSB; it possessed experienced staff and suitable resources. Two additional full-time personnel were employed to carry out the activities of this project. Strict protocols for donor/patient blood sample screening, smear preparation, mass staining, quality control and slide validation were followed. Slides from the MSB were used for training and proficiency testing purposes. The initial and recurrent yearly costs to set up and maintain the MSB were calculated. Results Over 35 months, 154 batches (26,623 slides) were prepared; the majority were Plasmodium falciparum. Ninety-two percent (141/154) of batches passed internal quality control, and 89% (93/104) passed external validation. From these slides, two training slide sets and six proficiency testing slide sets were sent out. The initial year's cost to establish an MSB was calculated at approximately $165,000, and the recurrent year-on-year cost was $130,000. Conclusions The key components for maintaining a high-quality MSB are consistent funding, competent staff and adherence to standardized protocols. Travel to malaria-endemic areas for access to non-falciparum malaria species, and dilution of P. falciparum blood to desired parasite densities, are extremely useful to ensure variety. The MSB created here supported multiple laboratories in eight countries, and has the potential to expand.