Expanding community case management of malaria to all ages can improve universal access to malaria diagnosis and treatment: results from a cluster randomized trial in Madagascar.

BACKGROUND: Global progress on malaria control has stalled recently, partly due to challenges in universal access to malaria diagnosis and treatment. Community health workers (CHWs) can play a key role in improving access to malaria care for children under 5 years (CU5), but national policies rarely permit them to treat older individuals. We conducted a two-arm cluster randomized trial in rural Madagascar to assess the impact of expanding malaria community case management (mCCM) to all ages on health care access and use. METHODS: Thirty health centers and their associated CHWs in Farafangana District were randomized 1:1 to mCCM for all ages (intervention) or mCCM for CU5 only (control). Both arms were supported with CHW trainings on malaria case management, community sensitization on free malaria care, monthly supervision of CHWs, and reinforcement of the malaria supply chain. Cross-sectional household surveys in approximately 1600 households were conducted at baseline (Nov-Dec 2019) and endline (Nov-Dec 2021). Monthly data were collected from health center and CHW registers for 36 months (2019-2021). Intervention impact was assessed via difference-in-differences analyses for survey data and interrupted time-series analyses for health system data. RESULTS: Rates of care-seeking for fever and malaria diagnosis nearly tripled in both arms (from less than 25% to over 60%), driven mostly by increases in CHW care. Age-expanded mCCM yielded additional improvements for individuals over 5 years in the intervention arm (rate ratio for RDTs done in 6-13-year-olds, RRRDT6-13 years = 1.65; 95% CIs 1.45-1.87), but increases were significant only in health system data analyses. Age-expanded mCCM was associated with larger increases for populations living further from health centers (RRRDT6-13 years = 1.21 per km; 95% CIs 1.19-1.23). CONCLUSIONS: Expanding mCCM to all ages can improve universal access to malaria diagnosis and treatment. In addition, strengthening supply chain systems can achieve significant improvements even in the absence of age-expanded mCCM. TRIAL REGISTRATION: The trial was registered at the Pan-African Clinical Trials Registry (#PACTR202001907367187).

Effectiveness of Bivalent mRNA COVID-19 Vaccines in Preventing SARS-CoV-2 Infection in Children and Adolescents Aged 5 to 17 Years.

Importance: Bivalent mRNA COVID-19 vaccines were recommended in the US for children and adolescents aged 12 years or older on September 1, 2022, and for children aged 5 to 11 years on October 12, 2022; however, data demonstrating the effectiveness of bivalent COVID-19 vaccines are limited. Objective: To assess the effectiveness of bivalent COVID-19 vaccines against SARS-CoV-2 infection and symptomatic COVID-19 among children and adolescents. Design, Setting, and Participants: Data for the period September 4, 2022, to January 31, 2023, were combined from 3 prospective US cohort studies (6 sites total) and used to estimate COVID-19 vaccine effectiveness among children and adolescents aged 5 to 17 years. A total of 2959 participants completed periodic surveys (demographics, household characteristics, chronic medical conditions, and COVID-19 symptoms) and submitted weekly self-collected nasal swabs (irrespective of symptoms); participants submitted additional nasal swabs at the onset of any symptoms. Exposure: Vaccination status was captured from the periodic surveys and supplemented with data from state immunization information systems and electronic medical records. Main Outcome and Measures: Respiratory swabs were tested for the presence of the SARS-CoV-2 virus using reverse transcriptase-polymerase chain reaction. SARS-CoV-2 infection was defined as a positive test regardless of symptoms. Symptomatic COVID-19 was defined as a positive test and 2 or more COVID-19 symptoms within 7 days of specimen collection. Cox proportional hazards models were used to estimate hazard ratios for SARS-CoV-2 infection and symptomatic COVID-19 among participants who received a bivalent COVID-19 vaccine dose vs participants who received no vaccine or monovalent vaccine doses only. Models were adjusted for age, sex, race, ethnicity, underlying health conditions, prior SARS-CoV-2 infection status, geographic site, proportion of circulating variants by site, and local virus prevalence. Results: Of the 2959 participants (47.8% were female; median age, 10.6 years [IQR, 8.0-13.2 years]; 64.6% were non-Hispanic White) included in this analysis, 25.4% received a bivalent COVID-19 vaccine dose. During the study period, 426 participants (14.4%) had laboratory-confirmed SARS-CoV-2 infection. Among these 426 participants, 184 (43.2%) had symptomatic COVID-19, 383 (89.9%) were not vaccinated or had received only monovalent COVID-19 vaccine doses (1.38 SARS-CoV-2 infections per 1000 person-days), and 43 (10.1%) had received a bivalent COVID-19 vaccine dose (0.84 SARS-CoV-2 infections per 1000 person-days). Bivalent vaccine effectiveness against SARS-CoV-2 infection was 54.0% (95% CI, 36.6%-69.1%) and vaccine effectiveness against symptomatic COVID-19 was 49.4% (95% CI, 22.2%-70.7%). The median observation time after vaccination was 276 days (IQR, 142-350 days) for participants who received only monovalent COVID-19 vaccine doses vs 50 days (IQR, 27-74 days) for those who received a bivalent COVID-19 vaccine dose. Conclusion and Relevance: The bivalent COVID-19 vaccines protected children and adolescents against SARS-CoV-2 infection and symptomatic COVID-19. These data demonstrate the benefit of COVID-19 vaccine in children and adolescents. All eligible children and adolescents should remain up to date with recommended COVID-19 vaccinations.

Proactive community case management decreased malaria prevalence in rural Madagascar: results from a cluster randomized trial.

BACKGROUND: Malaria remains a leading cause of morbidity and mortality worldwide, with progress in malaria control stalling in recent years. Proactive community case management (pro-CCM) has been shown to increase access to diagnosis and treatment and reduce malaria burden. However, lack of experimental evidence may hinder the wider adoption of this intervention. We conducted a cluster randomized community intervention trial to assess the efficacy of pro-CCM at decreasing malaria prevalence in rural endemic areas of Madagascar. METHODS: Twenty-two fokontany (smallest administrative unit) of the Mananjary district in southeast Madagascar were selected and randomized 1:1 to pro-CCM (intervention) or conventional integrated community case management (iCCM). Residents of all ages in the intervention arm were visited by a community health worker every 2 weeks from March to October 2017 and screened for fever; those with fever were tested by a rapid diagnostic test (RDT) and treated if positive. Malaria prevalence was assessed using RDTs on all consenting study area residents prior to and following the intervention. Hemoglobin was measured among women of reproductive age. Intervention impact was assessed via difference-in-differences analyses using logistic regressions in generalized estimating equations. RESULTS: A total of 27,087 and 20,475 individuals participated at baseline and endline, respectively. Malaria prevalence decreased from 8.0 to 5.4% in the intervention arm for individuals of all ages and from 6.8 to 5.7% in the control arm. Pro-CCM was associated with a significant reduction in the odds of malaria positivity in children less than 15 years (OR = 0.59; 95% CI [0.38-0.91]), but not in older age groups. There was no impact on anemia among women of reproductive age. CONCLUSION: This trial suggests that pro-CCM approaches could help reduce malaria burden in rural endemic areas of low- and middle-income countries, but their impact may be limited to younger age groups with the highest malaria burden. TRIAL REGISTRATION: NCT05223933. Registered on February 4, 2022.

Identification of factors associated with residual malaria transmission using school-based serological surveys in settings pursuing elimination.

BACKGROUND: Targeted research on residual malaria transmission is important to improve strategies in settings pursuing elimination, where transmission reductions prove challenging. This study aimed to detect and characterize spatial heterogeneity and factors associated with Plasmodium falciparum infections and exposure, P. falciparum apical membrane antigen 1 (PfAMA1) antibody (Ab) response, in the Central Highlands of Madagascar (CHL). METHODS: From May to July 2014, a cross-sectional school-based survey was carried out in 182 fokontany (villages) within 7 health districts of the CHL. Rapid diagnostic tests (RDTs) and a bead-based immunoassay including PfAMA1 antigen biomarker were used to estimate malaria prevalence and seroprevalence, respectively. Local Moran's I index was used to detect spatial "hotspots". Remotely sensed environmental data-temperature, vegetation indices, land covers, and elevation-were used in multivariable mixed-effects logistic regression models to characterize factors associated with malaria infection and cumulative exposure. RESULTS: Among 6,293 school-children ages 2-14 years surveyed, RDT prevalence was low at 0.8% (95% CI 0.6-1.1%), while PfAMA1 Ab seroprevalence was 7.0% (95% CI 6.4-7.7%). Hotspots of PfAMA1 Ab seroprevalence were observed in two districts (Ankazobe and Mandoto). Seroprevalence increased for children living > 5 km from a health centre (adjusted odds ratio (OR) = 1.6, 95% CI 1.2-2.2), and for those experiencing a fever episode in the previous 2 weeks (OR 1.7, 95% CI 1.2-2.4), but decreased at higher elevation (for each 100-m increase, OR = 0.7, 95% CI 0.6-0.8). A clear age pattern was observed whereby children 9-10 years old had an OR of 1.8 (95% CI 1.2-2.4), children 11-12 years an OR of 3.7 (95% CI 2.8-5.0), and children 13-14 years an OR of 5.7 (95% CI 4.0-8.0) for seropositivity, compared with younger children (2-8 years). CONCLUSION: The use of serology in this study provided a better understanding of malaria hotspots and associated factors, revealing a pattern of higher transmission linked to geographical barriers in health care access. The integration of antibody-assays into existing surveillance activities could improve exposure assessment, and may help to monitor the effectiveness of malaria control efforts and adapt elimination interventions.

Experiences and perceptions of care-seeking for febrile illness among caregivers, pregnant women, and health providers in eight districts of Madagascar.

BACKGROUND: Prompt diagnosis and treatment of malaria contributes to reduced morbidity, particularly among children and pregnant women; however, in Madagascar, care-seeking for febrile illness is often delayed. To describe factors influencing decisions for prompt care-seeking among caregivers of children aged < 15 years and pregnant women, a mixed-methods assessment was conducted with providers (HP), community health volunteers (CHV) and community members. METHODS: One health district from each of eight malaria-endemic zones of Madagascar were purposefully selected based on reported higher malaria transmission. Within districts, one urban and one rural community were randomly selected for participation. In-depth interviews (IDI) and focus group discussions (FGD) were conducted with caregivers, pregnant women, CHVs and HPs in these 16 communities to describe practices and, for HPs, system characteristics that support or inhibit care-seeking. Knowledge tests on malaria case management guidelines were administered to HPs, and logistics management systems were reviewed. RESULTS: Participants from eight rural and eight urban communities included 31 HPs from 10 public and 8 private Health Facilities (HF), five CHVs, 102 caregivers and 90 pregnant women. All participants in FGDs and IDIs reported that care-seeking for fever is frequently delayed until the ill person does not respond to home treatment or symptoms become more severe. Key care-seeking determinants for caregivers and pregnant women included cost, travel time and distance, and perception that the quality of care in HFs was poor. HPs felt that lack of commodities and heavy workloads hindered their ability to provide quality malaria care services. Malaria commodities were generally more available in public versus private HFs. CHVs were generally not consulted for malaria care and had limited commodities. CONCLUSIONS: Reducing cost and travel time to care and improving the quality of care may increase prompt care-seeking among vulnerable populations experiencing febrile illness. For patients, perceptions and quality of care could be improved with more reliable supplies, extended HF operating hours and staffing, supportive demeanors of HPs and seeking care with CHVs. For providers, malaria services could be improved by increasing the reliability of supply chains and providing additional staffing. CHVs may be an under-utilized resource for sick children.

School-Based Serosurveys to Assess the Validity of Using Routine Health Facility Data to Target Malaria Interventions in the Central Highlands of Madagascar.

BACKGROUND: In low-malaria-transmission areas of Madagascar, annual parasite incidence (API) from routine data has been used to target indoor residual spraying at subdistrict commune level. To assess validity of this approach, we conducted school-based serological surveys and health facility (HF) data quality assessments in 7 districts to compare API to gold-standard commune-level serological measures. METHODS: At 2 primary schools in each of 93 communes, 60 students were randomly selected with parents and teachers. Capillary blood was drawn for rapid diagnostic tests (RDTs) and serology. Multiplex bead-based immunoassays to detect antibodies to 5 Plasmodium falciparum antigens were conducted, and finite mixture models used to characterize seronegative and seropositive populations. Reversible catalytic models generated commune-level annual seroconversion rates (SCRs). HF register data were abstracted to assess completeness and accuracy. RESULTS: RDT positivity from 12 770 samples was 0.5%. Seroprevalence to tested antigens ranged from 17.9% (MSP-1) to 59.7% (PF13). Median commune-level SCR was 0.0108 (range, 0.001-0.075). Compared to SCRs, API identified 71% (95% confidence interval, 51%-87%) of the 30% highest-transmission communes; sensitivity declined at lower levels. Routine data accuracy did not substantially affect API performance. CONCLUSIONS: API performs reasonably well at identifying higher-transmission communes but sensitivity declined at lower transmission levels.

Cross-Reactivity of Two SARS-CoV-2 Serological Assays in a Setting Where Malaria Is Endemic.

Accurate SARS-CoV-2 serological assays are critical for COVID-19 serosurveillance. However, previous studies have indicated possible cross-reactivity of these assays, including in areas where malaria is endemic. We tested 213 well-characterized prepandemic samples from Nigeria using two SARS-CoV-2 serological assays, Abbott Architect IgG and Euroimmun NCP IgG assay, both targeting SARS-CoV-2 nucleocapsid protein. To assess antibody binding strength, an avidity assay was performed on these samples and on plasma from SARS-CoV-2 PCR-positive persons. Thirteen (6.1%) of 212 samples run on the Abbott assay and 38 (17.8%) of 213 run on the Euroimmun assay were positive. Anti-Plasmodium IgG levels were significantly higher among false positives for both Abbott and Euroimmun; no association was found with active Plasmodium falciparum infection. An avidity assay using various concentrations of urea wash in the Euroimmun assay reduced loosely bound IgG: of 37 positive/borderline prepandemic samples, 46%, 86%, 89%, and 97% became negative using 2 M, 4 M, 5 M, and 8 M urea washes, respectively. The wash slightly reduced avidity of antibodies from SARS-CoV-2 patients within 28 days of PCR confirmation; thereafter, avidity increased for all urea concentrations except 8 M. This validation found moderate to substantial cross-reactivity on two SARS-CoV-2 serological assays using samples from a setting where malaria is endemic. A simple urea wash appeared to alleviate issues of cross-reactivity.

Cost-effectiveness of district-wide seasonal malaria chemoprevention when implemented through routine malaria control programme in Kita, Mali using fixed point distribution.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is a strategy for malaria control recommended by the World Health Organization (WHO) since 2012 for Sahelian countries. The Mali National Malaria Control Programme adopted a plan for pilot implementation and nationwide scale-up by 2016. Given that SMC is a relatively new approach, there is an urgent need to assess the costs and cost effectiveness of SMC when implemented through the routine health system to inform decisions on resource allocation. METHODS: Cost data were collected from pilot implementation of SMC in Kita district, which targeted 77,497 children aged 3-59 months. Starting in August 2014, SMC was delivered by fixed point distribution in villages with the first dose observed each month. Treatment consisted of sulfadoxine-pyrimethamine and amodiaquine once a month for four consecutive months, or rounds. Economic and financial costs were collected from the provider perspective using an ingredients approach. Effectiveness estimates were based upon a published mathematical transmission model calibrated to local epidemiology, rainfall patterns and scale-up of interventions. Incremental cost effectiveness ratios were calculated for the cost per malaria episode averted, cost per disability adjusted life years (DALYs) averted, and cost per death averted. RESULTS: The total economic cost of the intervention in the district of Kita was US $357,494. Drug costs and personnel costs accounted for 34% and 31%, respectively. Incentives (payment other than salary for efforts beyond routine activities) accounted for 25% of total implementation costs. Average financial and economic unit costs per child per round were US $0.73 and US $0.86, respectively; total annual financial and economic costs per child receiving SMC were US $2.92 and US $3.43, respectively. Accounting for coverage, the economic cost per child fully adherent (receiving all four rounds) was US $6.38 and US $4.69, if weighted highly adherent, (receiving 3 or 4 rounds of SMC). When costs were combined with modelled effects, the economic cost per malaria episode averted in children was US $4.26 (uncertainty bound 2.83-7.17), US $144 (135-153) per DALY averted and US $ 14,503 (13,604-15,402) per death averted. CONCLUSIONS: When implemented at fixed point distribution through the routine health system in Mali, SMC was highly cost-effective. As in previous SMC implementation studies, financial incentives were a large cost component.

Efficacy of artesunate-amodiaquine and artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria in Madagascar, 2018.

BACKGROUND: Since 2005, artemisinin-based combination therapy (ACT) has been recommended to treat uncomplicated falciparum malaria in Madagascar. Artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) are the first- and second-line treatments, respectively. A therapeutic efficacy study was conducted to assess ACT efficacy and molecular markers of anti-malarial resistance. METHODS: Children aged six months to 14 years with uncomplicated falciparum malaria and a parasitaemia of 1000-100,000 parasites/µl determined by microscopy were enrolled from May-September 2018 in a 28-day in vivo trial using the 2009 World Health Organization protocol for monitoring anti-malarial efficacy. Participants from two communes, Ankazomborona (tropical, northwest) and Matanga (equatorial, southeast), were randomly assigned to ASAQ or AL arms at their respective sites. PCR correction was achieved by genotyping seven neutral microsatellites in paired pre- and post-treatment samples. Genotyping assays for molecular markers of resistance in the pfk13, pfcrt and pfmdr1 genes were conducted. RESULTS: Of 344 patients enrolled, 167/172 (97%) receiving ASAQ and 168/172 (98%) receiving AL completed the study. For ASAQ, the day-28 cumulative PCR-uncorrected efficacy was 100% (95% CI 100-100) and 95% (95% CI 91-100) for Ankazomborona and Matanga, respectively; for AL, it was 99% (95% CI 97-100) in Ankazomborona and 83% (95% CI 76-92) in Matanga. The day-28 cumulative PCR-corrected efficacy for ASAQ was 100% (95% CI 100-100) and 98% (95% CI 95-100) for Ankazomborona and Matanga, respectively; for AL, it was 100% (95% CI 99-100) in Ankazomborona and 95% (95% CI 91-100) in Matanga. Of 83 successfully sequenced samples for pfk13, no mutation associated with artemisinin resistance was observed. A majority of successfully sequenced samples for pfmdr1 carried either the NFD or NYD haplotypes corresponding to codons 86, 184 and 1246. Of 82 successfully sequenced samples for pfcrt, all were wild type at codons 72-76. CONCLUSION: PCR-corrected analysis indicated that ASAQ and AL have therapeutic efficacies above the 90% WHO acceptable cut-off. No genetic evidence of resistance to artemisinin was observed, which is consistent with the clinical outcome data. However, the most common pfmdr1 haplotypes were NYD and NFD, previously associated with tolerance to lumefantrine.

Baseline malaria prevalence and care-seeking behaviours in rural Madagascar prior to a trial to expand malaria community case management to all ages.

BACKGROUND: Integrated community case management of malaria, pneumonia, and diarrhoea can reduce mortality in children under five years (CU5) in resource-poor countries. There is growing interest in expanding malaria community case management (mCCM) to older individuals, but limited empirical evidence exists to guide this expansion. As part of a two-year cluster-randomized trial of mCCM expansion to all ages in southeastern Madagascar, a cross-sectional survey was conducted to assess baseline malaria prevalence and healthcare-seeking behaviours. METHODS: Two enumeration areas (EAs) were randomly chosen from each catchment area of the 30 health facilities (HFs) in Farafangana district designated for the mCCM age expansion trial; 28 households were randomly selected from each EA for the survey. All household members were asked about recent illness and care-seeking, and malaria prevalence was assessed by rapid diagnostic test (RDT) among children < 15 years of age. Weighted population estimates and Rao-Scott chi-squared tests were used to examine illness, care-seeking, malaria case management, and malaria prevalence patterns. RESULTS: Illness in the two weeks prior to the survey was reported by 459 (6.7%) of 8050 respondents in 334 of 1458 households surveyed. Most individuals noting illness (375/459; 82.3%) reported fever. Of those reporting fever, 28.7% (112/375) sought care; this did not vary by participant age (p = 0.66). Most participants seeking care for fever visited public HFs (48/112, 46.8%), or community healthcare volunteers (CHVs) (40/112, 31.0%). Of those presenting with fever at HFs or to CHVs, 87.0% and 71.0%, respectively, reported being tested for malaria. RDT positivity among 3,316 tested children < 15 years was 25.4% (CI: 21.5-29.4%) and increased with age: 16.9% in CU5 versus 31.8% in 5-14-year-olds (p < 0.0001). Among RDT-positive individuals, 28.4% of CU5 and 18.5% of 5-14-year-olds reported fever in the two weeks prior to survey (p = 0.044). CONCLUSIONS: The higher prevalence of malaria among older individuals coupled with high rates of malaria testing for those who sought care at CHVs suggest that expanding mCCM to older individuals may substantially increase the number of infected individuals with improved access to care, which could have additional favorable effects on malaria transmission.

Evaluation of health system readiness and coverage of intermittent preventive treatment of malaria in infants (IPTi) in Kambia district to inform national scale-up in Sierra Leone.

BACKGROUND: Intermittent preventive treatment of malaria in infants (IPTi) with sulfadoxine-pyrimethamine (SP) is a proven strategy to protect infants against malaria. Sierra Leone is the first country to implement IPTi nationwide. IPTi implementation was evaluated in Kambia, one of two initial pilot districts, to assess quality and coverage of IPTi services. METHODS: This mixed-methods evaluation had two phases, conducted 3 (phase 1) and 15-17 months (phase 2) after IPTi implementation. Methods included: assessments of 18 health facilities (HF), including register data abstraction (phases 1 and 2); a knowledge, attitudes and practices survey with 20 health workers (HWs) in phase 1; second-generation sequencing of SP resistance markers (pre-IPTi and phase 2); and a cluster-sample household survey among caregivers of children aged 3-15 months (phase 2). IPTi and vaccination coverage from the household survey were calculated from child health cards and maternal recall and weighted for the complex sampling design. Interrupted time series analysis using a Poisson regression model was used to assess changes in malaria cases at HF before and after IPTi implementation. RESULTS: Most HWs (19/20) interviewed had been trained on IPTi; 16/19 reported feeling well prepared to administer it. Nearly all HFs (17/18 in phase 1; 18/18 in phase 2) had SP for IPTi in stock. The proportion of parasite alleles with dhps K540E mutations increased but remained below the 50% WHO-recommended threshold for IPTi (4.1% pre-IPTi [95%CI 2-7%]; 11% post-IPTi [95%CI 8-15%], p < 0.01). From the household survey, 299/459 (67.4%) children ≥ 10 weeks old received the first dose of IPTi (versus 80.4% for second pentavalent vaccine, given simultaneously); 274/444 (62.5%) children ≥ 14 weeks old received the second IPTi dose (versus 65.4% for third pentavalent vaccine); and 83/217 (36.4%) children ≥ 9 months old received the third IPTi dose (versus 52.2% for first measles vaccine dose). HF register data indicated no change in confirmed malaria cases among infants after IPTi implementation. CONCLUSIONS: Kambia district was able to scale up IPTi swiftly and provide necessary health systems support. The gaps between IPTi and childhood vaccine coverage need to be further investigated and addressed to optimize the success of the national IPTi programme.

Safety, Tolerability, and Immunogenicity of Plasmodium falciparum Sporozoite Vaccine Administered by Direct Venous Inoculation to Infants and Young Children: Findings From an Age De-escalation, Dose-Escalation, Double-blind, Randomized Controlled Study in Western Kenya.

BACKGROUND: The whole Plasmodium falciparum sporozoite (PfSPZ) vaccine is being evaluated for malaria prevention. The vaccine is administered intravenously for maximal efficacy. Direct venous inoculation (DVI) with PfSPZ vaccine has been safe, tolerable, and feasible in adults, but safety data for children and infants are limited. METHODS: We conducted an age de-escalation, dose-escalation randomized controlled trial in Siaya County, western Kenya. Children and infants (aged 5-9 years, 13-59 months, and 5-12 months) were enrolled into 13 age-dose cohorts of 12 participants and randomized 2:1 to vaccine or normal saline placebo in escalating doses: 1.35 × 105, 2.7 × 105, 4.5 × 105, 9.0 × 105, and 1.8 × 106 PfSPZ, with the 2 highest doses given twice, 8 weeks apart. Solicited adverse events (AEs) were monitored for 8 days after vaccination, unsolicited AEs for 29 days, and serious AEs throughout the study. Blood taken prevaccination and 1 week postvaccination was tested for immunoglobulin G antibodies to P. falciparum circumsporozoite protein (PfCSP) using enzyme-linked immunosorbent assay. RESULTS: Rates of AEs were similar in vaccinees and controls for solicited (35.7% vs 41.5%) and unsolicited (83.9% vs 92.5%) AEs, respectively. No related grade 3 AEs, serious AEs, or grade 3 laboratory abnormalities occurred. Most (79.0%) vaccinations were administered by a single DVI. Among those in the 9.0 × 105 and 1.8 × 106 PfSPZ groups, 36 of 45 (80.0%) vaccinees and 4 of 21 (19.0%) placebo controls developed antibodies to PfCSP (P < .001). CONCLUSIONS: PfSPZ vaccine in doses as high as 1.8 × 106 can be administered to infants and children by DVI, and was safe, well tolerated, and immunogenic. CLINICAL TRIALS REGISTRATION: NCT02687373.

Caregiver and community perceptions and experiences participating in an infant malaria prevention trial of PfSPZ Vaccine administered by direct venous inoculation: a qualitative study in Siaya County, western Kenya.

BACKGROUND: Despite available control strategies, malaria morbidity and mortality, especially in infants and young children in sub-Saharan Africa, remain intractable. Malaria vaccination could substantially reduce malaria episodes and deaths. One vaccine candidate is the whole sporozoite PfSPZ Vaccine, consisting of irradiated cryopreserved sporozoites administered by direct venous inoculation (DVI). DVI may be less acceptable than more familiar administration routes, particularly intramuscular. As part of a PfSPZ Vaccine trial among infants in western Kenya, a qualitative study was conducted to explore caregiver and community perceptions of the malaria vaccine trial, including the unique DVI administration procedure. METHODS: Twelve focus groups and 28 in-depth interviews explored perceptions of the DVI procedure in infants, factors influencing trial acceptability, and barriers to sustained trial participation. Purposively sampled participants included mothers of enrolled children, fathers and mothers who withdrew their children from the trial, village elders, and study clinicians from two trial enrollment sites. An iterative, multi-stage analytic approach, adapted from the Framework Method, was used to synthesize and interpret textual data. RESULTS: Desires to prevent malaria and participation incentives (e.g., free consultations and medication) motivated caregivers to enroll their children in the trial. However, numerous factors also demotivated trial participation. Family members' (i.e., fathers') objections to required blood draws were cited most frequently as drivers of early trial withdrawal, in many cases prior to receiving any vaccine. Among mothers whose children received PfSPZ Vaccine (or placebo), many spoke favourably of DVI administration, describing improved tolerability relative to intramuscularly administered immunizations. Other trial-related challenges cited by caregivers included negative interactions with study clinicians and perceived delays in administering trial procedures. CONCLUSIONS: Despite high acceptance of DVI among caregivers whose children received PfSPZ Vaccine (or placebo), objections to trial procedures from other non-sensitized household and family members prompted early trial withdrawal and inhibited successful completion of trial procedures for some infants. Implications for future trials include targeting heads of household during sensitization and recruitment activities, as well as equipping trial staff to effectively respond to participant and community concerns regarding trial procedures.

The effectiveness of older insecticide-treated bed nets (ITNs) to prevent malaria infection in an area of moderate pyrethroid resistance: results from a cohort study in Malawi.

BACKGROUND: A previous cohort study in Malawi showed that users of new insecticide-treated bed nets (ITNs) were significantly protected against malaria compared to non-users, despite moderate levels of pyrethroid resistance among the primary mosquito vectors. The present study investigated whether ITNs that were 1-2 years old continued to protect users in the same area with moderate pyrethroid resistance. METHODS: One year following a baseline cross-sectional malaria parasitaemia prevalence survey and universal distribution of deltamethrin ITNs (May 2012), a fixed cohort of 1223 children aged 6-59 months was enrolled (April 2013). Children were tested for parasitaemia at monthly scheduled visits and at unscheduled sick visits from May to December 2013 using rapid diagnostic tests. ITN use the prior night and the condition of ITNs (based on presence of holes) was assessed by caregiver self-report. The incidence rate ratio (RR) comparing malaria infection among users and non-users of ITNs was modelled using generalized estimating equations adjusting for potential confounders and accounting for repeated measures on each child. The protective efficacy (PE) of ITN use was calculated as 1 - RR. RESULTS: In this cohort, self-reported ITN use remained consistently high (> 95%) over the study period. Although users of ITNs were slightly more protected compared to non-users of ITNs, the difference in incidence of infection was not statistically significant (RR 0.83, 95% confidence interval [CI] 0.54-1.27). Among ITN users, malaria incidence was significantly lower in users of ITNs with no holes (of any size) compared to users of ITNs with ≥ 1 hole (RR 0.82, 95% CI 0.69-0.98). CONCLUSIONS: There was no significant PE of using 1-2 year-old ITNs on the incidence of malaria in children in an area of moderate pyrethroid resistance, but among ITN users, the authors found increased protection by ITNs with no holes compared to ITNs with holes. Given the moderate levels of pyrethroid resistance in the primary malaria vector and recent evidence of added benefits of ITNs with synergists or non-pyrethroid insecticides, next-generation ITNs may be a useful strategy to address pyrethroid resistance and should be further explored in Malawi.

Malaria case management and elimination readiness in health facilities of five districts of Madagascar in 2018.

BACKGROUND: Madagascar's Malaria National Strategic Plan 2018-2022 calls for progressive malaria elimination beginning in low-incidence districts (< 1 case/1000 population). Optimizing access to prompt diagnosis and quality treatment and improving outbreak detection and response will be critical to success. A malaria elimination readiness assessment (MERA) was performed in health facilities (HFs) of selected districts targeted for malaria elimination. METHODS: A mixed methods survey was performed in September 2018 in five districts of Madagascar. Randomly selected HFs were assessed for availability of malaria commodities and frequency of training and supervision conducted. Health providers (HPs) and community health volunteers (CHVs) were interviewed, and outpatient consultations at HFs were observed. To evaluate elimination readiness, a composite score ranging from 0 to 100 was designed from all study tools and addressed four domains: (1) resource availability, (2) case management (CM), (3) data management and use, and (4) training, supervision, and technical assistance; scores were calculated for each HF catchment area and district based on survey responses. Stakeholder interviews on malaria elimination planning were conducted at national, regional and district levels. RESULTS: A quarter of the 35 HFs surveyed had no rapid diagnostic tests (RDTs). Of 129 patients with reported or recorded fever among 300 consultations observed, HPs tested 56 (43%) for malaria. Three-quarters of the 35 HF managers reviewed data for trends. Only 68% of 41 HPs reported receiving malaria-specific training. Of 34 CHVs surveyed, 24% reported that treating fever was no longer among their responsibilities. Among treating CHVs, 13 (50%) reported having RDTs, and 11 (42%) had anti-malarials available. The average district elimination readiness score was 52 out of 100, ranging from 48 to 57 across districts. Stakeholders identified several challenges to commodity management, malaria CM, and epidemic response related to lack of training and funding disruptions. CONCLUSION: This evaluation highlighted gaps in malaria CM and elimination readiness in Madagascar to address during elimination planning. Strategies are needed that include training, commodity provision, supervision, and support for CHVs. The MERA can be repeated to assess progress in filling identified gaps and is a feasible tool that could be used to assess elimination targets in other countries.

Multiplex malaria antigen detection by bead-based assay and molecular confirmation by PCR shows no evidence of Pfhrp2 and Pfhrp3 deletion in Haiti.

BACKGROUND: The Plasmodium falciparum parasite is the only human malaria that produces the histidine-rich protein 2 and 3 (HRP2/3) antigens. Currently, HRP2/3 are widely used in malaria rapid diagnostic tests (RDTs), but several global reports have recently emerged showing genetic deletion of one or both of these antigens in parasites. Deletion of these antigens could pose a major concern for P. falciparum diagnosis in Haiti which currently uses RDTs based solely on the detection of the HRP2/3 antigens. METHODS: From September 2012 through February 2014, dried blood spots (DBS) were collected in Haiti from 9317 febrile patients presenting to 17 health facilities in 5 departments throughout the country as part of a bed net intervention study. All DBS from RDT positive persons and a random sampling of DBS from RDT negative persons were assayed for P. falciparum DNA by nested and PET-PCR (n = 2695 total). All PCR positive samples (n = 331) and a subset of PCR negative samples (n = 95) were assayed for three malaria antigens by a multiplex bead assay: pan-Plasmodium aldolase (pAldo), pan-Plasmodium lactate dehydrogenase (pLDH), and HRP2/3. Any samples positive for P. falciparum DNA, but negative for HRP2/3 antigens were tested by nested PCR for Pfhrp2 and Pfhrp3 gene deletions. RESULTS: Of 2695 DBS tested for Plasmodium DNA, 345 (12.8%) were originally found to be positive for P. falciparum DNA; 331 of these had DBS available for antigen detection. Of these, 266 (80.4%) were positive for pAldo, 221 (66.8%) positive for pLDH, and 324 (97.9%) were positive for HRP2/3 antigens. Seven samples (2.1%) positive for P. falciparum DNA were not positive for any of the three antigens by the bead assay, and were investigated for potential Pfhrp2/3 gene deletion by PCR. These samples either successfully amplified Pfhrp2/3 genes or were at an estimated parasite density too low for sufficient DNA to perform successful genotyping. CONCLUSIONS: Malaria positive samples in multiple Haitian sites were found to contain the HRP2/3 antigens, and no evidence was found of Pfhrp2/3 deletions. Malaria RDTs based on the detection of the HRP2/3 antigens remain a reliable P. falciparum diagnostic tool as Haiti works towards malaria elimination.

Universal versus conditional day 3 follow-up for children with non-severe unclassified fever at the community level in Ethiopia: A cluster-randomised non-inferiority trial.

BACKGROUND: With declining malaria prevalence and improved use of malaria diagnostic tests, an increasing proportion of children seen by community health workers (CHWs) have unclassified fever. Current community management guidelines by WHO advise that children seen with non-severe unclassified fever (on day 1) should return to CHWs on day 3 for reassessment. We compared the safety of conditional follow-up reassessment only in cases where symptoms do not resolve with universal follow-up on day 3. METHODS AND FINDINGS: We undertook a 2-arm cluster-randomised controlled non-inferiority trial among children aged 2-59 months presenting with fever and without malaria, pneumonia, diarrhoea, or danger signs to 284 CHWs affiliated with 25 health centres (clusters) in Southern Nations, Nationalities, and Peoples' Region, Ethiopia. The primary outcome was treatment failure (persistent fever, development of danger signs, hospital admission, death, malaria, pneumonia, or diarrhoea) at 1 week (day 8) of follow-up. Non-inferiority was defined as a 4% or smaller difference in the proportion of treatment failures with conditional follow-up compared to universal follow-up. Secondary outcomes included the percentage of children brought for reassessment, antimicrobial prescription, and severe adverse events (hospitalisations and deaths) after 4 weeks (day 29). From December 1, 2015, to November 30, 2016, we enrolled 4,595 children, of whom 3,946 (1,953 universal follow-up arm; 1,993 conditional follow-up arm) adhered to the CHW's follow-up advice and also completed a day 8 study visit within ±1 days. Overall, 2.7% had treatment failure on day 8: 0.8% (16/1,993) in the conditional follow-up arm and 4.6% (90/1,953) in the universal follow-up arm (risk difference of treatment failure -3.81%, 95% CI -∞, 0.65%), meeting the prespecified criterion for non-inferiority. There were no deaths recorded by day 29. In the universal follow-up arm, 94.6% of caregivers reported returning for reassessment on day 3, in contrast to 7.5% in the conditional follow-up arm (risk ratio 22.0, 95% CI 17.9, 27.2, p < 0.001). Few children sought care from another provider after their initial visit to the CHW: 3.0% (59/1,993) in the conditional follow-up arm and 1.1% (22/1,953) in the universal follow-up arm, on average 3.2 and 3.4 days later, respectively, with no significant difference between arms (risk difference 1.79%, 95% CI -1.23%, 4.82%, p = 0.244). The mean travel time to another provider was 2.2 hours (95% CI 0.01, 5.3) in the conditional follow-up arm and 2.6 hours (95% CI 0.02, 4.5) in the universal follow-up arm (p = 0.82); the mean cost for seeking care after visiting the CHW was 26.5 birr (95% CI 7.8, 45.2) and 22.8 birr (95% CI 15.6, 30.0), respectively (p = 0.69). Though this study was an important step to evaluate the safety of conditional follow-up, the high adherence seen may have resulted from knowledge of the 1-week follow-up visit and may therefore not transfer to routine practice; hence, in an implementation setting it is crucial that CHWs are well trained in counselling skills to advise caregivers on when to come back for follow-up. CONCLUSIONS: Conditional follow-up of children with non-severe unclassified fever in a low malaria endemic setting in Ethiopia was non-inferior to universal follow-up through day 8. Allowing CHWs to advise caregivers to bring children back only in case of continued symptoms might be a more efficient use of resources in similar settings. TRIAL REGISTRATION: www.clinicaltrials.gov, identifier NCT02926625.

Universal versus conditional day 3 follow-up for children with non-severe unclassified fever at the community level in the Democratic Republic of the Congo: A cluster-randomized, community-based non-inferiority trial.

BACKGROUND: The World Health Organization's integrated community case management (iCCM) guidelines recommend that all children presenting with uncomplicated fever and no danger signs return for follow-up on day 3 following the initial consultation on day 1. Such fevers often resolve rapidly, however, and previous studies suggest that expectant home care for uncomplicated fever can be safely recommended. We aimed to determine if a conditional follow-up visit was non-inferior to a universal follow-up visit for these children. METHODS AND FINDINGS: We conducted a cluster-randomized, community-based non-inferiority trial among children 2-59 months old presenting to community health workers (CHWs) with non-severe unclassified fever in Tanganyika Province, Democratic Republic of the Congo. Clusters (n = 28) of CHWs were randomized to advise caregivers to either (1) return for a follow-up visit on day 3 following the initial consultation on day 1, regardless of illness resolution (as per current WHO guidelines; universal follow-up group) or (2) return for a follow-up visit on day 3 only if illness continued (conditional follow-up group). Children in both arms were assessed again at day 8, and classified as a clinical failure if fever (caregiver-reported), malaria, diarrhea, pneumonia, or decline of health status (development of danger signs, hospitalization, or death) was noted (failure definition 1). Alternative failure definitions were examined, whereby caregiver-reported fever was first restricted to caregiver-reported fever of at least 3 days (failure definition 2) and then replaced with fever measured via axillary temperature (failure definition 3). Study participants, providers, and investigators were not masked. Among 4,434 enrolled children, 4,141 (93.4%) met the per-protocol definition of receipt of the arm-specific advice from the CHW and a timely day 8 assessment (universal follow-up group: 2,210; conditional follow-up group: 1,931). Failure was similar (difference: -0.7%) in the conditional follow-up group (n = 188, 9.7%) compared to the universal follow-up group (n = 230, 10.4%); however, the upper bound of a 1-sided 95% confidence interval around this difference (-∞, 5.1%) exceeded the prespecified non-inferiority margin of 4.0% (non-inferiority p = 0.089). When caregiver-reported fever was restricted to fevers lasting ≥3 days, failure in the conditional follow-up group (n = 159, 8.2%) was similar to that in the universal follow-up group (n = 200, 9.1%) (difference: -0.8%; 95% CI: -∞, 4.1%; p = 0.053). If caregiver-reported fever was replaced by axillary temperature measurement in the definition of failure, failure in the conditional follow-up group (n = 113, 5.9%) was non-inferior to that in the universal follow-up group (n = 160, 7.2%) (difference: -1.4%; 95% CI: -∞, 2.5%; p = 0.012). In post hoc analysis, when the definition of failure was limited to malaria, diarrhea, pneumonia, development of danger signs, hospitalization, or death, failure in the conditional follow-up group (n = 108, 5.6%) was similar to that in the universal follow-up group (n = 147, 6.7%), and within the non-inferiority margin (95% CI: -∞, 2.9%; p = 0.017). Limitations include initial underestimation of the proportion of clinical failures as well as substantial variance in cluster-specific failure rates, reducing the precision of our estimates. In addition, heightened security concerns slowed recruitment in the final months of the study. CONCLUSIONS: We found that advising caregivers to return only if children worsened or remained ill on day 3 resulted in similar rates of caregiver-reported fever and other clinical outcomes on day 8, compared to advising all caregivers to return on day 3. Policy-makers could consider revising guidelines for management of uncomplicated fever within the iCCM framework. TRIAL REGISTRATION: ClinicalTrials.gov NCT02595827.

The effect of mobile phone text message reminders on health workers' adherence to case management guidelines for malaria and other diseases in Malawi: lessons from qualitative data from a cluster-randomized trial.

BACKGROUND: Mobile health (mHealth), which uses technology such as mobile phones to improve patient health and health care delivery, is increasingly being tested as an intervention to promote health worker (HW) performance. This study assessed the effect of short messaging services (SMS) reminders in a study setting. Following a trial of text-message reminders to HWs to improve case management of malaria and other childhood diseases in southern Malawi that showed little effect, qualitative data was collected to explore the reasons why the intervention was ineffective and describe lessons learned. METHODS: Qualitative data collection was undertaken to lend insight into quantitative results from a trial in which 105 health facilities were randomized to three arms: (1) twice-daily text-message reminders to HWs, including clinicians and drug dispensers, on case management of malaria; (2) twice-daily text-message reminders to HWs on case management of malaria, pneumonia and diarrhoea; and, (3) a control arm. In-depth interviews were conducted with 50 HWs in the intervention arms across seven districts. HWs were asked about acceptability and feasibility of the text-messaging intervention and its perceived impact on recommended case management. The interviews were recorded, transcribed and translated into English for a thematic and framework analysis. Nvivo 11 software was used for data management and analysis. RESULTS: A total of 50 HWs were interviewed at 22 facilities. HWs expressed high acceptance of text-message reminders and appreciated messages as job aids and practical reference material for their day-to-day work. However, HWs said that health systems barriers, including very high outpatient workload, commodity stock-outs, and lack of supportive supervision and financial incentives demotivated them, limited their ability to act on messages and therefore adherence to case management guidelines. Drug dispensers were more likely than clinicians to report usage of text-message reminders. Despite these challenges, nearly all HWs expressed a desire for a longer duration of the SMS intervention. CONCLUSIONS: Text-message reminders to HWs can provide a platform to improve understanding of treatment guidelines and case management decision-making skills, but might not improve actual adherence to guidelines. More interaction, for example through targeted supervision or two-way technology communication, might be an essential intervention component to help address structural barriers and facilitate improved clinical practice.

Capacity Development through the US President's Malaria Initiative-Supported Antimalarial Resistance Monitoring in Africa Network.

Antimalarial drug resistance is an evolving global health security threat to malaria control. Early detection of Plasmodium falciparum resistance through therapeutic efficacy studies and associated genetic analyses may facilitate timely implementation of intervention strategies. The US President's Malaria Initiative-supported Antimalarial Resistance Monitoring in Africa Network has assisted numerous laboratories in partner countries in acquiring the knowledge and capability to independently monitor for molecular markers of antimalarial drug resistance.