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).

Innate immune activation restricts priming and protective efficacy of the radiation-attenuated PfSPZ malaria vaccine.

A systems analysis was conducted to determine the potential molecular mechanisms underlying differential immunogenicity and protective efficacy results of a clinical trial of the radiation-attenuated whole-sporozoite PfSPZ vaccine in African infants. Innate immune activation and myeloid signatures at prevaccination baseline correlated with protection from P. falciparum parasitemia in placebo controls. These same signatures were associated with susceptibility to parasitemia among infants who received the highest and most protective PfSPZ vaccine dose. Machine learning identified spliceosome, proteosome, and resting DC signatures as prevaccination features predictive of protection after highest-dose PfSPZ vaccination, whereas baseline circumsporozoite protein-specific (CSP-specific) IgG predicted nonprotection. Prevaccination innate inflammatory and myeloid signatures were associated with higher sporozoite-specific IgG Ab response but undetectable PfSPZ-specific CD8+ T cell responses after vaccination. Consistent with these human data, innate stimulation in vivo conferred protection against infection by sporozoite injection in malaria-naive mice while diminishing the CD8+ T cell response to radiation-attenuated sporozoites. These data suggest a dichotomous role of innate stimulation for malaria protection and induction of protective immunity by whole-sporozoite malaria vaccines. The uncoupling of vaccine-induced protective immunity achieved by Abs from more protective CD8+ T cell responses suggests that PfSPZ vaccine efficacy in malaria-endemic settings may be constrained by opposing antigen presentation pathways.

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.

Contextual Factors to Improve Implementation of Malaria Chemoprevention in Children: A Systematic Review.

Malaria remains a leading cause of childhood morbidity and mortality in sub-Saharan Africa, particularly among children under 5 years of age. To help address this challenge, the WHO recommends chemoprevention for certain populations. For children and infants, the WHO recommends seasonal malaria chemoprevention (SMC), perennial malaria chemoprevention (PMC; formerly intermittent preventive treatment in infants [IPTi]), and, more recently, intermittent preventive treatment in school children (IPTsc). This review describes the contextual factors, including feasibility, acceptability, health equity, financial considerations, and values and preferences, that impact implementation of these strategies. A systematic search was conducted on July 5, 2022, and repeated April 13, 2023, to identify relevant literature. Two reviewers independently screened titles for eligibility, extracted data from eligible articles, and identified and summarized themes. Of 6,295 unique titles identified, 65 were included. The most frequently evaluated strategy was SMC (n = 40), followed by IPTi (n = 18) and then IPTsc (n = 6). Overall, these strategies were highly acceptable, although with IPTsc, there were community concerns with providing drugs to girls of reproductive age and the use of nonmedical staff for drug distribution. For SMC, door-to-door delivery resulted in higher coverage, improved caregiver acceptance, and reduced cost. Lower adherence was noted when caregivers were charged with giving doses 2 and 3 unsupervised. For SMC and IPTi, travel distances and inclement weather limited accessibility. Sensitization and caregiver education efforts, retention of high-quality drug distributors, and improved transportation were key to improving coverage. Additional research is needed to understand the role of community values and preferences in chemoprevention implementation.

Reactive Case Detection and Treatment and Reactive Drug Administration for Reducing Malaria Transmission: A Systematic Review and Meta-Analysis.

Many countries pursuing malaria elimination implement "reactive" strategies targeting household members and neighbors of index cases to reduce transmission. These strategies include reactive case detection and treatment (RACDT; testing and treating those positive) and reactive drug administration (RDA; providing antimalarials without testing). We conducted systematic reviews of RACDT and RDA to assess their effect on reducing malaria transmission and gathered evidence about key contextual factors important to their implementation. Two reviewers screened titles/abstracts and full-text records using defined criteria (Patient = those in malaria-endemic/receptive areas; Intervention = RACDT or RDA; Comparison = standard of care; Outcome = malaria incidence/prevalence) and abstracted data for meta-analyses. The Grading of Recommendations, Assessment, Development, and Evaluations approach was used to rate certainty of evidence (CoE) for each outcome. Of 1,460 records screened, reviewers identified five RACDT studies (three cluster-randomized controlled trials [cRCTs] and two nonrandomized studies [NRS]) and seven RDA studies (six cRCTs and one NRS); three cRCTs comparing RDA to RACDT were included in both reviews. Compared with RDA, RACDT was associated with nonsignificantly higher parasite prevalence (odds ratio [OR] = 1.85; 95% CI: 0.96-3.57; one study) and malaria incidence (rate ratio [RR] = 1.30; 95% CI: 0.94-1.79; three studies), both very low CoE. Compared with control or RACDT, RDA was associated with non-significantly lower parasite incidence (RR = 0.73; 95% CI: 0.36-1.47; 2 studies, moderate CoE), prevalence (OR = 0.78; 95% CI: 0.52-1.17; 4 studies, low CoE), and malaria incidence (RR = 0.93; 95% CI: 0.82-1.05; six studies, moderate CoE). Evidence for reactive strategies' impact on malaria transmission is limited, especially for RACDT, but suggests RDA might be more effective.

Reducing Malaria Transmission through Reactive Indoor Residual Spraying: A Systematic Review.

In the final stages of malaria elimination, interventions to reduce malaria transmission are often centered around a confirmed case of malaria, as cases tend to cluster together at very low levels of transmission. The WHO commissioned a systematic review of the literature and synthesis of evidence for reactive indoor residual spraying (IRS) to develop official recommendations for countries. Several electronic databases were searched in November 2020. A total of 455 records were identified and screened; 20 full-text articles were assessed for eligibility. Two cluster-randomized trials met the inclusion criteria for epidemiological outcomes. Risk of bias was assessed using standard criteria. Because one study was a superiority trial in which the comparator included reactive case detection or mass drug administration and the other was a noninferiority trial in which the comparator was proactive, focal IRS, results could not be pooled. In the superiority trial, reactive IRS reduced malaria prevalence by 68% (risk ratio [RR]: 0.32; 95% CI: 0.13-0.80; certainty of evidence: HIGH) compared with no reactive IRS. No difference was observed for clinical malaria (RR: 0.65; 95% CI: 0.38-1.11; certainty of evidence: MODERATE). In the noninferiority study, the mean difference in incidence between reactive IRS and proactive IRS was 0.10 additional case per 1,000 person-years, which was within the prespecified noninferiority bound (95% CI: -0.38 to 0.58; certainty of evidence: MODERATE). The evidence indicates that reactive IRS may be a cost-effective tool for the prevention of malaria in elimination settings. As only two cluster-randomized controlled trials from sub-Saharan Africa were found, additional high-quality studies should be encouraged.

Development of Systematic Reviews to Inform WHO's Recommendations for Elimination and Prevention of Re-Establishment of Malaria: Methodology.

The basis for an evidence-based recommendation is a well-conducted systematic review that synthesizes the primary literature relevant to the policy or program question of interest. In 2020, the WHO commissioned 10 systematic reviews of potential interventions in elimination or post-elimination settings to summarize their impact on malaria transmission. This paper describes the general methods used to conduct this series of systematic reviews and notes where individual reviews diverged from the common methodology. The paper also presents lessons learned from conducting the systematic reviews to make similar future efforts more efficient, standardized, and streamlined.

Dynamics of IgG antibody response against Plasmodium antigens among Nigerian infants and young children.

Background: Plasmodium falciparum malaria is a leading cause of child mortality in Nigeria. Neonates are born with maternal antibodies from placental transfer which may protect against malaria infection in the first months of life. The IgG dynamics of the transition from passively transferred antimalarial antibodies to actively acquired IgG from natural exposure have not been well elucidated. Methods: Blood samples collected during a 2018 Nigeria nationwide HIV/AIDS household survey were available for 9,443 children under 5 years of age, with a subset of infants under 2 months of age having maternal samples available (n=41). Samples were assayed for the P. falciparum HRP2 antigen and anti-malarial IgG antibodies. LOESS regression examined the dynamics in IgG response in the first 5 years of life. Correlation with maternal IgG levels was assessed for mother/child pairs. Results: Consistent decreases were observed in median IgG levels against all Plasmodium spp. antigen targets for the first months of life. At a population level, P. falciparum apical membrane antigen-1 (AMA1) and merozoite surface protein-1 19kD (PfMSP1) IgG decreased during the first 12 months of life before reaching a nadir, whereas IgGs to other targets only declined for the first 4 months of life. Seropositivity showed a similar decline with the lowest seropositivity against AMA1 and PfMSP1 at 10-12 months, though remaining above 50% during the first 2 years of life in higher transmission areas. No protective association was observed between IgG positivity and P. falciparum infection in infants. Maternal antibody levels showed a strong positive correlation with infant antibody levels for all P. falciparum antigens from birth to 2 months of age, but this correlation was lost by 6 months of age. Discussion: Maternally transferred anti-malarial IgG antibodies rapidly decline during the first 6 months of life, with variations among specific antigens and malaria transmission intensity. From 3-23 months of age, there was a wide range in IgG levels for the blood-stage antigens indicating high individual variation in antibody production as children are infected with malaria. Non-falciparum species-specific antigens showed similar patterns in waning immunity and correlation with paired mother's IgG levels compared to P. falciparum antigens.

Sporozoite immunization: innovative translational science to support the fight against malaria.

INTRODUCTION: Malaria, a devastating febrile illness caused by protozoan parasites, sickened 247,000,000 people in 2021 and killed 619,000, mostly children and pregnant women in sub-Saharan Africa. A highly effective vaccine is urgently needed, especially for Plasmodium falciparum (Pf), the deadliest human malaria parasite. AREAS COVERED: Sporozoites (SPZ), the parasite stage transmitted by Anopheles mosquitoes to humans, are the only vaccine immunogen achieving >90% efficacy against Pf infection. This review describes >30 clinical trials of PfSPZ vaccines in the U.S.A., Europe, Africa, and Asia, based on first-hand knowledge of the trials and PubMed searches of 'sporozoites,' 'malaria,' and 'vaccines.' EXPERT OPINION: First generation (radiation-attenuated) PfSPZ vaccines are safe, well tolerated, 80-100% efficacious against homologous controlled human malaria infection (CHMI) and provide 18-19 months protection without boosting in Africa. Second generation chemo-attenuated PfSPZ are more potent, 100% efficacious against stringent heterologous (variant strain) CHMI, but require a co-administered drug, raising safety concerns. Third generation, late liver stage-arresting, replication competent (LARC), genetically-attenuated PfSPZ are expected to be both safe and highly efficacious. Overall, PfSPZ vaccines meet safety, tolerability, and efficacy requirements for protecting pregnant women and travelers exposed to Pf in Africa, with licensure for these populations possible within 5 years. Protecting children and mass vaccination programs to block transmission and eliminate malaria are long-term objectives.

Non-falciparum malaria infection and IgG seroprevalence among children under 15 years in Nigeria, 2018.

Plasmodium falciparum (Pf) is the dominant malaria parasite in Nigeria though P. vivax (Pv), P. ovale (Po), and P. malariae (Pm) are also endemic. Blood samples (n = 31,234) were collected from children aged 0-14 years during a 2018 nationwide HIV survey and assayed for Plasmodium antigenemia, Plasmodium DNA, and IgG against Plasmodium MSP1-19 antigens. Of all children, 6.6% were estimated to have Pm infection and 1.4% Po infection with no Pv infections detected. The highest household wealth quintile was strongly protective against infection with Pm (aOR: 0.11, 95% CI: 0.05-0.22) or Po (aOR= 0.01, 0.00-0.10). Overall Pm seroprevalence was 34.2% (95% CI: 33.3-35.2) with lower estimates for Po (12.1%, 11.6-12.5) and Pv (6.3%, 6.0-6.7). Pm seropositivity was detected throughout the country with several local government areas showing >50% seroprevalence. Serological and DNA indicators show widespread exposure of Nigerian children to Pm with lower rates to Po and Pv.

Plasmodium falciparum infection prevalence among children aged 6-59 months from independent DHS and HIV surveys: Nigeria, 2018.

Prevalence estimates are critical for malaria programming efforts but generating these from non-malaria surveys is not standard practice. Malaria prevalence estimates for 6-59-month-old Nigerian children were compared between two national household surveys performed simultaneously in 2018: a Demographic and Health Survey (DHS) and the Nigeria HIV/AIDS Indicator and Impact Survey (NAIIS). DHS tested via microscopy (n = 8298) and HRP2-based rapid diagnostic test (RDT, n = 11,351), and NAIIS collected dried blood spots (DBS) which were later tested for histidine-rich protein 2 (HRP2) antigen (n = 8029). National Plasmodium falciparum prevalence was 22.6% (95% CI 21.2- 24.1%) via microscopy and 36.2% (34.6- 37.8%) via RDT according to DHS, and HRP2 antigenemia was 38.3% (36.7-39.9%) by NAIIS DBS. Between the two surveys, significant rank-order correlation occurred for state-level malaria prevalence for RDT (Rho = 0.80, p < 0.001) and microscopy (Rho = 0.75, p < 0.001) versus HRP2. RDT versus HRP2 positivity showed 24 states (64.9%) with overlapping 95% confidence intervals from the two independent surveys. P. falciparum prevalence estimates among 6-59-month-olds in Nigeria were highly concordant from two simultaneous, independently conducted household surveys, regardless of malaria test utilized. This provides evidence for the value of post-hoc laboratory HRP2 detection to leverage non-malaria surveys with similar sampling designs to obtain accurate P. falciparum estimates.

Comparison of one single-antigen assay and three multi-antigen SARS-CoV-2 IgG assays in Nigeria.

Objectives: Determining an accurate estimate of SARS-CoV-2 seroprevalence has been challenging in African countries where malaria and other pathogens are endemic. We compared the performance of one single-antigen assay and three multi-antigen SARS-CoV-2 IgG assays in a Nigerian population endemic for malaria. Methods: De-identified plasma specimens from SARS-CoV-2 RT-PCR positive, dried blood spot (DBS) SARS-CoV-2 RT-PCR positive, and pre-pandemic negatives were used to evaluate the performance of the four SARS-CoV-2 assays (Tetracore, SARS2MBA, RightSign, xMAP). Results: Results showed higher sensitivity with the multi-antigen (81% (Tetracore), 96% (SARS2MBA), 85% (xMAP)) versus the single-antigen (RightSign (64%)) SARS-CoV-2 assay. The overall specificities were 98% (Tetracore), 100% (SARS2MBA and RightSign), and 99% (xMAP). When stratified based on <15 days to ≥15 days post-RT-PCR confirmation, the sensitivities increased from 75% to 88.2% for Tetracore; from 93% to 100% for the SARS2MBA; from 58% to 73% for RightSign; and from 83% to 88% for xMAP. With DBS, there was no positive increase after 15-28 days for the three assays (Tetracore, SARS2MBA, and xMAP). Conclusion: Multi-antigen assays performed well in Nigeria, even with samples with known malaria reactivity, and might provide more accurate measures of COVID-19 seroprevalence and vaccine efficacy.

Drivers of COVID-19 policy stringency in 175 countries and territories: COVID-19 cases and deaths, gross domestic products per capita, and health expenditures.

Background: New data on COVID-19 may influence the stringency of containment policies, but these potential effect are not understood. We aimed to understand the associations of new COVID-19 cases and deaths with policy stringency globally and regionally. Methods: We modelled the marginal effects of new COVID-19 cases and deaths on policy stringency (scored 0-100) in 175 countries and territories, adjusting for gross domestic product (GDP) per capita and health expenditure (% of GDP), and public expenditure on health. The time periods examined were March to August 2020, September 2020 to February 2021, and March to August 2021. Results: Policy response to new cases and deaths was faster and more stringent early in the COVID-19 pandemic (March to August 2020) compared to subsequent periods. New deaths were more strongly associated with stringent policies than new cases. In an average week, one new death per 100 000 people was associated with a stringency increase of 2.1 units in the March to August 2020 period, 1.3 units in the September 2020 to February 2021 period, and 0.7 units in the March to August 2021 period. New deaths in Africa and the Western Pacific were associated with more stringency than in other regions. Higher health expenditure as a percentage of GDP was associated with less stringent policies. Similarly, higher public expenditure on health by governments was mostly associated with less stringency across all three periods. GDP per capita did not have consistent patterns of associations with stringency. Conclusions: The stringency of COVID-19 policies was more strongly associated with new deaths than new cases. Our findings demonstrate the need for enhanced mortality surveillance to ensure policy alignment during health emergencies. Countries that invest less in health or have a lower public expenditure on health may be inclined to enact more stringent policies. This new empirical understanding of COVID-19 policy drivers can help public health officials anticipate and shape policy responses in future health emergencies.

Increased levels of anti-PfCSP antibodies in post-pubertal females versus males immunized with PfSPZ Vaccine does not translate into increased protective efficacy.

Background: While prior research has shown differences in the risk of malaria infection and sickness between males and females, little is known about sex differences in vaccine-induced immunity to malaria. Identifying such differences could elucidate important aspects of malaria biology and facilitate development of improved approaches to malaria vaccination. Methods: Using a standardized enzyme-linked immunosorbent assay, IgG antibodies to the major surface protein on Plasmodium falciparum (Pf) sporozoites (SPZ), the Pf circumsporozoite protein (PfCSP), were measured before and two weeks after administration of a PfSPZ-based malaria vaccine (PfSPZ Vaccine) to 5-month to 61-year-olds in 11 clinical trials in Germany, the US and five countries in Africa, to determine if there were differences in vaccine elicited antibody response between males and females and if these differences were associated with differential protection against naturally transmitted Pf malaria (Africa) or controlled human malaria infection (Germany, the US and Africa). Results: Females ≥ 11 years of age made significantly higher levels of antibodies to PfCSP than did males in most trials, while there was no indication of such differences in infants or children. Although adult females had higher levels of antibodies, there was no evidence of improved protection compared to males. In 2 of the 7 trials with sufficient data, protected males had significantly higher levels of antibodies than unprotected males, and in 3 other trials protected females had higher levels of antibodies than did unprotected females. Conclusion: Immunization with PfSPZ Vaccine induced higher levels of antibodies in post-pubertal females but showed equivalent protection in males and females. We conclude that the increased antibody levels in post-pubertal females did not contribute substantially to improved protection. We hypothesize that while antibodies to PfCSP (and PfSPZ) may potentially contribute directly to protection, they primarily correlate with other, potentially protective immune mechanisms, such as antibody dependent and antibody independent cellular responses in the liver.

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.

Predicting Plasmodium falciparum infection status in blood using a multiplexed bead-based antigen detection assay and machine learning approaches.

BACKGROUND: Plasmodium blood-stage infections can be identified by assaying for protein products expressed by the parasites. While the binary result of an antigen test is sufficient for a clinical result, greater nuance can be gathered for malaria infection status based on quantitative and sensitive detection of Plasmodium antigens and machine learning analytical approaches. METHODS: Three independent malaria studies performed in Angola and Haiti enrolled persons at health facilities and collected a blood sample. Presence and parasite density of P. falciparum infection was determined by microscopy for a study in Angola in 2015 (n = 193), by qRT-PCR for a 2016 study in Angola (n = 208), and by qPCR for a 2012-2013 Haiti study (n = 425). All samples also had bead-based detection and quantification of three Plasmodium antigens: pAldolase, pLDH, and HRP2. Decision trees and principal component analysis (PCA) were conducted in attempt to categorize P. falciparum parasitemia density status based on continuous antigen concentrations. RESULTS: Conditional inference trees were trained using the known P. falciparum infection status and corresponding antigen concentrations, and PCR infection status was predicted with accuracies ranging from 73-96%, while level of parasite density was predicted with accuracies ranging from 59-72%. Multiple decision nodes were created for both pAldolase and HRP2 antigens. For all datasets, dichotomous infectious status was more accurately predicted when compared to categorization of different levels of parasite densities. PCA was able to account for a high level of variance (>80%), and distinct clustering was found in both dichotomous and categorical infection status. CONCLUSIONS: This pilot study offers a proof-of-principle of the utility of machine learning approaches to assess P. falciparum infection status based on continuous concentrations of multiple Plasmodium antigens.

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.

Validation of xMAP SARS-CoV-2 Multi-Antigen IgG assay in Nigeria.

OBJECTIVE: There is a need for reliable serological assays to determine accurate estimates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence. Most single target antigen assays have shown some limitations in Africa. To assess the performance of a multi-antigen assay, we evaluated a commercially available SARS-CoV-2 Multi-Antigen IgG assay for human coronavirus disease 2019 (COVID-19) in Nigeria. METHODS: Validation of the xMAP SARS-CoV-2 Multi-Antigen IgG assay was carried out using well-characterized SARS-CoV-2 reverse transcription polymerase chain reactive positive (97) and pre-COVID-19 pandemic (86) plasma panels. Cross-reactivity was assessed using pre-COVID-19 pandemic plasma specimens (213) from the 2018 Nigeria HIV/AIDS Indicator and Impact Survey (NAIIS). RESULTS: The overall sensitivity of the xMAP SARS-CoV-2 Multi-Antigen IgG assay was 75.3% [95% CI: 65.8%- 82.8%] and specificity was 99.0% [95% CI: 96.8%- 99.7%]. The sensitivity estimate increased to 83.3% [95% CI: 70.4%- 91.3%] for specimens >14 days post-confirmation of diagnosis. However, using the NAIIS pre-pandemic specimens, the false positivity rate was 1.4% (3/213). CONCLUSIONS: Our results showed overall lower sensitivity and a comparable specificity with the manufacturer's validation. There appears to be less cross-reactivity with NAIIS pre-pandemic COVID-19 specimens using the xMAP SARS-CoV-2 Multi-Antigen IgG assay. In-country SARS-CoV-2 serology assay validation can help guide the best choice of assays in Africa.

Seroprevalence of SARS-CoV-2 in four states of Nigeria in October 2020: A population-based household survey.

The observed epidemiology of SARS-CoV-2 in sub-Saharan Africa has varied greatly from that in Europe and the United States, with much lower reported incidence. Population-based studies are needed to estimate true cumulative incidence of SARS-CoV-2 to inform public health interventions. This study estimated SARS-CoV-2 seroprevalence in four selected states in Nigeria in October 2020. We implemented a two-stage cluster sample household survey in four Nigerian states (Enugu, Gombe, Lagos, and Nasarawa) to estimate age-stratified prevalence of SARS-CoV-2 antibodies. All individuals in sampled households were eligible for interview, blood draw, and nasal/oropharyngeal swab collection. We additionally tested participants for current/recent malaria infection. Seroprevalence estimates were calculated accounting for the complex survey design. Across all four states, 10,629 (96·5%) of 11,015 interviewed individuals provided blood samples. The seroprevalence of SARS-CoV-2 antibodies was 25·2% (95% CI 21·8-28·6) in Enugu State, 9·3% (95% CI 7·0-11·5) in Gombe State, 23·3% (95% CI 20·5-26·4) in Lagos State, and 18·0% (95% CI 14·4-21·6) in Nasarawa State. Prevalence of current/recent malaria infection ranged from 2·8% in Lagos to 45·8% in Gombe and was not significantly related to SARS-CoV-2 seroprevalence. The prevalence of active SARS-CoV-2 infection in the four states during the survey period was 0·2% (95% CI 0·1-0·4). Approximately eight months after the first reported COVID-19 case in Nigeria, seroprevalence indicated infection levels 194 times higher than the 24,198 officially reported COVID-19 cases across the four states; however, most of the population remained susceptible to COVID-19 in October 2020.