Geospatial joint modeling of vector and parasite serology to microstratify malaria transmission.

The World Health Organization identifies a strong surveillance system for malaria and its mosquito vector as an essential pillar of the malaria elimination agenda. Anopheles salivary antibodies are emerging biomarkers of exposure to mosquito bites that potentially overcome sensitivity and logistical constraints of traditional entomological surveys. Using samples collected by a village health volunteer network in 104 villages in Southeast Myanmar during routine surveillance, the present study employs a Bayesian geostatistical modeling framework, incorporating climatic and environmental variables together with Anopheles salivary antigen serology, to generate spatially continuous predictive maps of Anopheles biting exposure. Our maps quantify fine-scale spatial and temporal heterogeneity in Anopheles salivary antibody seroprevalence (ranging from 9 to 99%) that serves as a proxy of exposure to Anopheles bites and advances current static maps of only Anopheles occurrence. We also developed an innovative framework to perform surveillance of malaria transmission. By incorporating antibodies against the vector and the transmissible form of malaria (sporozoite) in a joint Bayesian geostatistical model, we predict several foci of ongoing transmission. In our study, we demonstrate that antibodies specific for Anopheles salivary and sporozoite antigens are a logistically feasible metric with which to quantify and characterize heterogeneity in exposure to vector bites and malaria transmission. These approaches could readily be scaled up into existing village health volunteer surveillance networks to identify foci of residual malaria transmission, which could be targeted with supplementary interventions to accelerate progress toward elimination.

Reactive surveillance and response strategies for malaria elimination in Myanmar: a literature review.

Myanmar, a country in Greater Mekong Sub-region, aims to eliminate malaria by 2030. To achieve malaria elimination, Myanmar adopted a reactive surveillance and response strategy of malaria case notification within 1 day and case investigation, foci investigation and response activities within 7 days. A literature review was conducted to gain a better understanding of how the reactive surveillance and response strategies are being implemented in Myanmar including enablers and barriers to their implementation. Only two assessments of the completeness and timeliness of reactive surveillance and response strategy in Myanmar have been published to date. The proportion of positive cases notified within one day was 27.9% and the proportion of positive cases investigated within 7 days as recommended by the national guidelines varied from 32.5 to 91.8% under different settings in reported studies. Strong collaboration between the National Malaria Control Programme and implementing partners, and adequate human resource and financial support contributed to a successful and timely implementation of reactive surveillance and response strategy. Documented enablers for successful implementation of reactive surveillance and response strategy included frontline health workers having good knowledge of reactive surveillance and response activities and availability of Basic Health Staff for timely implementation of foci response activities. Barriers for implementation of reactive surveillance and response activities were also identified, including shortage of human resources especially in hard-to-reach settings, limited mobile phone network services and internet coverage leading to delays in timely notification of malaria cases, lengthy and complex case investigation forms and different reporting systems between Basic Health Staff and volunteers.

Performance and feasibility of reactive surveillance and response strategies for malaria elimination in Vietnam: a mixed-methods study.

BACKGROUND: To enhance malaria elimination, Vietnam adopted a Reactive Surveillance and Response (RASR) Strategy in which malaria case notification and investigation must be completed within 2 days followed by a focus investigation within 7 days. The nationwide performance of Vietnam's RASR strategy has yet to be evaluated. This study aims to evaluate the performance and feasibility of RASR in Vietnam, thereby providing recommendations for improved RASR. METHODS: To assess malaria RASR in Vietnam, a mixed-methods study of (1) secondary data analysis of nationwide malaria case-based dataset from 2017 to 2021; (2) a quantitative survey, and (3) qualitative in-depth interviews and focus group discussions administered to central, provincial and district level stakeholders/staff and to the commune and community level front line health services providers was conducted. RESULTS: In Vietnam, there are guidelines and procedures for implementation of each step of RASR. The completeness of case notification on the reported monthly aggregated data was very high in both the paper-based (12,463/12,498, 99.7% in 2017-2020) and electronic reporting systems (467/467, 100% in 2021 when electronic reporting was introduced); however, there were delays in notification while using the paper-based system (timely notification-7,978/12,498, 63.8%). In 2021, the completeness (453/467, 97.0%) and timeliness (371/467, 79.4%) of case investigation were found to be high. Reactive case detection was the major focus investigation response, with fever screening achievement of 88.6% (11,481 / 12,965) and 88.5% (11,471 / 12,965) among index case and neighbouring household members, respectively. CONCLUSIONS: Overall, there was policy commitment for implementation of RASR in Vietnam. The completeness and timeliness of case notification and case investigation were high and improved after the introduction of the electronic reporting system. More evidence is required for reactive case detection in defining the screening area or population.

Anopheles diversity, biting behaviour and transmission potential in forest and farm environments of Gia Lai province, Vietnam.

BACKGROUND: Despite recent reductions in Vietnam, malaria transmission persists in some areas in forests and farmlands where a high density of Anopheles mosquitoes relative to other environments occurs. To inform effective malaria control measures, it is important to understand vector bionomics and the malaria transmission role of Anopheles spp. in the highland regions of Vietnam. This study was conducted to quantify the abundance, composition and biting behaviour of the Anopheles mosquito population, and the proportion of Plasmodium spp. infected mosquitoes collected from forest and agricultural farm sites in Gia Lai province, Vietnam. METHODS: Forest and agricultural farm sites in Gia Lai province were selected for mosquito collections (total eight sites). Mosquito collection was performed by Human-baited Double Net Trap (HDNT), animal-baited traps (ABT) using cattle, and CDC light traps. Captured mosquitoes were identified morphologically, and salivary glands of Anopheles mosquitoes were examined for sporozoites using microscopy. Plasmodium infection was determined by Polymerase Chain Reaction (PCR), and identification of blood meal type was determined by PCR and diffuse serum agglutination assay. RESULTS: A total of 1815 Anopheles mosquitoes belonging to 19 species were collected by ABT (n = 1169), HDNT (n = 471) and CDC light trap (n = 175). Anopheles abundance and diversity varied by district and environment. Capture by HDNT of Anopheles of vectorial concern was observed between early evening and early morning. Plasmodium vivax infection was determined by PCR in two Anopheles dirus specimens captured by HDNT in forest sites. Blood from a range of hosts could, including human blood, could be detected in species considered primary and secondary vectors An. dirus, and Anopheles aconitus, and Anopheles maculatus, respectively. CONCLUSIONS: A low number of Anopheles spp. considered primary vectors of concern and very low numbers of Plasmodium spp. infected Anopheles mosquitoes were captured at the end of the rainy season in the Central Highlands of Vietnam. However, capture species of vectorial concern by HDNT throughout the early to late evening demonstrates that use of additional personal protective measures could supplement current preventative measures, such as bed nets to prevent exposure to vectors of concern in this region.

Low knowledge of newborn danger signs among pregnant women in Papua New Guinea and implications for health seeking behaviour in early infancy - findings from a longitudinal study.

BACKGROUND: Globally, 2.5 million babies die in the first 28 days of life each year with most of these deaths occurring in low- and middle-income countries. Early recognition of newborn danger signs is important in prompting timely care seeking behaviour. Little is known about women's knowledge of newborn danger signs in Papua New Guinea. This study aims to assess this knowledge gap among a cohort of women in East New Britain Province. METHODS: This study assessed knowledge of newborn danger signs (as defined by the World Health Organization) at three time points from a prospective cohort study of women in East New Britain Province, factors associated with knowledge of danger signs after childbirth were assessed using logistic regression. This study includes quantitative and qualitative interview data from 699 pregnant women enrolled at their first antenatal clinic visit, followed up after childbirth (n = 638) and again at one-month post-partum (n = 599). RESULTS: Knowledge of newborn danger signs was very low. Among the 638 women, only 9.4% knew three newborn danger signs after childbirth and only one knew all four essential danger signs defined by Johns Hopkins University 'Birth Preparedness and Complication Readiness' Index. Higher knowledge scores were associated with higher gravidity, income level, partner involvement in antenatal care, and education. CONCLUSION: Low levels of knowledge of newborn danger signs among pregnant women are a potential obstacle to timely care-seeking in rural Papua New Guinea. Antenatal and postnatal education, and policies that support enhanced education and decision-making powers for women and their families, are urgently needed.

Comparison of Antibody Responses and Parasite Clearance in Artemisinin Therapeutic Efficacy Studies in the Democratic Republic of Congo and Asia.

BACKGROUND: Understanding the effect of immunity on Plasmodium falciparum clearance is essential for interpreting therapeutic efficacy studies designed to monitor emergence of artemisinin drug resistance. In low-transmission areas of Southeast Asia, where resistance has emerged, P. falciparum antibodies confound parasite clearance measures. However, variation in naturally acquired antibodies across Asian and sub-Saharan African epidemiological contexts and their impact on parasite clearance re yet to be quantified. METHODS: In an artemisinin therapeutic efficacy study, antibodies to 12 pre-erythrocytic and erythrocytic P. falciparum antigens were measured in 118 children with uncomplicated P. falciparum malaria in the Democratic Republic of Congo (DRC) and compared with responses in patients from Asian sites, described elsewhere. RESULTS: Parasite clearance half-life was shorter in DRC patients (median, 2 hours) compared with most Asian sites (median, 2-7 hours), but P. falciparum antibody levels and seroprevalences were similar. There was no evidence for an association between antibody seropositivity and parasite clearance half-life (mean difference between seronegative and seropositive, -0.14 to +0.40 hour) in DRC patients. CONCLUSIONS: In DRC, where artemisinin remains highly effective, the substantially shorter parasite clearance time compared with Asia was not explained by differences in the P. falciparum antibody responses studied.

Induction, decay, and determinants of functional antibodies following vaccination with the RTS,S malaria vaccine in young children.

BACKGROUND: RTS,S is the first malaria vaccine recommended for implementation among young children at risk. However, vaccine efficacy is modest and short-lived. Antibodies play the major role in vaccine-induced immunity, but knowledge on the induction, decay, and determinants of antibody function is limited, especially among children. Antibodies that promote opsonic phagocytosis and other cellular functions appear to be important contributors to RTS,S immunity. METHODS: We studied a phase IIb trial of RTS,S/AS02 conducted in young children in malaria-endemic regions of Mozambique. We evaluated the induction of antibodies targeting the circumsporozoite protein (CSP, vaccine antigen) that interact with Fcγ-receptors (FcRγs) and promote phagocytosis (neutrophils, monocytes, THP-1 cells), antibody-dependent respiratory burst (ADRB) by neutrophils, and natural killer (NK) cell activity, as well as the temporal kinetics of responses over 5 years of follow-up (ClinicalTrials.gov registry number NCT00197041). RESULTS: RTS,S vaccination induced CSP-specific IgG with FcγRIIa and FcγRIII binding activity and promoted phagocytosis by neutrophils, THP-1 monocytes, and primary human monocytes, neutrophil ADRB activity, and NK cell activation. Responses were highly heterogenous among children, and the magnitude of neutrophil phagocytosis by antibodies was relatively modest, which may reflect modest vaccine efficacy. Induction of functional antibodies was lower among children with higher malaria exposure. Functional antibody magnitude and the functional activity of antibodies largely declined within a year post-vaccination, and decay were highest in the first 6 months, consistent with the decline in vaccine efficacy over that time. Decay rates varied for different antibody parameters and decay was slower for neutrophil phagocytosis. Biostatistical modelling suggested IgG1 and IgG3 contribute in promoting FcγR binding and phagocytosis, and IgG targeting the NANP-repeat and C-terminal regions CSP were similarly important for functional activities. CONCLUSIONS: Results provide new insights to understand the modest and time-limited efficacy of RTS,S in children and the induction of antibody functional activities. Improving the induction and maintenance of antibodies that promote phagocytosis and cellular functions, and combating the negative effect of malaria exposure on vaccine responses are potential strategies for improving RTS,S efficacy and longevity.

Molecular approaches to Malaria 2020.

Twenty years ago the Molecular Approaches to Malaria conference was conceived as a forum to present the very latest advances in malaria research and to consolidate and forge new collaborative links between international researchers. The 6th MAM conference, held in February 2020 in Australia, provided 5 days of stimulating scientific exchange and highlighted the incredible malaria research conducted globally that is providing the critical knowledge and cutting-edge technological tools needed to control and ultimately eliminate malaria.

Quantification of the dynamics of antibody response to malaria to inform sero-surveillance in pregnant women.

BACKGROUND: Malaria remains a major public health threat and tools sensitive to detect infections in low malaria transmission areas are needed to progress elimination efforts. Pregnant women are particularly vulnerable to malaria infections. Throughout pregnancy they access routine antenatal care, presenting a unique sentinel population to apply novel sero-surveillance tools to measure malaria transmission. The aim of this study was to quantify the dynamic antibody responses to multiple antigens during pregnancy so as to identify a single or multiple antibody response of exposure to malaria in pregnancy. METHODS: This study involved a secondary analysis of antibody responses to six parasite antigens [five commonly studied merozoite antigens and the variant surface antigen 2-chondroitin sulphate A (VAR2CSA), a pregnancy-specific erythrocytic antigen] measured by enzyme-linked immunosorbent assay (ELISA) over the gestation period until delivery (median of 7 measurements/woman) in 250 pregnant women who attended antenatal clinics located at the Thai-Myanmar border. A multivariate mixture linear mixed model was used to cluster the pregnant women into groups that have similar longitudinal antibody responses to all six antigens over the gestational period using a Bayesian approach. The variable-specific entropy was calculated to identify the antibody responses that have the highest influence on the classification of the women into clusters, and subsequent agreement with grouping of women based on exposure to malaria during pregnancy. RESULTS: Of the 250 pregnant women, 135 had a Plasmodium infection detected by light microscopy during pregnancy (39% Plasmodium falciparum only, 33% Plasmodium vivax only and 28% mixed/other species), defined as cases. The antibody responses to all six antigens accurately identified the women who did not have a malaria infection detected during pregnancy (93%, 107/115 controls). Antibody responses to P. falciparum merozoite surface protein 3 (PfMSP3) and P. vivax apical membrane antigen 1 (PvAMA1) were the least dynamic. Antibody responses to the antigens P. falciparum apical membrane antigen 1 (PfAMA1) and PfVAR2CSA were able to identify the majority of the cases more accurately (63%, 85/135). CONCLUSION: These findings suggest that the combination of antibodies, PfAMA1 and PfVAR2CSA, may be useful for sero-surveillance of malaria infections in pregnant women, particularly in low malaria transmission settings. Further investigation of other antibody markers is warranted considering these antibodies combined only detected 63% of the malaria infections during pregnancy.

Reducing malaria transmission in forest-going mobile and migrant populations in Lao PDR and Cambodia: protocol for stepped-wedge cluster-randomised controlled trial.

BACKGROUND: Countries of the Greater Mekong Sub-region aim to achieve malaria elimination by 2030. In the region, malaria is concentrated in high-risk areas and populations such as forest-going mobile and migrant populations (MMPs). However, routine protective measures such as long-lasting insecticidal nets do not prevent all infectious bites in these high-risk populations. Evidence for the effectiveness of a personal protection package tailored to forest-going MMPs which is acceptable, feasible, and cost-effective for reducing malaria transmission is required to inform the malaria elimination toolkit in the region. METHODS: A personal protection package consisting of long-lasting insecticidal hammock net, insect repellent and health communication pamphlet was developed in consultation with relevant implementing partners from Cambodia and Lao PDR. An open stepped-wedge cluster-randomised controlled trial will be conducted over a period of 12 months in a minimum of 488 villages (~ 428 in Lao PDR and ~ 60 in Cambodia) to evaluate the effectiveness of the personal protection package. Villages will be randomised into 11 blocks, with blocks transitioned in random order from control to intervention states at monthly intervals, following a 1-month baseline period. The primary outcome of the trial is the prevalence of Plasmodium spp. infection diagnosed by rapid diagnostic test. Difference in prevalence of malaria infection will be estimated across intervention and control periods using generalized linear mixed modelling. Nested within the stepped-wedge cluster-randomised controlled trial is a mixed-methods study to explore the acceptability of the personal protection package, feasibility of implementing a personal protection package as a vector control intervention, and knowledge, attitude and practice of MMPs regarding malaria prevention; and cost-analysis to determine the cost-effectiveness of implementing a personal protection package. DISCUSSION: This study, using a rigorous design and mixed-methods methodology, will evaluate whether a personal protection package can reduce residual malaria transmission among forest-going MMPs in Cambodia and Lao PDR. It will also measure implementation research outcomes such as effectiveness of the intervention package, cost-effectiveness, acceptability, and feasibility, in order to inform potential national and regional policy. Trial registration This trial was prospectively registered on ClinicalTrials.gov (NCT05117567) on 11th November 2021.

Associated factors and global adherence of cervical cancer screening in 2019: a systematic analysis and modelling study.

BACKGROUND: Cervical cancer screening is vital for its prevention. Adherence is a crucial indicator that implies the individual willingness to take cervical cancer screening. We aimed to estimate the global and regional adherence rates of cervical cancer screening in 2019 and identify its associated factors among general women. METHOD: We searched studies in PubMed, Web of Science, Embase, China National Knowledge Infrastructure, Wanfang Database, ProQuest theses database and Google Web, without a lower time limit and until 23 June, 2021. Survey studies were considered eligible if they investigated cervical cancer screening adherence among general women, with data on sample size, the number of adherent subjects, and/or adherence rate. Random-effects were used to pool the odds ratios (ORs) of associated factors of adherence. Using modelling analysis, we estimated 2019 overall and age-specific adherence rates at the global and regional levels in women aged 20-69 years. RESULTS: Eight thousand two hundred ninety records were identified, and 153 articles were included. Being married (vs not married: OR, 1.34; 95% confidence interval [CI]: 1.23-1.46), higher educational attainment (higher than high school vs less than high school: OR, 1.44; 95% CI: 1.35-1.53), having healthcare (OR, 1.64; 95% CI: 1.43-1.88), former smoking (OR, 1.20; 95% CI: 1.07-1.34), physical activity (OR, 1.19; 95% CI: 1.05-1.36), parity (OR, 1.07; 95% CI: 1.01-1.12), and chronic disease (OR, 1.17; 95% CI: 1.04-1.32) were associated with better adherence, whereas obesity (vs normal: OR, 0.85; 95% CI: 0.74-0.97) and current smoking (vs former/never: OR, 0.64; 95% CI: 0.54-0.76) were associated with worse adherence. In 2019, the adherence was at 33.66% (95% CI: 23.34-39.30%) worldwide, and was higher in high-income countries (HICs) (75.66, 95% CI: 66.74-82.81%) than in low and middle-income countries (LMICs) (24.91, 95% CI: 14.30-30.24%). It varied across regions, the highest in the European region (65.36, 95% CI: 55.40-74.19%), but the lowest in the African region (5.28, 95% CI: 3.43-8.03%). CONCLUSIONS: Cervical cancer screening adherence remained low globally, exhibiting geographical discrepancy with HICs higher than LMICs. Further implementations of screening programs should comprehensively consider the local economy, social benefits, and demographic structure to adapt delivery for vulnerable or underserved women to boost screening adherence.

Multifunctional Antibodies Are Induced by the RTS,S Malaria Vaccine and Associated With Protection in a Phase 1/2a Trial.

BACKGROUND: RTS,S is the leading malaria vaccine candidate but only confers partial efficacy against malaria in children. RTS,S is based on the major Plasmodium falciparum sporozoite surface antigen, circumsporozoite protein (CSP). The induction of anti-CSP antibodies is important for protection; however, it is unclear how these protective antibodies function. METHODS: We quantified the induction of functional anti-CSP antibody responses in healthy malaria-naive adults (N = 45) vaccinated with RTS,S/AS01. This included the ability to mediate effector functions via the fragment crystallizable (Fc) region, such as interacting with human complement proteins and Fcγ-receptors (FcγRs) that are expressed on immune cells, which promote various immunological functions. RESULTS: Our major findings were (1) RTS,S-induced antibodies mediated Fc-dependent effector functions, (2) functional antibodies were generally highest after the second vaccine dose, (3) functional antibodies targeted multiple regions of CSP, (4) participants with higher levels of functional antibodies had a reduced probability of developing parasitemia following homologous challenge (P < .05), and (5) nonprotected subjects had higher levels of anti-CSP IgM. CONCLUSIONS: Our data suggest a role for Fc-dependent antibody effector functions in RTS,S-induced immunity. Enhancing the induction of these functional activities may be a strategy to improve the protective efficacy of RTS,S or other malaria vaccines. CLINICAL TRIALS REGISTRATION: NCT00075049.

Mycoplasma genitalium and Other Reproductive Tract Infections in Pregnant Women, Papua New Guinea, 2015-2017.

Much about the range of pathogens, frequency of coinfection, and clinical effects of reproductive tract infections (RTIs) among pregnant women remains unknown. We report on RTIs (Mycoplasma genitalium, Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, Treponema pallidum subspecies pallidum, bacterial vaginosis, and vulvovaginal candidiasis) and other reproductive health indicators in 699 pregnant women in Papua New Guinea during 2015-2017. We found M. genitalium, an emerging pathogen in Papua New Guinea, in 12.5% of participants. These infections showed no evidence of macrolide resistance. In total, 74.1% of pregnant women had >1 RTI; most of these infections were treatable. We detected sexually transmitted infections (excluding syphilis) in 37.7% of women. Our findings showed that syndromic management of infections is greatly inadequate. In total, 98.4% of women had never used barrier contraception. These findings will inform efforts to improve reproductive healthcare in Papua New Guinea.

Development and Validation of an In Silico Decision Tool To Guide Optimization of Intravenous Artesunate Dosing Regimens for Severe Falciparum Malaria Patients.

Most deaths from severe falciparum malaria occur within 24 h of presentation to a hospital. Intravenous (i.v.) artesunate is the first-line treatment for severe falciparum malaria, but its efficacy may be compromised by delayed parasitological responses. In patients with severe malaria, the life-saving benefit of the artemisinin derivatives is their ability to clear circulating parasites rapidly, before they can sequester and obstruct the microcirculation. To evaluate the dosing of i.v. artesunate for the treatment of artemisinin-sensitive and reduced ring stage sensitivity to artemisinin severe falciparum malaria infections, Bayesian pharmacokinetic-pharmacodynamic modeling of data from 94 patients with severe malaria (80 children from Africa and 14 adults from Southeast Asia) was performed. Assuming that delayed parasite clearance reflects a loss of ring stage sensitivity to artemisinin derivatives, the median (95% credible interval) percentage of patients clearing ≥99% of parasites within 24 h (PC24≥99%) for standard (2.4 mg/kg body weight i.v. artesunate at 0 and 12 h) and simplified (4 mg/kg i.v. artesunate at 0 h) regimens was 65% (52.5% to 74.5%) versus 44% (25% to 61.5%) for adults, 62% (51.5% to 74.5%) versus 39% (20.5% to 58.5%) for larger children (≥20 kg), and 60% (48.5% to 70%) versus 36% (20% to 53.5%) for smaller children (<20 kg). The upper limit of the credible intervals for all regimens was below a PC24≥99% of 80%, a threshold achieved on average in clinical studies of severe falciparum malaria infections. In severe falciparum malaria caused by parasites with reduced ring stage susceptibility to artemisinin, parasite clearance is predicted to be slower with both the currently recommended and proposed simplified i.v. artesunate dosing regimens.

Reduced risk of placental parasitemia associated with complement fixation on Plasmodium falciparum by antibodies among pregnant women.

BACKGROUND: The pathogenesis of malaria in pregnancy (MiP) involves accumulation of P. falciparum-infected red blood cells (pRBCs) in the placenta, contributing to poor pregnancy outcomes. Parasite accumulation is primarily mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1). Magnitude of IgG to pRBCs has been associated with reduced risk of MiP in some studies, but associations have been inconsistent. Further, antibody effector mechanisms are poorly understood, and the role of antibody complement interactions is unknown. METHODS: Studying a longitudinal cohort of pregnant women (n=302) from a malaria-endemic province in Papua New Guinea (PNG), we measured the ability of antibodies to fix and activate complement using placental binding pRBCs and PfEMP1 recombinant domains. We determined antibody-mediated complement inhibition of pRBC binding to the placental receptor, chondroitin sulfate A (CSA), and associations with protection against placental parasitemia. RESULTS: Some women acquired antibodies that effectively promoted complement fixation on placental-binding pRBCs. Complement fixation correlated with IgG1 and IgG3 antibodies, which dominated the response. There was, however, limited evidence for membrane attack complex activity or pRBC lysis or killing. Importantly, a higher magnitude of complement fixing antibodies was prospectively associated with reduced odds of placental infection at delivery. Using genetically modified P. falciparum and recombinant PfEMP1 domains, we found that complement-fixing antibodies primarily targeted a specific variant of PfEMP1 (known as VAR2CSA). Furthermore, complement enhanced the ability of antibodies to inhibit pRBC binding to CSA, which was primarily mediated by complement C1q protein. CONCLUSIONS: These findings provide new insights into mechanisms mediating immunity to MiP and reveal potential new strategies for developing malaria vaccines that harness antibody-complement interactions.

Community-based molecular and serological surveillance of subclinical malaria in Myanmar.

BACKGROUND: In the Greater Mekong Subregion (GMS), current malaria surveillance strategies rely on a network of village health volunteers (VHVs) reporting the results of rapid diagnostic tests (RDTs), known to miss many asymptomatic infections. Integration of more sensitive diagnostic molecular and serological measures into the VHV network may improve surveillance of residual malaria transmission in hard-to-reach areas in the region and inform targeted interventions and elimination responses. However, data on residual malaria transmission that would be captured by these measures in the VHV-led testing and treatment surveillance network in the GMS is unknown. METHODS: A total of 114 VHVs were trained to collect dried blood spots from villagers undergoing routine RDTs as part of VHV-led active and passive case detection from April 2015 to June 2016. Samples were subjected to molecular testing (quantitative polymerase chain reaction [qPCR]) to determine Plasmodium falciparum and P. vivax infection and serological testing (against P. falciparum and P. vivax antigens) to determine exposure to P. falciparum and P. vivax. RESULTS: Over 15 months, 114 VHVs performed 32,194 RDTs and collected samples for molecular (n = 13,157) and serological (n = 14,128) testing. The prevalence of molecular-detectable P. falciparum and P. vivax infection was 3.2% compared to the 0.16% prevalence of Plasmodium spp. by RDT, highlighting the large burden of infections undetected by standard surveillance. Peaks in anti-P. falciparum, but not P. vivax, merozoite IgG seroprevalence coincided with seasonal P. falciparum transmission peaks, even in those with no molecularly detectable parasites. At the individual level, antibody seropositivity was associated with reduced odds of contemporaneous P. falciparum (OR for PfCSP 0.51 [95%CI 0.35, 0.76], p = 0.001, PfAMA1 0.70 [95%CI 0.52, 0.93], p = 0.01, and PfMSP2 0.81 [95%CI 0.61, 1.08], p = 0.15), but not P. vivax infection (OR PvAMA1 1.02 [95%CI 0.73, 1.43], p = 0.89) indicating a potential role of immunity in protection against molecular-detectable P. falciparum parasitaemia. CONCLUSIONS: We demonstrated that integration and implementation of sample collection for molecular and serological surveillance into networks of VHV servicing hard-to-reach populations in the GMS is feasible, can capture significant levels of ongoing undetected seasonal malaria transmission and has the potential to supplement current routine RDT testing. Improving malaria surveillance by advancing the integration of molecular and serological techniques, through centralised testing approaches or novel point-of-contact tests, will advance progress, and tracking, towards malaria elimination goals in the GMS.

Community demand for comprehensive primary health care from malaria volunteers in South-East Myanmar: a qualitative study.

BACKGROUND: Malaria volunteers have contributed significantly to malaria control achieving a reduction of annual parasite incidence to pre-elimination levels in several townships across Myanmar. However, the volunteers' role is changing as Myanmar transitions from a malaria control to elimination programme and towards the goal of universal health coverage. The aim of the study is to explore the perspectives of community leaders, members and malaria volunteers in South-East Myanmar on community-delivered models to inform an optimal design that targets malaria elimination in the context of primary health care in Myanmar. METHODS: Qualitative methods including focus group discussions (FGDs) with community members and current or ex-malaria volunteers, and participatory workshops with community leaders were conducted. All data collection tools were pilot tested with similar participants. The FGDs were stratified into male and female participants in consideration of diverse gender roles among the ethnic groups of Myanmar. Data saturation was the key cut-off point to cease recruitment of participants. Inductive thematic analysis was used. RESULTS: Community members were willing to be tested for malaria because they were concerned about the consequences of malaria although they were aware that malaria prevalence is low in their villages. Malaria volunteers were the main service providers for malaria and other infectious diseases in the community. Apart from malaria, the community identified common health problems such as the flu (fever, sneezing and coughing), diarrhoea, skin infections and tuberculosis as priority diseases in this order. Incorporating preventive, and whenever possible curative, services for those diseases into the current malaria volunteer model was recommended. DISCUSSION AND CONCLUSION: There was a gap between the communities' expectations of health services and the health services currently being delivered by volunteers in the community that highlights the need for reassessment and reform of the volunteer model in the changing context. An evidence-based, community preferred, pragmatic community-delivered integrated model should be constructed based on the context of malaria elimination and progressing towards universal health coverage in Myanmar.

Optimizing Myanmar's community-delivered malaria volunteer model: a qualitative study of stakeholders' perspectives.

BACKGROUND: In parallel with the change of malaria policy from control to elimination and declines in the malaria burden in Greater Mekong Sub-region, the motivation and social role of malaria volunteers has declined. To address this public health problem, in Myanmar, the role and responsibilities of malaria volunteers have been transformed into integrated community malaria volunteers (ICMV), that includes the integration of activities for five additional diseases (dengue, lymphatic filariasis, tuberculosis, HIV/AIDS and leprosy) into their current activities. However, this transformation was not evidence-based and did not consider inputs of different stakeholders. Therefore, qualitative stakeholder consultations were performed to optimize future malaria volunteer models in Myanmar. METHODS: Semi-structured interviews were conducted with key health stakeholders from the Myanmar Ministry of Health and Sports (MoHS) and malaria implementing partners to obtain their perspectives on community-delivered malaria models. A qualitative descriptive approach was used to explore the experiences of the stakeholders in policymaking and programme implementation. Interview topic guides were used during the interviews and inductive thematic data analysis was performed. RESULTS: While ICMVs successfully provided malaria services in the community, the stakeholders considered the ICMV model as not optimal and suggested that many aspects needed to be improved including better training, supervision, support, and basic health staff's recognition for ICMVs. Stakeholders believe that the upgraded ICMV model could contribute significantly to achieving malaria elimination and universal health care in Myanmar. DISCUSSION AND CONCLUSION: In the context of high community demand for non-malaria treatment services from volunteers, the integrated volunteer service package must be developed carefully in order to make it effective in malaria elimination programme and to contribute in Myanmar's pathway to universal health coverage (UHC), but without harming the community. An evidenced-based, community-delivered and preferred model, that is also accepted by the MoHS, is yet to be developed to effectively contribute to achieving malaria elimination and UHC goals in Myanmar by 2030.

A mobile phone application for malaria case-based reporting to advance malaria surveillance in Myanmar: a mixed methods evaluation.

BACKGROUND: To achieve malaria elimination in the Greater Mekong Subregion, including Myanmar, it is necessary to ensure all malaria cases are detected, treated, and reported in a timely manner. Mobile phone-based applications for malaria reporting, case management, and surveillance implemented at a community-level may overcome reporting limitations associated with current paper-based reporting (PBR), but their effectiveness in this context is unknown. METHODS: A mixed methods evaluation study was undertaken to determine the effectiveness of a national Malaria Case-Based Reporting (MCBR) mobile phone application in improving malaria case reporting compared to the existing PBR reporting system in Myanmar. Methods included secondary analysis of malaria case report data, questionnaires, focus group discussions and field observations of community volunteers, interviews and direct observations of malaria programme stakeholders, and cost analysis. Using a combination of these approaches the following areas were investigated: data quality and completeness, data access and usage, capacity for timely reporting, the acceptability, functionality, and ease of use of the application and facilitators and barriers to its use, and the relative cost of MCBR compared to the PBR system. RESULTS: Compared to PBR, MCBR enabled more accurate and complete data to be reported in a much timelier manner, with 63% of MCBR users reporting they transmit rapid diagnostic test outcomes within 24 h, compared to 0% of PBR users. MCBR was favoured by integrated community malaria volunteers and their supervisors because of its efficiency. However, several technical and operational challenges associated with internet coverage, data transmission, and e-literacy were identified and stakeholders reported not being confident to rely solely on MCBR data for programmatic decision-making. CONCLUSIONS: Implementation of MCBR provided timely and accurate data for malaria surveillance. Findings from this evaluation study will enable the optimization of an application-based reporting system for malaria monitoring and surveillance in the Greater Mekong Subregion and advance systems to track progress towards, and certify, the achievement of malaria elimination targets.

Sustainability of a mobile phone application-based data reporting system in Myanmar's malaria elimination program: a qualitative study.

BACKGROUND: Strengthening surveillance systems to collect near-real-time case-based data plays a fundamental role in achieving malaria elimination in the Greater Mekong Subregion (GMS). With the advanced and widespread use of digital technology, mHealth is increasingly taking a prominent role in malaria surveillance systems in GMS countries, including Myanmar. In Myanmar's malaria elimination program, an mHealth system called Malaria Case-based Reporting (MCBR) has been applied for case-based reporting of malaria data by integrated community malaria volunteers (ICMVs). However, the sustainability of such mHealth systems in the context of existing malaria elimination programs in Myanmar is unknown. METHODS: Focus group discussions were conducted with ICMVs and semi-structured in-depth interviews were conducted with malaria program stakeholders from Myanmar's Ministry of Health and Sports and its malaria program implementing partners. Thematic (deductive followed by inductive) analysis was undertaken using a qualitative descriptive approach. RESULTS: Technological and financial constraints such as inadequate internet access, software errors, and insufficient financial resources to support mobile phone-related costs have hampered users' access to MCBR. Poor system integrity, unpredictable reporting outcomes, inadequate human resources for system management, and inefficient user support undermined the perceived quality of the system and user satisfaction, and hence its sustainability. Furthermore, multiple parallel systems with functions overlapping those of MCBR were in use. CONCLUSIONS: Despite its effectiveness and efficiency in malaria surveillance, the sustainability of nationwide implementation of MCBR is uncertain. To make it sustainable, stakeholders should deploy a dedicated human workforce with the necessary technical and technological capacities; secure sustainable, long-term funding for implementation of MCBR; find an alternative cost-effective plan for ensuring sustainable system access by ICMVs, such as using volunteer-owned mobile phones for reporting rather than supporting new mobile phones to them; and find a solution to the burden of multiple parallel systems. TRIAL REGISTRATION: Not applicable.