Introducing a Regulatory Sandbox Into the Indonesian Health System Using e-Malaria as a Use Case: Participatory Action Study.

BACKGROUND: Regulatory sandboxes offer an alternative solution to address regulatory challenges in adopting disruptive technologies. Although regulatory sandboxes have been widely implemented in the financial sector across more than 50 countries, their application to the health sector remains limited. OBJECTIVE: This study aims to explore stakeholders' perspectives on introducing a regulatory sandbox into the Indonesian health system using e-malaria as a use case. METHODS: Using a participatory action research approach, this study conducted qualitative research, including desk reviews, focus group discussions, and in-depth interviews with stakeholders. This study sought to understand stakeholders' concerns and interests regarding the regulatory sandbox and to collaboratively develop a regulatory sandbox model to support the malaria program. RESULTS: The study revealed that most stakeholders had limited awareness of the regulatory sandbox concept. Concerns have been raised regarding the time required to establish regulations, knowledge gaps among stakeholders, data protection issues, and limited digital infrastructure in malaria endemic areas. Existing regulations have been found to be inadequate to accommodate disruptive healthtech for malaria. Nevertheless, through a collaborative process, stakeholders successfully developed a regulatory sandbox model specifically for e-malaria, with the crucial support of the Ministry of Health. CONCLUSIONS: The regulatory sandbox holds the potential for adoption in the Indonesian health system to address the limited legal framework and to facilitate the rapid and safe adoption of disruptive healthtech in support of the malaria elimination program. Through stakeholder involvement, guidelines for implementing the regulatory sandbox were developed and innovators were successfully invited to participate in the first-ever trial of a health regulatory sandbox for e-malaria in Indonesia. Future studies should provide further insights into the challenges encountered during the e-malaria regulatory sandbox pilot study, offering a detailed account of the implementation process.

Identifying forms of interventions towards cross border malaria in the Asia-Pacific region: a scoping review protocol.

INTRODUCTION: An ambitious epidemiology strategy has been set by the WHO, targeting malaria elimination for at least 35 countries in 2030. Challenges in preventing malaria cross borders require greater attention to achieve the elimination target. This scoping review aims to identify successful forms of interventions to control malaria transmission across national borders in the Asia-Pacific region. METHODS AND ANALYSIS: This scoping review will search four electronic databases (PubMed, ScienceDirect, EBSCOhost and ProQuest) limiting the time of publication to the last 10 years. Two independent reviewers will screen all titles and abstracts during the second stage. Study characteristics will be recorded; qualitative data will be extracted and evaluated, while quantitative data will be extracted and summarised. Overall, we will follow the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews guidelines. ETHICS AND DISSEMINATION: This scoping review has received ethical approval from the Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada. The results will be disseminated through peer-reviewed publications, conference presentations and policy briefs.

A participatory approach to address within-country cross-border malaria: the case of Menoreh Hills in Java, Indonesia.

BACKGROUND: Malaria remains a significant public health issue in Indonesia. Most of the endemic areas are in the eastern parts of Indonesia, but there are a few remaining foci of persistent endemic malaria in Java, particularly in Menoreh Hills, a region bordering three districts of two provinces on this island. Despite a commitment to build a partnership to eliminate cross-border malaria, there is a lack of understanding of how this partnership might be translated into an implementable strategic plan. The study aims to provide evidence of how a participatory approach was used to strengthen the cross-border collaboration and stakeholders' capacity to develop a joint strategic, operational, and costing plan for cross-border malaria elimination. METHODS: A participatory action research was conducted from January to August 2017, involving participants from the village, district, provincial, and national levels. This study was conducted in seven phases, including document review, focus group discussions (FGDs), planning and costing workshops, and a dissemination meeting. A total of 44 participants from primary health centres (PHC) and 27 representatives of affected villages in three districts, 16 participants from the district and provincial malaria programmes and planning bureaus, and 11 participants from the national level were involved in the processes. Data on priority issues, costing, programme coverage, and administration were collected. Thematic coding and feedback were used for analysis. RESULTS: Problems identified by stakeholders included low community awareness and participation in malaria prevention, high mobility across three districts, lack of financial and human resources, lack of inter-district coordination, and poor implementation of migration surveillance. Cross-border strategies identified to address malaria were improving cross-border migration surveillance, strengthening the network, governance, and advocacy of malaria control implementation across borders, and developing the malaria information system. A working group composed of the three districts' representatives authorized to decide on cross-border issues will be created. CONCLUSIONS: The participatory approach was applicable in cross-border malaria planning for within-country settings and useful in enhancing stakeholders' capacities as implementers. While done in a participatory way, the joint plan crafted was a non-binding agreement; stakeholders should advocate to ensure adequate funds are poured into mobilizing the programme.

Genetic diversity of Merozoite surface protein 1-42 (MSP1-42) fragment of Plasmodium vivax from Indonesian isolates: Rationale implementation of candidate MSP1 vaccine.

Morbidity and mortality related to malaria in Indonesia are attributed to both Plasmodium falciparum and P. vivax parasites. In addition to vaccines for P. falciparum, vaccines against P. vivax are urgently needed for the prevention of the disease. An extensively studied antigen is the carboxyl-terminus of the 42 kDa region of P. vivax merozoite surface protein-1 (PvMSP1-42). The design of a vaccine based on this antigen requires an understanding of the extent of polymorphism. However, there is no information on the genetic diversity of the antigen in Indonesia. This study aimed to profile the diversity of PvMSP1-42 and its two subdomains (PvMSP1-33 and PvMSP1-19) among Indonesian P. vivax isolates. A total of 52 P. vivax-infected blood samples were collected from patients in two different endemic areas in Indonesia: Banjarmasin (Kalimantan) and Sumba Timur (Nusa Tenggara Timur). The polymorphic characteristics and natural selection of PvMSP1-42 were analyzed using the DnaSP, MEGA, and Structure software. Thirty distinct haplotypes of PvMSP1-42 were identified. They displayed amino acid changes compared to the reference PVP01 sequence. Most of the mutations were concentrated in the 33 kDa fragment. PvMSP1-42 of the Indonesian isolates appeared to be under positive selection. Recombination may also play a role in the resulting genetic diversity of PvMSP1. In conclusion, PvMSP1-42 of Indonesian isolates displayed allelic polymorphisms caused by mutation, recombination, and positive selection. These results will aid the understanding of the P. vivax population in Indonesia and to develop a PvMSP1 based vaccine against P. vivax.

Epidemiology and risk factors of Strongyloides stercoralis infection in Papua, Indonesia: a molecular diagnostic study.

Strongyloides stercoralis is a parasitic worm that is of considerable clinical relevance. Indeed, it may persist asymptomatically for many years, but can lead to potentially fatal dissemination when the host's immune status is impaired. As commonly employed stool microscopy techniques (e.g. Kato-Katz thick smear) fail to detect S. stercoralis, the epidemiology is poorly understood. In 2013, we conducted a cross-sectional household survey in the district of Mimika in Papua, Indonesia. A total of 331 individuals, aged 1 month to 44 years, had a single stool sample subjected to real-time polymerase chain reaction (PCR) for S. stercoralis diagnosis. The prevalence of S. stercoralis infection was 32.0% (106/331 individuals); higher than any of the three main soil-transmitted helminths (Ascaris lumbricoides, 23.9%; Trichuris trichiura, 18.4%; and hookworm, 17.2%). Amongst the S. stercoralis-infected individuals, 73.6% were concurrently infected with another helminth, with hookworm being the most frequent co-infection (27.4%). Fourteen percent of the S. stercoralis infections had low cycle threshold values on real-time PCR, which may indicate a higher infection intensity. Multivariate logistic regression analysis revealed that age ≥5 years (adjusted odds ratio (OR) 5.8, 95% confidence interval (CI): 3.1-10.8) was significantly associated with S. stercoralis infection. There is a need for in-depth clinical and diagnostic studies to elucidate the public health impact of S. stercoralis infection in Indonesia.

Spatiotemporal patterns of malaria at cross-boundaries area in Menoreh Hills, Java, Indonesia.

BACKGROUND: Comprehensive reports of malaria in Menoreh Hills, Central Java, Indonesia, a unique district cross-boundaries area under three districts and two provinces have been published previously. However, no study was performed to identify the hotspots of malaria in this cross-boundaries area, Kaligesing and Bagelen Subdistricts in Purworejo, Jawa Tengah Province and Kokap Subdistrict in Kulon Progo, Yogyakarta Province, using a longitudinal spatial data. METHODS: Monthly reports of malaria cases at primary health centres during 2005-2015 were collected and processed with ArcGIS and SaTScan to identify the malaria distribution at the village level. Malaria distribution was analysed using global spatial autocorrelation (Moran index) in ArcGIS. Cluster analysis was conducted using SaTScan purely spatial clustering and purely temporal clustering. Cluster characteristics resulted from three different approach were compared and analysed. RESULTS: During the last 11 years, 3812 malaria cases were reported and the number of high case incidence (HCI) villages were increased continuously. Malaria spatial distribution in Menoreh Hills was clustered spatially. Using three different approaches of time period ranges, consistent conclusion was found i.e. most likely clusters always occurred in the Purworejo district while the secondary clusters appeared later in the cross-boundaries districts. CONCLUSION: Spatiotemporal analysis of an 11 years surveillance data showed that hotspots of malaria cases in Menoreh Hills were continuously located in Purworejo district. The success of malaria elimination in the cross boundaries area of Menoreh Hills might be depended on the success in malaria case management and surveillance in this hotspot area.

Intravenous artesunate plus oral dihydroartemisinin-piperaquine or intravenous quinine plus oral quinine for optimum treatment of severe malaria: lesson learnt from a field hospital in Timika, Papua, Indonesia.

BACKGROUND: Intravenous artesunate and its follow on full course dihydroartemisinin-piperaquine are the standard treatment for severe malaria in Indonesia. The current policy suggests that intravenous and oral quinine could be used when standard therapy is not available. Its pragmatic use of both treatment combinations in a field hospital is evaluated. METHODS: A retrospective study among hospitalized malaria patients receiving intravenous anti-malarial treatments at Mitra Masyarakat Hospital, Timika from April 2004 to December 2013 was conducted. The length of hospital stay (LoS) and the risk of malaria recurrence within 28 days after hospital admission were compared between patients receiving intravenous artesunate and oral dihydroartemisinin-piperaquine (Iv Art + DHP) and those receiving intravenous and oral quinine (Iv + Oral Qu). RESULTS: Of 10,514 patients requiring intravenous therapy, 2759 received Iv + Oral Qu and 7755 received Iv Art + DHP. Plasmodium falciparum infection accounted for 65.8% (6915), while Plasmodium vivax, Mixed infections, Plasmodium malariae and Plasmodium ovale were accounted for 17.0% (1789), 16.4% (1729), 0.8% (79) and 0.01% (2) of the infections, respectively. The majority of severe malaria hospital admissions were highland Papuans (78.0%, 8201/10,501). In total 49% (5158) of patients were older than 15 years and 3463 (32.9%) were children under 5 years old. The median LoS was shorter in patients receiving intravenous artesunate compared to those treated with intravenous quinine (median = 2 [IQR 1-3] versus 3 days [IQR 2-4], p < 0.0001). Patients treated with intravenous quinine had higher risk of being hospitalized longer than 2 days (aOR of 1.70 [95% CI 1.54-1.88], p < 0.0001). The risk of recurrences within 28 days after hospital admission was 1.94 times higher (95% CI aHR 1.57-2.39, p < 0.0001) in patients receiving intravenous quinine with follow on oral quinine treatment than in patients treated with DHP after intravenous artesunate therapy. CONCLUSIONS: Intravenous artesunate reduced the LoS of malaria patients and in combination with DHP reduced the risk of malaria recurrence within 28 days after hospital admission compared to those with Iv + Oral Qu treatment. Thus, ensuring continuous supply of intravenous artesunate and artemisinin-based combination therapy (ACT) should be a priority.

Diagnostic comparison of Baermann funnel, Koga agar plate culture and polymerase chain reaction for detection of human Strongyloides stercoralis infection in Maluku, Indonesia.

Human infection with the nematode Strongyloides stercoralis, which may have a life-threatening course, primarily occurs in tropical settings. Epidemiological data on the occurrence of strongyloidiasis are scarce, and microscopic stool-based detection methods are insensitive. Polymerase chain reaction (PCR) assays have been developed, yet conflicting results have been reported. Our goal was to determine whether there was diagnostic agreement between an in-house PCR and two microscopic techniques, the Baermann funnel (BM) and the Koga agar plate culture (KAP) for the detection of S. stercoralis in stool samples. Eighty ethanol-fixed stool samples stemming from a cross-sectional survey in Maluku, Indonesia, were purposefully selected for PCR analysis. The final sample size comprised four groups, each with 20 samples: group 1, positive for S. stercoralis on both BM and KAP; group 2, positive only by BM; group 3, positive only by KAP; and group 4, negative on both BM and KAP. A Strongyloides-specific PCR targeting the internal transcribed spacer 2 (ITS2) region was carried out in an Indonesian reference laboratory. The overall agreement between PCR and microscopy was 61% (49/80 samples), being highest in group 1 (15/20, 75%) and lowest in group 3 (9/20, 45%). PCR revealed eight additional S. stercoralis infections in group 4. Future studies should elucidate the 'true' infection status of samples that are negative by PCR, but positive upon microscopy. Taken together, there is a lack of agreement between microscopy and PCR results for the diagnosis of human S. stercoralis infection in Indonesia. ClinicalTrials.gov (identifier: NCT02105714).

A Time Series Analysis: Weather Factors, Human Migration and Malaria Cases in Endemic Area of Purworejo, Indonesia, 2005-2014.

BACKGROUND: Climatic and weather factors become important determinants of vector-borne diseases transmission like malaria. This study aimed to prove relationships between weather factors with considering human migration and previous case findings and malaria cases in endemic areas in Purworejo during 2005-2014. METHODS: This study employed ecological time series analysis by using monthly data. The independent variables were the maximum temperature, minimum temperature, maximum humidity, minimum humidity, precipitation, human migration, and previous malaria cases, while the dependent variable was positive malaria cases. Three models of count data regression analysis i.e. Poisson model, quasi-Poisson model, and negative binomial model were applied to measure the relationship. The least Akaike Information Criteria (AIC) value was also performed to find the best model. Negative binomial regression analysis was considered as the best model. RESULTS: The model showed that humidity (lag 2), precipitation (lag 3), precipitation (lag 12), migration (lag1) and previous malaria cases (lag 12) had a significant relationship with malaria cases. CONCLUSION: Weather, migration and previous malaria cases factors need to be considered as prominent indicators for the increase of malaria case projection.

Change of strategy is required for malaria elimination: a case study in Purworejo District, Central Java Province, Indonesia.

BACKGROUND: Malaria has been targeted for elimination from Indonesia by 2030, with varying timelines for specific geographical areas based on disease endemicity. The regional deadline for malaria elimination for Java island, given the steady decrease of malaria cases, was the end of 2015. Purworejo District, a malaria-endemic area in Java with an annual parasite incidence (API) of 0.05 per 1,000 population in 2009, aims to enter this elimination stage. This study documents factors that affect incidence and spatial distribution of malaria in Purworejo, such as geomorphology, topography, health system issues, and identifies potential constraints and challenges to achieve the elimination stage, such as inter-districts coordination, decentralization policy and allocation of financial resources for the programme. METHODS: Historical malaria data from 2007 to 2011 were collected through secondary data, in-depth interviews and focus group discussions during study year (2010-2011). Malaria cases were mapped using the village-centroid shape file to visualize its distribution with geomorphologic characteristics overlay and spatial distribution of malaria. API in each village in Purworejo and its surrounding districts from 2007 to 2011 was stratified into high, middle or low case incidence to show the spatiotemporal mapping pattern. RESULTS: The spatiotemporal pattern of malaria cases in Purworejo and the adjacent districts demonstrate repeated concentrated occurrences of malaria in specific areas from 2007 to 2011. District health system issues, i.e., suboptimal coordination between primary care and referral systems, suboptimal inter-district collaboration for malaria surveillance, decentralization policy and the lack of resources, especially district budget allocations for the malaria programme, were major constraints for programme sustainability. CONCLUSIONS: A new malaria elimination approach that fits the local disease transmission, intervention and political system is required. These changes include timely measurements of malaria transmission, revision of the decentralized government system and optimizing the use of the district capitation fund followed by an effective technical implementation of the intervention strategy.

Early malaria resurgence in pre-elimination areas in Kokap Subdistrict, Kulon Progo, Indonesia.

BACKGROUND: Indonesia is among those countries committed to malaria eradication, with a continuously decreasing incidence of malaria. However, at district level the situation is different. This study presents a case of malaria resurgence Kokap Subdistrict of the Kulon Progo District in Yogyakarta Province, Java after five years of low endemicity. This study also aims to describe the community perceptions and health services delivery situation that contribute to this case. METHODS: All malaria cases (2007-2011) in Kulon Progo District were stratified to annual parasite incidence (API). Two-hundred and twenty-six cases during an outbreak (May 2011 to April 2012) were geocoded by household addresses using a geographic information system (GIS) technique and clusters were identified by SaTScan software analysis (Arc GIS 10.1). Purposive random sampling was conducted on respondents living inside the clusters to identify community perceptions and behaviour related to malaria. Interviews were conducted with malaria health officers to understand the challenges of malaria surveillance and control. RESULTS: After experiencing three consecutive years with API less than 1 per thousand, malaria in Kokap subdistrict increased almost ten times higher than API in the district level and five times higher than national API. Malaria cases were found in all five villages in 2012. One primary and two secondary malaria clusters in Hargotirto and Kalirejo villages were identified during the 2011-2012 outbreak. Most of the respondents were positively aware with malaria signs and activities of health workers to prevent malaria, although some social economic activities could not be hindered. Return transmigrants or migrant workers entering to their villages, reduced numbers of village malaria workers and a surge in malaria cases in the neighbouring district contributed to the resurgence. CONCLUSION: Community perception, awareness and participation could constitute a solid foundation for malaria elimination in Kokap. However, decreasing number of village malaria workers and ineffective communication between primary health centres (PHCs) within boundary areas with similar malaria problems needs attention. Decentralization policy was allegedly the reason for the less integrated malaria control between districts, especially in the cross border areas. Malaria resurgence needs attention particularly when it occurs in an area that is entering the elimination phase.

Growth-inhibitory antibodies are not necessary for protective immunity to malaria infection.

The absence of a validated surrogate marker for the immune state has complicated the design of a subunit vaccine against asexual stages of Plasmodium falciparum. In particular, it is not known whether the capacity to induce antibodies that inhibit parasite growth in vitro is an important criterion for selection of P. falciparum proteins to be assessed in human vaccine trials. We examined this issue in the Plasmodium yoelii rodent malaria model using the 19-kDa C-terminal fragment of merozoite surface protein 1 (MSP1(19)). To examine the relationship between inhibitory antibodies in immunized mice and the immune state, as indicated by resistance to a blood-stage challenge, we used an allelic replacement strategy to generate a transgenic P. falciparum line that expresses MSP1(19) from P. yoelii. We show that MSP1(19) is functionally conserved across these two divergent Plasmodium species, and replacing PfMSP1(19) with PyMSP1(19) has no detectable effect on parasite growth in vitro. By comparing growth rates of this transgenic line with a matched transgenic line that expresses the endogenous PfMSP1(19), we developed an assay to measure the specific growth-inhibitory activity directed exclusively to the PyMSP1(19) protein in the sera from vaccinated animals. To validate this assay, sera from rabbits immunized with recombinant PyMSP1(19) were tested and showed specific inhibitory activity in a concentration-dependent manner. In mice that were immunized with recombinant PyMSP1(19), the levels of PyMSP1(19)-specific inhibitory activity did not correlate with the total antibody levels measured by enzyme-linked immunosorbent assay. Furthermore, they did not correlate with resistance to subsequent blood-stage infection, and some mice with complete protection showed no detectable inhibitory activity in their prechallenge sera. These data indicated that growth-inhibitory activity measured in vitro was not a reliable predictor of immune status in vivo, and the reliance on this criterion to select vaccine candidates for human clinical trials may be misplaced. The transgenic lines further offer useful tools for comparing the efficacy of MSP1(19)-based vaccines that utilize different immunization regimens and antigen formulations.

Inhibitory antibodies specific for the 19-kilodalton fragment of merozoite surface protein 1 do not correlate with delayed appearance of infection with Plasmodium falciparum in semi-immune individuals in Vietnam.

Inhibitory antibodies specific for the 19-kDa fragment of merozoite surface protein 1 (MSP1(19)) are a significant component of inhibitory responses in individuals immune to malaria. Nevertheless, conflicting results have been obtained in determining whether this antibody specificity correlates with protection in residents of areas where malaria is endemic. In this study, we examined sera collected from a population of semi-immune individuals living in an area of Vietnam with meso-endemicity during a 6-month period. We used two Plasmodium falciparum parasite lines that express either endogenous MSP1(19) or the homologous region from Plasmodium yoelii to measure the MSP1(19)-specific inhibitory activity. We showed that (i) the level of MSP1(19)-specific inhibitory antibodies was not associated with a delay in P. falciparum infection, (ii) MSP1(19)-specific inhibitory antibodies declined significantly during the convalescent period after infection, and (iii) there was no significant correlation between the MSP1(19)-specific inhibitory antibodies and the total antibodies measured by enzyme-linked immunosorbent assay. These results have implications for understanding naturally acquired immunity to malaria and for the development and evaluation of MSP1(19)-based vaccines.

Acquisition of invasion-inhibitory antibodies specific for the 19-kDa fragment of merozoite surface protein 1 in a transmigrant population requires multiple infections.

Antibodies against the 19 kDa C-terminal fragment of merozoite surface protein 1 (MSP1(19)) are a major component of the invasion-inhibitory response in individuals immune to malaria. We report here the acquisition of MSP1(19)-specific invasion-inhibitory antibodies in a group of transmigrants who experienced their sequential malaria infections during settlement in an area of Indonesia where malaria is highly endemic. We used 2 transgenic Plasmodium falciparum parasite lines that expressed either endogenous MSP1(19) or the homologous region from P. chabaudi to measure the MSP1(19)-specific invasion-inhibitory antibodies. The results revealed that the acquisition of MSP1(19)-specific invasion-inhibitory antibodies required 2 or more P. falciparum infections. In contrast, enzyme-linked immunosorbent assays on the same serum samples showed that MSP1(19)-specific antibodies are present after the first malaria infection. This delay in the acquisition of functional antibodies by residents of areas where malaria is endemic is consistent with the observation that multiple malaria infections are required before clinical immunity is acquired.

Active immunisation with RAMA does not provide protective immunity against Plasmodium yoelii challenge despite its association with protective responses in endemic populations.

The rhoptry associated membrane antigen (RAMA) of Plasmodium falciparum has been proposed as a potential candidate for inclusion in a multivalent subunit vaccine against malaria. Previous studies have found that the RAMA gene is refractory to genetic deletion in vitro and is conserved in a range of clinical isolates. Importantly, two independent studies demonstrated that antibodies against the C-terminal region of RAMA are associated with immunity in endemic populations of both Asia and Africa. However, there is presently no direct evidence that anti-RAMA immune responses have a demonstrable anti-parasitic effect either in vitro or in vivo. In this study we used an in vitro invasion inhibition assay and the Plasmodium yoelii mouse model of infection to evaluate the potential of RAMA as a vaccine candidate. Our results demonstrate that anti-PfRAMA antibodies have only a weak inhibitory effect on P. falciparum invasion in vitro. Immunisation with recombinant PyRAMA protein did not protect mice against a lethal P. yoelii infection and did not boost the level of protection induced by a known protective antigen, merozoite surface protein 4/5. Taken together, these data do not support RAMA as a priority vaccine candidate.