Imported malaria into Australia: surveillance insights and opportunities

Background: Malaria continues to pose a significant burden in endemic countries, many of which lack access to molecular surveillance. Insights from malaria cases in travellers returning to non-endemic areas can provide valuable data to inform endemic country programmes. To evaluate the potential for novel global insights into malaria, we examined epidemiological and molecular data from imported malaria cases to Australia. Methods: We analysed malaria cases reported in Australia from 2012 to 2022 using National Notifiable Disease Surveillance System data. Molecular data on imported malaria cases were obtained from literature searches. Results: Between 2012 and 2022, 3204 malaria cases were reported in Australia. Most cases (69%) were male and 44% occurred in young adults aged 20–39 years. Incidence rates initially declined between 2012 and 2015, then increased until 2019. During 2012–2019, the incidence in travellers ranged from 1.34 to 7.71 per 100 000 trips. Cases were primarily acquired in Sub-Saharan Africa (n = 1433; 45%), Oceania (n = 569; 18%) and Southern and Central Asia (n = 367; 12%). The most common countries of acquisition were Papua New Guinea (n = 474) and India (n = 277). Plasmodium falciparum accounted for 58% (1871/3204) of cases and was predominantly acquired in Sub-Saharan Africa, and Plasmodium vivax accounted for 32% (1016/3204), predominantly from Oceania and Asia. Molecular studies of imported malaria cases to Australia identified genetic mutations and deletions associated with drug resistance and false-negative rapid diagnostic test results, and led to the establishment of reference genomes for P. vivax and Plasmodium malariae. Conclusions: Our analysis highlights the continuing burden of imported malaria into Australia. Molecular studies have offered valuable insights into drug resistance and diagnostic limitations, and established reference genomes. Integrating molecular data into national surveillance systems could provide important infectious disease intelligence to optimize treatment guidelines for returning travellers and support endemic country surveillance programmes

Disentangling fine-scale effects of environment on malaria detection and infection to design risk-based disease surveillance systems in changing landscapes

AbstractLandscape changes have complex effects on malaria transmission, disrupting social and ecological systems determining the spatial distribution of risk. Within Southeast Asia, forested landscapes are associated with both increased malaria transmission and reduced healthcare access. Here, we adapt an ecological modelling framework to identify how local environmental factors influence the spatial distributions of malaria infections, diagnostic sensitivity and detection probabilities in the Philippines. Using convenience sampling of health facility attendees and Bayesian latent process models, we demonstrate how risk-based surveillance incorporating forest data increases the probability of detecting malaria foci over three-fold and enables estimation of underlying distributions of malaria infections. We show the sensitivity of routine diagnostics varies spatially, with the decreased sensitivity in closed canopy forest areas limiting the utility of passive reporting to identify spatial patterns of transmission. By adjusting for diagnostic sensitivity and targeting spatial coverage of health systems, we develop a model approach for how to use landscape data within disease surveillance systems. Together, this illustrates the essential role of environmental data in designing risk-based surveillance to provide an operationally feasible and cost-effective method to characterise malaria transmission while accounting for imperfect detection.</jats:p

Analytical approaches for antimalarial antibody responses to confirm historical and recent malaria transmission: an example from the Philippines

Background: Assessing the status of malaria transmission in endemic areas becomes increasingly challenging as countries approach elimination. Serology can provide robust estimates of malaria transmission intensities, and multiplex serological assays allow for simultaneous assessment of markers of recent and historical malaria exposure. Methods: Here, we evaluated different statistical and machine learning methods for analyzing multiplex malaria-specific antibody response data to classify recent and historical exposure to Plasmodium falciparum and Plasmodium vivax. To assess these methods, we utilized samples from a health-facility based survey (n = 9132) in the Philippines, where we quantified antibody responses against 8 P. falciparum and 6 P. vivax-specific antigens from 3 sites with varying transmission intensity. Findings: Measurements of antibody responses and seroprevalence were consistent with the 3 sites’ known endemicity status. Among the models tested, a machine learning (ML) approach (Random Forest model) using 4 serological markers (PfGLURP R2, Etramp5.Ag1, GEXP18, and PfMSP119) gave better predictions for P. falciparum recent infection in Palawan (AUC: 0.9591, CI 0.9497–0.9684) than individual antigen seropositivity. Although the ML approach did not improve P. vivax infection predictions, ML classifications confirmed the absence of recent exposure to P. falciparum and P. vivax in both Occidental Mindoro and Bataan. For predicting historical P. falciparum and P. vivax transmission, seroprevalence and seroconversion rates based on cumulative exposure markers AMA1 and MSP119 showed reliable trends in the 3 sites. Interpretation: Our study emphasizes the utility of serological markers in predicting recent and historical exposure in a sub-national elimination setting, and also highlights the potential use of machine learning models using multiplex antibody responses to improve assessment of the malaria transmission status of countries aiming for elimination. This work also provides baseline antibody data for monitoring risk in malaria-endemic areas in the Philippines. Funding: Newton Fund, Philippine Council for Health Research and Development, UK Medical Research Council

Comparison of commercial ELISA kits to confirm the absence of transmission in malaria elimination settings

Background: Antimalarial antibody measurements are useful because they reflect historical and recent exposure to malaria. As such, they may provide additional information to assess ongoing transmission in low endemic or pre-elimination settings where cases are rare. In addition, the absence of antibody responses in certain individuals can indicate the cessation of transmission. Commercial malaria enzyme-linked immunosorbent assays (ELISA) detect antimalarial antibodies and are commonly used to screen blood donations for possible malaria infection. However, there is no standardized test to detect antimalarial antibodies for epidemiological use. Here we compared five commercially available ELISA kits (Trinity Biotech, newbio, DiaPro, Cellabs, and NovaTec) in search of a standardized tool for supporting claims of absence of malaria transmission. For comparison, a research-based (RB) ELISA protocol was performed alongside the commercial kits. Results: The commercial kits were first compared using serum samples from known malaria-unexposed individuals (n = 223) and Toxoplasma-infected individuals (n = 191) to assess specificity and cross-reactivity against non-malaria infections. In addition, 134 samples from ≥10-year-olds collected in a hyperendemic region in the Gambia in the early 1990s were used to assess sensitivity. Three out of five kits showed high sensitivity (90–92%), high specificity (98–99%), low cross-reactivity (0–3%) and were considered user-friendly (Trinity Biotech, newbio and NovaTec). Two of these kits (Trinity Biotech and NovaTec) were taken forward for epidemiological evaluation and results were compared to those using the RB-ELISA. Samples from two pre-elimination settings (Praia, Cape Verde; n = 1,396, and Bataan, the Philippines; n = 1,824) were tested. Serological results from both the Trinity Biotech kit and the RB-ELISA concurred with recent passively detected case counts in both settings. Results from the Trinity Biotech kit reflected a significant decrease in the number of reported cases in Bataan in the 1990s better than the RB-ELISA. Results from the NovaTec kit did not reflect transmission patterns in either setting. Conclusion: The Trinity Biotech commercial ELISA kit was considered reliable for epidemiological use and accurately described transmission patterns in two (previously) malaria endemic settings. The use of this simple and standardized serological tool may aid national control and elimination programs by confirming that regions are free from malaria

Enhanced health facility surveys to support malaria control and elimination across different transmission settings in the Philippines

Following substantial progress in malaria control in the Philippines, new surveillance approaches are needed to identify and target residual malaria transmission. This study evaluated an enhanced surveillance approach using rolling cross-sectional surveys of all health facility attendees augmented with molecular diagnostics and geolocation. Facility surveys were carried out in three sites representing different transmission intensities: Morong, Bataan (pre-elimination), Abra de Ilog, Occidental Mindoro (stable medium risk), and Rizal, Palawan (high risk, control). Only one rapid diagnostic test (RDT)–positive infection and no PCR confirmed infections were found in Bataan and Occidental Mindoro, suggesting the absence of transmission. In Palawan, the inclusion of all health facility attendees, regardless of symptoms, and use of molecular diagnostics identified 313 infected individuals in addition to 300 cases identified by routine screening of febrile patients with the RDT or microscopy. Of these, the majority (313/613) were subpatent infections and only detected using molecular methods. Simultaneous collection of GPS coordinates on tablet-based applications allowed real-time mapping of malaria infections. Risk factor analysis showed higher risks in children and indigenous groups, with bed net use having a protective effect. Subpatent infections were more common in men and older age-groups. Overall, malaria risks were not associated with participants’ classification, and some of the non-patient clinic attendees reported febrile illnesses (1.9%, 26/1,369), despite not seeking treatment, highlighting the widespread distribution of infection in communities. Together, these data illustrate the utility of health facility–based surveys to augment surveillance data to increase the probability of detecting infections in the wider community

Enhanced health facility surveys to support malaria control and elimination across different transmission settings in The Philippines

Abstract Following substantial progress in malaria control in the Philippines, new surveillance approaches are needed to identify and target residual malaria transmission. This study evaluated an enhanced surveillance approach using rolling cross-sectional surveys of all health facility attendees augmented with molecular diagnostics and geolocation. Facility surveys were carried out in 3 sites representing different transmission intensities: Morong, Bataan (pre-elimination), Abra de Ilog, Occidental Mindoro (stable-medium risk) and Rizal, Palawan (high risk, control). Only 1 RDT positive infection and no PCR confirmed infections were found in Bataan and Occidental Mindoro suggesting the absence of transmission. In Rizal, inclusion of all health facility attendees, regardless of symptoms, and use of molecular diagnostics identified an additional 313 infected individuals in addition to 300 cases identified by routine screening of febrile patients with RDT or microscopy. Of these, the majority (313/613) were subpatent infections and only detected using molecular methods. Simultaneous collection of GPS coordinates on tablet-based applications allowed real-time mapping of malaria infections. Risk factor analysis showed higher risks in children and indigenous groups, with bednet use having a protective effect. Subpatent infections were more common in men and older age groups. Overall, malaria risks were not associated with patient status and some of non-patient clinic attendees reported febrile illnesses (1.9%, 26/1369) despite not seeking treatment highlighting the widespread distribution of infection in communities. Together, these data illustrate the utility of health-facility based surveys to augment surveillance data to increase the probability of detecting infections in the wider community

Molecular surveillance of chloroquine (CQ) resistant Plasmodium vivax using pvmdr1 gene marker in selected municipalities in Palawan, Philippines

The rise of Chloroquine (CQ) resistant Plasmodium vivax presents a major health challenge fo the global control of this infectious disease. In this study, prevalence of P. vivax multidrug resistance 1 (pvmdr1) gene mutations Y976F and F1076L, suggested t

Prevalence and temporal changes of mutations linked to antimalarial drug resistance in Plasmodium falciparum and Plasmodium vivax in Palawan, Philippines.

OBJECTIVE: This study provides 2016 data on the prevalence of key single nucleotide polymorphisms (SNPs) associated with antimalarial drug resistance in Palawan, Philippines. Findings were combined with historical data to model temporal changes in the prevalence of these SNPs in Plasmodium isolates. METHODS: Plasmodium isolates were genotyped using drug resistance markers pfmdr1, pfcrt, pfdhfr, pfdhps, kelch-13, pvmdr1, pvdhfr, and pvdhps. Temporal trends in the probability of mutations were estimated as a function of time using a binomial generalised linear model. RESULTS: All samples sequenced for Plasmodium falciparum chloroquine markers pfmdr1 and pfcrt had wild-type alleles. Varying mutation patterns were observed for the sulphadoxine/pyrimethamine markers pfdhps and pfdhfr; complete quintuplet mutations were not found. No SNPs were observed for the artemisinin marker kelch-13. For Plasmodium vivax, differing patterns were detected for pvmdr1, pvdhfr, and pvdhps. CONCLUSIONS: The study findings suggest that the current drugs remain effective and that there is limited importation and establishment of resistant parasites in the area. Clear temporal trends were recognised, with prominent decreases in the proportions of pfcrt and pfmdr mutations detected within the past 15 years, consistent with a change in antimalarial drug policy. Continuous surveillance of antimalarial drug resistance is important to support malaria elimination efforts