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    Plasmodium vivax-How hidden reservoirs hinder global malaria elimination
    Angrisano, F ; Robinson, LJ (ELSEVIER IRELAND LTD, 2022-04-01)
    Plasmodium vivax is the most geographically widespread human malaria parasite. Global malaria efforts have been less successful at reducing the burden of P. vivax compared to P. falciparum, owing to the unique biology and related treatment complexity of P. vivax. As a result, P. vivax is now the dominant malaria parasite throughout the Asia-Pacific and South America causing up to 14 million clinical cases every year and is considered a major obstacle to malaria elimination. Key features circumventing existing malaria control tools are the transmissibility of asymptomatic, low-density circulating infections and reservoirs of persistent dormant liver stages (hypnozoites) that are undetectable but reactivate to cause relapsing infections and sustain transmission. In this review we summarise the new knowledge shaping our understanding of the global epidemiology of P. vivax infections, highlighting the challenges for elimination and the tools that will be required achieve this.
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    Individual Efficacy and Community Impact of Ivermectin, Diethylcarbamazine, and Albendazole Mass Drug Administration for Lymphatic Filariasis Control in Fiji: A Cluster Randomized Trial
    Hardy, M ; Samuela, J ; Kama, M ; Tuicakau, M ; Romani, L ; Whitfeld, MJ ; King, CL ; Weil, GJ ; Grobler, AC ; Robinson, LJ ; Kaldor, JM ; Steer, AC (OXFORD UNIV PRESS INC, 2021-03-16)
    BACKGROUND: Bancroftian filariasis remains endemic in Fiji despite >10 years of mass drug administration (MDA) using diethylcarbamazine and albendazole (DA). The addition of ivermectin to this combination (IDA) has improved efficacy of microfilarial clearance at 12 months in individually randomized trials in nocturnal transmission settings, but impact in a setting of diurnally subperiodic filarial transmission has not been evaluated. METHODS: This cluster randomized study compared the individual efficacy and community impact of IDA vs DA as MDA for lymphatic filariasis in 35 villages on 2 islands of Fiji. Participants were tested at enrollment for circulating filarial antigen and, if positive, for microfilariae. Weight-dosed treatment was offered according to village randomization. Communities were visited at 12 months and retested for lymphatic filariasis. Infected individuals from Rotuma were retested at 24 months. RESULTS: A total of 3816 participants were enrolled and 3616 were treated. At 12 months, microfilariae clearance was achieved in 72 of 111 participants detected with infection at baseline, with no difference in efficacy between treatment groups: DA, 69.2% (95% confidence interval [CI], 57.2%-79.1%) vs IDA, 62.5% (95% CI, 43.6%-78.2%); risk difference, 11.3 % (95% CI, -10% to 32.7%); P = .30. There was no difference between treatment groups in community prevalence of microfilariae at 12 months or individual clearance at 24 months. CONCLUSIONS: We found no difference between IDA and DA in individual clearance or community prevalence of lymphatic filariasis at 12 months, and no improved efficacy following a second annual round of IDA. Possible explanations for the apparent lack of benefit of IDA compared to DA include drug and parasite factors affecting clearance, and higher than expected reinfection rates. Clinical Trials Registration: NCT03177993 and Australian New Zealand Clinical Trial Registry: N12617000738325.
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    STRIVE PNG: using a partnership-based approach in implementation research to strengthen surveillance and health systems in Papua New Guinea
    Farquhar, R ; Dori, A ; MacCana, S ; Tefuarani, N ; Lavu, E ; Barry, A ; Karl, S ; Makita, L ; Robinson, L ; Laman, M (BMC, 2022-04-02)
    Successful implementation research requires effective and equitable relationships between policy-makers, researchers and implementers to effect evidence-based systems change. However, mainstream research grant models between Global North and Global South institutions often (unintentionally) reinforce power imbalances between partners, which result in missed opportunities for knowledge and learning exchange between policy-makers, researchers and implementers.This case study, centred on the STRIVE PNG project, describes how a partnership-based approach has been used to establish, maintain and review effective and equitable relationships between 13 partner organizations (independent research institutes, government health agencies and public health laboratories) to strengthen surveillance and health systems in Papua New Guinea (PNG). We provide an overview of key terms (with supporting conceptual frameworks), describe selected partnership processes and tools used within the project, and share observations regarding early outcomes achieved through this approach.
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    Developing sero-diagnostic tests to facilitate Plasmodium vivax Serological Test-and-Treat approaches: modeling the balance between public health impact and overtreatment.
    Obadia, T ; Nekkab, N ; Robinson, LJ ; Drakeley, C ; Mueller, I ; White, MT (Springer Science and Business Media LLC, 2022-03-18)
    BACKGROUND: Eliminating Plasmodium vivax will require targeting the hidden liver-stage reservoir of hypnozoites. This necessitates new interventions balancing the benefit of reducing vivax transmission against the risk of over-treating some individuals with drugs which may induce haemolysis. By measuring antibodies to a panel of vivax antigens, a strategy of serological-testing-and-treatment (PvSeroTAT) can identify individuals with recent blood-stage infections who are likely to carry hypnozoites and target them for radical cure. This provides a potential solution to selectively treat the vivax reservoir with 8-aminoquinolines. METHODS: PvSeroTAT can identify likely hypnozoite carriers with ~80% sensitivity and specificity. Diagnostic test sensitivities and specificities ranging 50-100% were incorporated into a mathematical model of vivax transmission to explore how they affect the risks and benefits of different PvSeroTAT strategies involving hypnozoiticidal regimens. Risk was measured as the rate of overtreatment and benefit as reduction of community-level vivax transmission. RESULTS: Across a wide range of combinations of diagnostic sensitivity and specificity, PvSeroTAT was substantially more effective than bloodstage mass screen and treat strategies and only marginally less effective than mass drug administration. The key test characteristic determining of the benefit of PvSeroTAT strategies is diagnostic sensitivity, with higher values leading to more hypnozoite carriers effectively treated and greater reductions in vivax transmission. The key determinant of risk is diagnostic specificity: higher specificity ensures that a lower proportion of uninfected individuals are unnecessarily treated with primaquine. These relationships are maintained in both moderate and low transmission settings (qPCR prevalence 10% and 2%). Increased treatment efficacy and adherence can partially compensate for lower test performance. Multiple rounds of PvSeroTAT with a lower performing test may lead to similar or higher reductions in vivax transmission than fewer rounds with a higher performing test, albeit with higher rate of overtreatment. CONCLUSIONS: At current performance, PvSeroTAT is predicted to be a safe and efficacious option for targeting the hypnozoite reservoir towards vivax elimination. P. vivax sero-diagnostic tests should aim for both high performance and ease of use in the field. The target product profiles informing such development should thus reflect the trade-offs between impact, overtreatment, and ease of programmatic implementation.
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    Community perceptions and acceptability of mass drug administration for the control of neglected tropical diseases in Asia-Pacific countries: A systematic scoping review of qualitative research
    Mitchell, E ; Kelly-Hanku, A ; Krentel, A ; Romani, L ; Robinson, LJ ; Vaz Nery, S ; Kaldor, J ; Steer, AC ; Bell, S ; Horstick, O (PUBLIC LIBRARY SCIENCE, 2022-03-01)
    BACKGROUND: Preventative chemotherapy and mass drug administration have been identified as effective strategies for the prevention, treatment, control and elimination of several NTDs in the Asia-Pacific region. Qualitative research can provide in-depth insight into the social dynamics and processes underlying effective implementation of and adherence to mass drug administration programs. This scoping review examines published qualitative literature to examine factors influencing community perceptions and acceptability of mass drug administration approaches to control NTDs in the Asia-Pacific region. METHODOLOGY: Twenty-four peer reviewed published papers reporting qualitative data from community members and stakeholders engaged in the implementation of mass drug administration programs were identified as eligible for inclusion. FINDINGS: This systematic scoping review presents available data from studies focussing on lymphatic filariasis, soil-transmitted helminths and scabies in eight national settings (India, Indonesia, Philippines, Bangladesh, Laos, American Samoa, Papua New Guinea, Fiji). The review highlights the profoundly social nature of individual, interpersonal and institutional influences on community perceptions of willingness to participate in mass drug administration programs for control of neglected tropical diseases (NTD). Future NTD research and control efforts would benefit from a stronger qualitative social science lens to mass drug administration implementation, a commitment to understanding and addressing the social and structural determinants of NTDs and NTD control in complex settings, and efforts to engage local communities as equal partners and experts in the co-design of mass drug administration and other efforts to prevent, treat, control and eliminate NTDs. CONCLUSION: For many countries in the Asia-Pacific region, the "low hanging fruit has been picked" in terms of where mass drug administration has worked and transmission has been stopped. The settings that remain-such as remote areas of Fiji and Papua New Guinea, or large, highly populated, multi-cultural urban settings in India and Indonesia-present huge challenges going forward.
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    Safety and efficacy of mass drug administration with a single-dose triple-drug regimen of albendazole plus diethylcarbamazine plus ivermectin for lymphatic filariasis in Papua New Guinea: An open-label, cluster-randomised trial
    Tavul, L ; Laman, M ; Howard, C ; Kotty, B ; Samuel, A ; Bjerum, C ; O'Brian, K ; Kumai, S ; Amuga, M ; Lorry, L ; Kerry, Z ; Kualawi, M ; Karl, S ; Makita, L ; John, LN ; Bieb, S ; Wangi, J ; Weil, GJ ; Goss, CW ; Tisch, DJ ; Pomat, W ; King, CL ; Robinson, LJ ; Walker, M (PUBLIC LIBRARY SCIENCE, 2022-02-01)
    BACKGROUND: Papua New Guinea (PNG) has a high burden of lymphatic filariasis (LF) caused by Wuchereria bancrofti, with an estimated 4.2 million people at risk of infection. A single co-administered dose of ivermectin, diethylcarbamazine and albendazole (IDA) has been shown to have superior efficacy in sustained clearance of microfilariae compared to diethylcarbamazine and albendazole (DA) in small clinical trials. A community-based cluster-randomised trial of DA versus IDA was conducted to compare the safety and efficacy of IDA and DA for LF in a moderately endemic, treatment-naive area in PNG. METHODOLOGY: All consenting, eligible residents of 24 villages in Bogia district, Madang Province, PNG were enrolled, screened for W. bancrofti antigenemia and microfilaria (Mf) and randomised to receive IDA (N = 2382) or DA (N = 2181) according to their village of residence. Adverse events (AE) were assessed by active follow-up for 2 days and passive follow-up for an additional 5 days. Antigen-positive participants were re-tested one year after MDA to assess treatment efficacy. PRINCIPAL FINDINGS: Of the 4,563 participants enrolled, 96% were assessed for AEs within 2 days after treatment. The overall frequency of AEs were similar after either DA (18%) or IDA (20%) treatment. For those individuals with AEs, 87% were mild (Grade 1), 13% were moderate (Grade 2) and there were no Grade 3, Grade 4, or serious AEs (SAEs). The frequency of AEs was greater in Mf-positive than Mf-negative individuals receiving IDA (39% vs 20% p<0.001) and in Mf-positive participants treated with IDA (39%), compared to those treated with DA (24%, p = 0.023). One year after treatment, 64% (645/1013) of participants who were antigen-positive at baseline were re-screened and 74% of these participants (475/645) remained antigen positive. Clearance of Mf was achieved in 96% (52/54) of infected individuals in the IDA arm versus 84% (56/67) of infected individuals in the DA arm (relative risk (RR) 1.15; 95% CI, 1.02 to 1.30; p = 0.019). Participants receiving DA treatment had a 4-fold higher likelihood of failing to clear Mf (RR 4.67 (95% CI: 1.05 to 20.67; p = 0.043). In the DA arm, a significant predictor of failure to clear was baseline Mf density (RR 1.54; 95% CI, 1.09 to 2.88; p = 0.007). CONCLUSION: IDA was well tolerated and more effective than DA for clearing Mf. Widespread use of this regimen could accelerate LF elimination in PNG. TRIAL REGISTRATION: Registration number NCT02899936; https://clinicaltrials.gov/ct2/show/NCT02899936.
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    Vector composition, abundance, biting patterns and malaria transmission intensity in Madang, Papua New Guinea: assessment after 7 years of an LLIN-based malaria control programme
    Keven, JB ; Katusele, M ; Vinit, R ; Rodriguez-Rodriguez, D ; Hetzel, MW ; Robinson, LJ ; Laman, M ; Karl, S ; Walker, ED (BMC, 2022-01-05)
    BACKGROUND: A malaria control programme based on distribution of long-lasting insecticidal bed nets (LLINs) and artemisinin combination therapy began in Papua New Guinea in 2009. After implementation of the programme, substantial reductions in vector abundance and malaria transmission intensity occurred. The research reported here investigated whether these reductions remained after seven years of sustained effort. METHODS: All-night (18:00 to 06:00) mosquito collections were conducted using human landing catches and barrier screen methods in four villages of Madang Province between September 2016 and March 2017. Anopheles species identification and sporozoite infection with Plasmodium vivax and Plasmodium falciparum were determined with molecular methods. Vector composition was expressed as the relative proportion of different species in villages, and vector abundance was quantified as the number of mosquitoes per barrier screen-night and per person-night. Transmission intensity was quantified as the number of sporozoite-infective vector bites per person-night. RESULTS: Five Anopheles species were present, but vector composition varied greatly among villages. Anopheles koliensis, a strongly anthropophilic species was the most prevalent in Bulal, Matukar and Wasab villages, constituting 63.7-73.8% of all Anopheles, but in Megiar Anopheles farauti was the most prevalent species (97.6%). Vector abundance varied among villages (ranging from 2.8 to 72.3 Anopheles per screen-night and 2.2-31.1 Anopheles per person-night), and spatially within villages. Malaria transmission intensity varied among the villages, with values ranging from 0.03 to 0.5 infective Anopheles bites per person-night. Most (54.1-75.1%) of the Anopheles bites occurred outdoors, with a substantial proportion (25.5-50.8%) occurring before 22:00. CONCLUSION: The estimates of vector abundance and transmission intensity in the current study were comparable to or higher than estimates in the same villages in 2010-2012, indicating impeded programme effectiveness. Outdoor and early biting behaviours of vectors are some of the likely explanatory factors. Heterogeneity in vector composition, abundance and distribution among and within villages challenge malaria control programmes and must be considered when planning them.
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    Infectivity of Symptomatic Malaria Patients to Anopheles farauti Colony Mosquitoes in Papua New Guinea
    Timinao, L ; Vinit, R ; Katusele, M ; Koleala, T ; Nate, E ; Czeher, C ; Burkot, TR ; Schofield, L ; Felger, I ; Mueller, I ; Laman, M ; Robinson, LJ ; Karl, S (FRONTIERS MEDIA SA, 2021-12-22)
    Plasmodium transmission from humans to mosquitoes is an understudied bottleneck in the transmission of malaria. Direct membrane feeding assays (DMFA) allow detailed malaria transmission studies from humans to mosquitoes. Especially for Plasmodium vivax, which cannot be cultured long-term under laboratory conditions, implementation of DMFAs requires proximity to P. vivax endemic areas. In this study, we investigated the infectivity of symptomatic Plasmodium infections to Anopheles farauti colony mosquitoes in Papua New Guinea (PNG). A total of 182 DMFAs were performed with venous blood collected from rapid diagnostic test (RDT) positive symptomatic malaria patients and subsequently analysed by light microscopy and quantitative real time polymerase chain reaction (qPCR). DMFAs resulted in mosquito infections in 20.9% (38/182) of cases. By light microscopy and qPCR, 10 - 11% of P. falciparum and 32 - 44% of P. vivax positive individuals infected An. farauti. Fifty-eight percent of P. vivax and 15% of P. falciparum gametocytaemic infections infected An farauti.
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    Nonrandom Selection and Multiple Blood Feeding of Human Hosts by Anopheles Vectors: Implications for Malaria Transmission in Papua New Guinea
    Keven, JB ; Katusele, M ; Vinit, R ; Rodriguez-Rodriguez, D ; Hetzel, MW ; Robinson, LJ ; Laman, M ; Karl, S ; Foran, DR ; Walker, ED (AMER SOC TROP MED & HYGIENE, 2021-12-01)
    Nonrandom selection and multiple blood feeding of human hosts by Anopheles mosquitoes may exacerbate malaria transmission. Both patterns of blood feeding and their relationship to malaria epidemiology were investigated in Anopheles vectors in Papua New Guinea (PNG). Blood samples from humans and mosquito blood meals were collected in villages and human genetic profiles ("fingerprints") were analyzed by genotyping 23 microsatellites and a sex-specific marker. Frequency of blood meals acquired from different humans, identified by unique genetic profiles, was fitted to Poisson and negative binomial distributions to test for nonrandom patterns of host selection. Blood meals with more than one genetic profiles were classified as mosquitoes that fed on multiple humans. The age of a person bitten by a mosquito was determined by matching the blood-meal genetic profile to the villagers' genetic profiles. Malaria infection in humans was determined by PCR test of blood samples. The results show nonrandom distribution of blood feeding among humans, with biased selection toward males and individuals aged 15-30 years. Prevalence of Plasmodium falciparum infection was higher in this age group, suggesting males in this age range could be super-spreaders of malaria parasites. The proportion of mosquitoes that fed on multiple humans ranged from 6% to 13% among villages. The patterns of host utilization observed here can amplify transmission and contribute to the persistence of malaria in PNG despite efforts to suppress it with insecticidal bed nets. Excessive feeding on males aged 15-30 years underscores the importance of targeted interventions focusing on this demographic group.
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    SARS-CoV-2 Multi-Antigen Serology Assay
    Mazhari, R ; Ruybal-Pesantez, S ; Angrisano, F ; Kiernan-Walker, N ; Hyslop, S ; Longley, RJ ; Bourke, C ; Chen, C ; Williamson, DA ; Robinson, LJ ; Mueller, I ; Eriksson, EM (MDPI, 2021-12-01)
    Serology tests are extremely useful for assessing whether a person has been infected with a pathogen. Since the onset of the COVID-19 pandemic, measurement of anti-SARS-CoV-2-specific antibodies has been considered an essential tool in identifying seropositive individuals and thereby understanding the extent of transmission in communities. The Luminex system is a bead-based technology that has the capacity to assess multiple antigens simultaneously using very low sample volumes and is ideal for high-throughput studies. We have adapted this technology to develop a COVID-19 multi-antigen serological assay. This protocol described here carefully outlines recommended steps to optimize and establish this method for COVID-19-specific antibody measurement in plasma and in saliva. However, the protocol can easily be customized and thus the assay is broadly applicable to measure antibodies to other pathogens.