Flexible and cost-effective genomic surveillance of P. falciparum malaria with targeted nanopore sequencing.

Genomic surveillance of Plasmodium falciparum malaria can provide policy-relevant information about antimalarial drug resistance, diagnostic test failure, and the evolution of vaccine targets. Yet the large and low complexity genome of P. falciparum complicates the development of genomic methods, while resource constraints in malaria endemic regions can limit their deployment. Here, we demonstrate an approach for targeted nanopore sequencing of P. falciparum from dried blood spots (DBS) that enables cost-effective genomic surveillance of malaria in low-resource settings. We release software that facilitates flexible design of amplicon sequencing panels and use this software to design two target panels for P. falciparum. The panels generate 3-4 kbp reads for eight and sixteen targets respectively, covering key drug-resistance associated genes, diagnostic test antigens, polymorphic markers and the vaccine target csp. We validate our approach on mock and field samples, demonstrating robust sequencing coverage, accurate variant calls within coding sequences, the ability to explore P. falciparum within-sample diversity and to detect deletions underlying rapid diagnostic test failure.

Diagnostic Performance of Loop-Mediated Isothermal Amplification and Ultrasensitive Rapid Diagnostic Tests for Malaria Screening Among Pregnant Women in Kenya.

BACKGROUND: Screen-and-treat strategies with sensitive diagnostic tests may reduce malaria-associated adverse pregnancy outcomes. We conducted a diagnostic accuracy study to evaluate new point-of-care tests to screen pregnant women for malaria at their first antenatal visit in western Kenya. METHODS: Consecutively women were tested for Plasmodium infection by expert microscopy, conventional rapid diagnostic test (cRDT), ultra sensitive RDT (usRDT), and loop-mediated isothermal amplification (LAMP). Photoinduced electron-transfer polymerase chain reaction (PET-PCR) served as the reference standard. Diagnostic performance was calculated and modelled at low parasite densities. RESULTS: Between May and September 2018, 172 of 482 screened participants (35.7%) were PET-PCR positive. Relative to PET-PCR, expert microscopy was least sensitive (40.1%; 95% confidence interval [CI], 32.7%-47.9%), followed by cRDT (49.4%; 95% CI, 41.7%-57.1), usRDT (54.7%; 95% CI, 46.9%-62.2%), and LAMP (68.6%; 95% CI, 61.1%-75.5%). Test sensitivities were comparable in febrile women (n = 90). Among afebrile women (n = 392), the geometric-mean parasite density was 29 parasites/µL and LAMP (sensitivity = 61.9%) and usRDT (43.2%) detected 1.74 (95% CI, 1.31-2.30) and 1.21 (95% CI, 88-2.21) more infections than cRDT (35.6%). Per our model, tests performed similarly at densities >200 parasites/µL. At 50 parasites/µL, the sensitivities were 45%, 56%, 62%, and 74% with expert microscopy, cRDT, usRDT, and LAMP, respectively. CONCLUSIONS: This first-generation usRDT provided moderate improvement in detecting low-density infections in afebrile pregnant women compared to cRDTs.

Evaluating the Impact of Programmatic Mass Drug Administration for Malaria in Zambia Using Routine Incidence Data.

BACKGROUND: In 2016, the Zambian National Malaria Elimination Centre started programmatic mass drug administration (pMDA) campaigns with dihydroartemisinin-piperaquine as a malaria elimination tool in Southern Province. Two rounds were administered, 2 months apart (coverage 70% and 57%, respectively). We evaluated the impact of 1 year of pMDA on malaria incidence using routine data. METHODS: We conducted an interrupted time series with comparison group analysis on monthly incidence data collected at the health facility catchment area (HFCA) level, with a negative binomial model using generalized estimating equations. Programmatic mass drug administration was conducted in HFCAs with greater than 50 cases/1000 people per year. Ten HFCAs with incidence rates marginally above this threshold (pMDA group) were compared with 20 HFCAs marginally below (comparison group). RESULTS: The pMDA HFCAs saw a 46% greater decrease in incidence at the time of intervention than the comparison areas (incidence rate ratio = 0.536; confidence interval = 0.337-0.852); however, incidence increased toward the end of the season. No HFCAs saw a transmission interruption. CONCLUSIONS: Programmatic mass drug administration, implemented during 1 year with imperfect coverage in low transmission areas with suboptimal vector control coverage, significantly reduced incidence. However, elimination will require additional tools. Routine data are important resources for programmatic impact evaluations and should be considered for future analyses.

Correction to: Mass testing and treatment for malaria followed by weekly fever screening, testing and treatment in Northern Senegal: feasibility, cost and impact.

An amendment to this paper has been published and can be accessed via the original article.

Impact of Four Rounds of Mass Drug Administration with Dihydroartemisinin-Piperaquine Implemented in Southern Province, Zambia.

Over the past decade, Zambia has made substantial progress against malaria and has recently set the ambitious goal of eliminating by 2021. In the context of very high vector control and improved access to malaria diagnosis and treatment in Southern Province, we implemented a community-randomized controlled trial to assess the impact of four rounds of community-wide mass drug administration (MDA) and household-level MDA (focal MDA) with dihydroartemisinin-piperaquine (DHAP) implemented between December 2014 and February 2016. The mass treatment campaigns achieved relatively good household coverage (63-79%), were widely accepted by the community (ranging from 87% to 94%), and achieved very high adherence to the DHAP regimen (81-96%). Significant declines in all malaria study end points were observed, irrespective of the exposure group, with the overall parasite prevalence during the peak transmission season declining by 87.2% from 31.3% at baseline to 4.0% in 2016 at the end of the trial. Children in areas of lower transmission (< 10% prevalence at baseline) that received four MDA rounds had a 72% (95% CI = 12-91%) reduction in malaria parasite prevalence as compared with those with the standard of care without any mass treatment. Mass drug administration consistently had the largest short-term effect size across study end points in areas of lower transmission following the first two MDA rounds. In the context of achieving very high vector control coverage and improved access to diagnosis and treatment for malaria, our results suggest that MDA should be considered for implementation in African settings for rapidly reducing malaria outcomes in lower transmission settings.

Mass testing and treatment for malaria followed by weekly fever screening, testing and treatment in Northern Senegal: feasibility, cost and impact.

BACKGROUND: Population-wide interventions using malaria testing and treatment might decrease the reservoir of Plasmodium falciparum infection and accelerate towards elimination. Questions remain about their effectiveness and evidence from different transmission settings is needed. METHODS: A pilot quasi-experimental study to evaluate a package of population-wide test and treat interventions was conducted in six health facility catchment areas (HFCA) in the districts of Kanel, Linguère, and Ranérou (Senegal). Seven adjacent HFCAs were selected as comparison. Villages within the intervention HFCAs were stratified according to the 2013 incidences of passively detected malaria cases, and those with an incidence ≥ 15 cases/1000/year were targeted for a mass test and treat (MTAT) in September 2014. All households were visited, all consenting individuals were tested with a rapid diagnostic test (RDT), and, if positive, treated with dihydroartemisinin-piperaquine. This was followed by weekly screening, testing and treatment of fever cases (PECADOM++) until the end of the transmission season in January 2015. Villages with lower incidence received only PECADOM++ or case investigation. To evaluate the impact of the interventions over that transmission season, the incidence of passively detected, RDT-confirmed malaria cases was compared between the intervention and comparison groups with a difference-in-difference analysis using negative binomial regression with random effects on HFCA. RESULTS: During MTAT, 89% (2225/2503) of households were visited and 86% (18,992/22,170) of individuals were tested, for a combined 77% effective coverage. Among those tested, 291 (1.5%) were RDT positive (range 0-10.8 by village), of whom 82% were < 20 years old and 70% were afebrile. During the PECADOM++ 40,002 visits were conducted to find 2784 individuals reporting fever, with an RDT positivity of 6.5% (170/2612). The combination of interventions resulted in an estimated 38% larger decrease in malaria case incidence in the intervention compared to the comparison group (adjusted incidence risk ratio = 0.62, 95% CI 0.45-0.84, p = 0.002). The cost of the MTAT was $14.3 per person. CONCLUSIONS: It was operationally feasible to conduct MTAT and PECADOM++ with high coverage, although PECADOM++ was not an efficient strategy to complement MTAT. The modest impact of the intervention package suggests a need for alternative or complementary strategies.

Estimating spatiotemporally varying malaria reproduction numbers in a near elimination setting.

In 2016 the World Health Organization identified 21 countries that could eliminate malaria by 2020. Monitoring progress towards this goal requires tracking ongoing transmission. Here we develop methods that estimate individual reproduction numbers and their variation through time and space. Individual reproduction numbers, Rc, describe the state of transmission at a point in time and differ from mean reproduction numbers, which are averages of the number of people infected by a typical case. We assess elimination progress in El Salvador using data for confirmed cases of malaria from 2010 to 2016. Our results demonstrate that whilst the average number of secondary malaria cases was below one (0.61, 95% CI 0.55-0.65), individual reproduction numbers often exceeded one. We estimate a decline in Rc between 2010 and 2016. However we also show that if importation is maintained at the same rate, the country may not achieve malaria elimination by 2020.

Factors Associated with the Rapid and Durable Decline in Malaria Incidence in El Salvador, 1980-2017.

A decade after the Global Malaria Eradication Program, El Salvador had the highest burden of malaria in Mesoamerica, with approximately 20% due to Plasmodium falciparum. A resurgence of malaria in the 1970s led El Salvador to alter its national malaria control strategy. By 1995, El Salvador recorded its last autochthonous P. falciparum case with fewer than 20 Plasmodium vivax cases annually since 2011. By contrast, its immediate neighbors continue to have the highest incidences of malaria in the region. We reviewed and evaluated the policies and interventions implemented by the Salvadoran National Malaria Program that likely contributed to this progress toward malaria elimination. Decentralization of the malaria program, early regional stratification by risk, and data-driven stratum-specific actions resulted in the timely and targeted allocation of resources for vector control, surveillance, case detection, and treatment. Weekly reporting by health workers and volunteer collaborators-distributed throughout the country by strata and informed via the national surveillance system-enabled local malaria teams to provide rapid, adaptive, and focalized program actions. Sustained investments in surveillance and response have led to a dramatic reduction in local transmission, with most current malaria cases in El Salvador due to importation from neighboring countries. Additional support for systematic elimination efforts in neighboring countries would benefit the region and may be needed for El Salvador to achieve and maintain malaria elimination. El Salvador's experience provides a relevant case study that can guide the application of similar strategies in other countries committed to malaria elimination.

The Potential Impact of Preventive HIV Vaccines in China: Results and Benefits of a Multi-Province Modeling Collaboration.

China's commitment to implementing established and emerging HIV/AIDS prevention and control strategies has led to substantial gains in terms of access to antiretroviral treatment and prevention services, but the evolving and multifaceted HIV/AIDS epidemic in China highlights the challenges of maintaining that response. This study presents modeling results exploring the potential impact of HIV vaccines in the Chinese context at varying efficacy and coverage rates, while further exploring the potential implications of vaccination programs aimed at reaching populations at highest risk of HIV infection. A preventive HIV vaccine would add a powerful tool to China's response, even if not 100% efficacious or available to the full population.

The end of the era of generosity? Global health amid economic crisis.

In the past decade donor commitments to health have increased by 200 percent. Correspondingly, there has been a swell of new players in the global health landscape. The unprecedented, global response to a single disease, HIV/AIDS, has been responsible for a substantial portion of this boon. Numerous health success have followed this windfall of funding and attention, yet the food, fuel, and economic crises of 2008 have shown the vulnerabilities of health and development initiatives focused on short term wins and reliant on a constant flow of foreign funding. For too long, the international community has responded to global health and development challenges with emergency solutions that often reflect the donor's priorities, values, and political leanings, rather than funding durable health systems that can withstand crises. Progress towards achieving the Millennium Development Goals has stalled in many countries. Disease specific initiatives have weakened health systems and limited efforts to improve maternal and child health. As we enter this era of scarce resources, there is a need to return to the foundations of the Alma Ata Declaration signed thirty years ago with the goal of providing universal access to primary healthcare. The global health community must now objectively evaluate how we can most effectively respond to the crises of 2008 and take advantage of this moment of extraordinary attention for global health and translate it into long term, sustainable health improvements for all.