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Background: Residual malaria transmission is the result of adaptive mosquito behavior that allows malaria vectors to thrive and sustain transmission in the presence of good access to bed nets or insecticide residual spraying. These behaviors include crepuscular and outdoor feeding as well as intermittent feeding upon livestock. Ivermectin is a broadly used antiparasitic drug that kills mosquitoes feeding on a treated subject for a dose-dependent period. Mass drug administration with ivermectin has been proposed as a complementary strategy to reduce malaria transmission. Methods: A cluster randomized, parallel arm, superiority trial conducted in two settings with distinct eco-epidemiological conditions in East and Southern Africa. There will be three groups, human intervention, consisting of a dose of ivermectin (400 mcg/kg) administered monthly for three months to all the eligible population in the cluster (>15 kg, non-pregnant and no medical contraindication), human and livestock intervention, consisting human treatment as above plus treatment of livestock in the area with a single dose of injectable ivermectin (200 mcg/kg) monthly for three months, and controls, consisting of a dose of albendazole (400 mg) monthly for three months. The main outcome measure will be malaria incidence in a cohort of children under five living in the core of each cluster followed prospectively with monthly RDTs Discussion: The second site for the implementation of this protocol has changed from Tanzania to Kenya. For simplicity, this summary presents the Mozambique-specific protocol. BOHEMIA will be the first large-scale trial evaluating the impact of ivermectin-only mass drug administration to humans or humans and cattle on local malaria transmission Trial registration: Clinicaltrials.gov: NCT04966702, Date of registration: July 19, 2021 URL: https://clinicaltrials.gov/ct2/show/NCT04966702

Background Ivermectin inhibits the replication of SARS-CoV-2 in vitro at concentrations not readily achievable with currently approved doses. There is limited evidence to support its clinical use in COVID-19 patients. We conducted a Pilot, randomized, double-blind, placebo-controlled trial to evaluate the efficacy of a single dose of ivermectin reduce the transmission of SARS-CoV-2 when administered early after disease onset. Methods Consecutive patients with non-severe COVID-19 and no risk factors for complicated disease attending the emergency room of the Clínica Universidad de Navarra between July 31, 2020 and September 11, 2020 were enrolled. All enrollments occurred within 72 h of onset of fever or cough. Patients were randomized 1:1 to receive ivermectin, 400 mcg/kg, single dose (n = 12) or placebo (n = 12). The primary outcome measure was the proportion of patients with detectable SARS-CoV-2 RNA by PCR from nasopharyngeal swab at day 7 post-treatment. The primary outcome was supported by determination of the viral load and infectivity of each sample. The differences between ivermectin and placebo were calculated using Fisher's exact test and presented as a relative risk ratio. This study is registered at ClinicalTrials.gov: NCT04390022. Findings All patients recruited completed the trial (median age, 26 [IQR 19-36 in the ivermectin and 21-44 in the controls] years; 12 [50%] women; 100% had symptoms at recruitment, 70% reported headache, 62% reported fever, 50% reported general malaise and 25% reported cough). At day 7, there was no difference in the proportion of PCR positive patients (RR 0·92, 95% CI: 0·77-1·09, p = 1·0). The ivermectin group had non-statistically significant lower viral loads at day 4 (p = 0·24 for gene E; p = 0·18 for gene N) and day 7 (p = 0·16 for gene E; p = 0·18 for gene N) post treatment as well as lower IgG titers at day 21 post treatment (p = 0·24). Patients in the ivermectin group recovered earlier from hyposmia/anosmia (76 vs 158 patient-days; p < 0.001). Interpretation Among patients with non-severe COVID-19 and no risk factors for severe disease receiving a single 400 mcg/kg dose of ivermectin within 72 h of fever or cough onset there was no difference in the proportion of PCR positives. There was however a marked reduction of self-reported anosmia/hyposmia, a reduction of cough and a tendency to lower viral loads and lower IgG titers which warrants assessment in larger trials. Funding ISGlobal, Barcelona Institute for Global Health and Clínica Universidad de Navarra.

To maintain momentum towards improved malaria control and elimination, a vaccine would be a key addition to the intervention toolkit. Two approaches are recommended: (1) promote the development and short to medium term deployment of first generation vaccine candidates and (2) support innovation and discovery to identify and develop highly effective, long-lasting and affordable next generation malaria vaccines.

In the context of stalling progress against malaria, resistance of mosquitoes to insecticides, and residual transmission, mass drug administration (MDA) of ivermectin, an endectocide used for neglected tropical diseases (NTDs), has emerged as a promising complementary vector control method. Ivermectin reduces the life span of Anopheles mosquitoes that feed on treated humans and/or livestock, potentially decreasing malaria parasite transmission when administered at the community level. Following the publication by WHO of the preferred product characteristics for endectocides as vector control tools, this roadmap provides a comprehensive view of processes needed to make ivermectin available as a vector control tool by 2024 with a completely novel mechanism of action. The roadmap covers various aspects, which include 1) the definition of optimal dosage/regimens for ivermectin MDA in both humans and livestock, 2) the risk of resistance to the drug and environmental impact, 3) ethical issues, 4) political and community engagement, 5) translation of evidence into policy, and 6) operational aspects of large-scale deployment of the drug, all in the context of a drug given as a prevention tool acting at the community level. The roadmap reflects the insights of a multidisciplinary group of global health experts who worked together to elucidate the path to inclusion of ivermectin in the toolbox against malaria, to address residual transmission, counteract insecticide resistance, and contribute to the end of this deadly disease.

There is ever-increasing anticipation for the potential of mass drug administration of endectocides (also known as systemic insecticides) to reduce malaria transmission, with ivermectin emerging as the most likely first-in-class endectocide. More than half of the 46 papers published on this subject in the past decade appeared in the past 2 years. 23 projects are registered in the MESA Track database, of which seven are active today; and, more importantly, trial mapping by the Malaria Ivermectin Roadmap shows that abundant new evidence on the topic will be available by 2020. Why is there so much interest in repurposing ivermectin? After achieving remarkable advances from 2000 to 2015, the global fight against malaria has stalled. Beyond funding and access gaps, residual transmission—driven by mosquito behavioural adaptations that allow avoidance of home-based insecticides—has become a key liability for vector control, and challenges achievement of the global goals set forth by WHO.

Afebrile Plasmodium falciparum infections usually remain undetected and untreated in the community and could potentially contribute to sustaining local malaria transmission in areas aiming for malaria elimination.Thirty-two men with afebrile P. falciparum infections detected with rapid diagnostic test (RDTs) were followed for 28 days. Kaplan-Meier estimates were computed to estimate probability of parasite positivity and of reducing parasitemia by half of its initial level by day 28. Trends of parasite densities quantified by microscopy and real-time quantitative polymerase chain reaction (qPCR) were assessed using Poisson regression models, and the microscopy-to-qPCR positivity ratio was calculated at each time point. Three survival distributions (Gompertz, Weibull, and gamma) were used to evaluate their strength of fit to the data and to predict the median lifetime of infection.The cumulative probability of parasite qPCR positivity by day 28 was 81% (95% confidence interval [CI], 60.2-91.6). Geometric mean parasitemia at recruitment was 516.1 parasites/μL and fell to100 parasites/μL by day 3, reaching 56.7 parasites/μL on day 28 (P.001). The ratio of P. falciparum-positive samples by microscopy to qPCR decreased from 0.9 to 0.52 from recruitment to day 28. The best model fit to the data was obtained assuming a Gompertz distribution.Afebrile P. falciparum infections detectable by RDT in semi-immune adults fall and stabilize at low-density levels during the first 4 days after detection, suggesting a rapid decline of potential transmissibility in this hidden parasite reservoir.NCT02698748.

Background Malaria programmes use Plasmodium falciparum histidine-rich protein-2 (PfHRP2) based rapid diagnostic tests (RDTs) for malaria diagnosis. The deletion of this target antigen could potentially lead to misdiagnosis, delayed treatment and continuation of active transmission. Methods Plasmodium falciparum isolates (n = 1162) collected in Southern Mozambique were assessed by RDTs, microscopy and/or 18SrRNA qPCR. pfhrp2 and pfhrp3 deletions were investigated in isolates from individuals who were negative by RDT but positive by microscopy and/or qPCR (n = 69) using gene-specific PCRs, with kelch13 PCR as the parasite DNA control. Results Lack of pfhrp2 PCR amplification was observed in one of the 69 isolates subjected to molecular analysis [1.45% (95% CI 0.3–7.8%)]. Conclusions The low prevalence of pfhrp2 deletions suggests that RDTs will detect the vast majority of the P. falciparum infections. Nevertheless, active surveillance for changing deletion frequencies is required.

The development of ivermectin as a complementary vector control tool will require good quality evidence. This paper reviews the different eco-epidemiological contexts in which mass drug administration with ivermectin could be useful. Potential scenarios and pharmacological strategies are compared in order to help guide trial design. The rationale for a particular timing of an ivermectin-based tool and some potentially useful outcome measures are suggested.

Ivermectin is an endectocide that has been used broadly in single dose community campaigns for the control of onchocerciasis and lymphatic filariasis for more than 30 years. There is now interest in the potential use of ivermectin regimens to reduce malaria transmission, envisaged as community-wide campaigns tailored to transmission patterns and as complement of the local vector control programme. The development of new ivermectin regimens or other novel endectocides will require integrated development of the drug in the context of traditional entomological tools and endpoints. This document examines the main pharmacokinetic and pharmacodynamic parameters of the medicine and their potential influence on its vector control efficacy and safety at population level. This information could be valuable for trial design and clinical development into regulatory and policy pathways.

Vector control is a task previously relegated to products that (a) kill the mosquitoes directly at different stages (insecticides, larvicides, baited traps), or (b) avoid/reduce human-mosquito contact (bed nets, repellents, house screening), thereby reducing transmission. The potential community-based administration of the endectocide ivermectin with the intent to kill mosquitoes that bite humans, and thus reduce malaria transmission, offers a novel approach using a well-known drug, but additional steps are required to address technical, regulatory and policy gaps. The proposed community administration of this drug presents dual novel paradigms; first, indirect impact on the community rather than on individuals, and second, the use of a drug for vector control. In this paper, the main questions related to the regulatory and policy pathways for such an application are identified. Succinct answers are proposed for how the efficacy, safety, acceptability, cost-effectiveness and programmatic suitability could result in regulatory approval and ultimately policy recommendations on the use of ivermectin as a complementary vector control tool.

The potential use of ivermectin as an additional vector control tool is receiving increased attention from the malaria elimination community, driven by the increased importance of outdoor/residual malaria transmission and the threat of insecticide resistance where vector tools have been scaled-up. This report summarizes the emerging evidence presented at a side meeting on "Ivermectin for malaria elimination: current status and future directions" at the annual meeting of the American Society of Tropical Medicine and Hygiene in New Orleans on November 4, 2014. One outcome was the creation of the "Ivermectin Research for Malaria Elimination Network" whose main goal is to establish a common research agenda to generate the evidence base on whether ivermectin-based strategies should be added to the emerging arsenal to interrupt malaria transmission.

The sudden and untimely death of Alan Jon Magill at age 61 on September 19, 2015 has led to a growing list of remembrances from a grieving community of friends and colleagues seeking to support his family and has been accompanied by a growing recognition of his extraordinary and unique contributions to the field of tropical diseases. At his death, Alan was the director of the Malaria Program at the Bill & Melinda Gates Foundation (BMGF) since 2012, and was also the immediate past president of the American Society of Tropical Medicine and Hygiene (ASTMH). Both positions underscored his enormous commitment and contributions to tropical medicine over the past decades. Alan's education was at Lamar University (BS 1976), University of Rhode Island (MS 1978), and Baylor College of Medicine (MD 1984). His post graduate training in the U.S. Army (at Tripler Army Medical Center in Hawaii and at Walter Reed Army Medical Center) was serendipitous, as it allowed him to join his partner and later wife Janiine as she trained as a pediatrician. Thus began the bulk of his career as a physician scientist within the Walter Reed system, combining clinical parasitology and research on product development of new interventions, including drugs and diagnostics. During his fellowship, Alan first focused on leishmaniasis, as troops from Desert Storm brought home challenging clinical presentations of cutaneous disease. He worked on rapid diagnostic tests and polymerase chain reaction-based assays for cutaneous leishmaniasis; the latter cleared Food and Drug Administration approval. This work established him as a lifelong leishmaniac, and his expertise was firmly grounded in clinical management and his strategic thinking about the need for new interventions. He was subsequently an advisor to leishmania vaccine development programs at the Infectious Diseases Research Institute and the BMGF. Alan then took on several broad roles; first, on detail to the parasitology program at the U.S. Naval Medical Research Unit No. 6 Peru; second, Chair of the U.S. Army Malaria Board for the Office of the Surgeon General; third, Director of the Division of Experimental Therapeutics at the Walter Reed Army Institute of Research; and finally research coordinator of both the Malaria Drug and Anti-Parasitic Research Programs at the U.S. Army Medical Research and Materiel Command. The breadth of these activities solidified Alan's knowledge of the clinical and product development challenges facing the malaria field. Alan's achievements in malaria within the Walter Reed Army Institute of Research program included the development of the first American malaria rapid diagnostic test and driving the development of two key treatments, intravenous artesunate and tafenoquine. He identified new malaria drug scaffolds that advanced into lead optimization. He led challenge trials of vaccine candidates in the United States and vaccine field trials in Africa. In addition, while in Peru, he helped to characterize malaria drug resistance patterns at a time when older therapies were losing efficacy, leading to engagement on methods of detection, monitoring of drug resistance, implementation of changes in national policy, and training on the use of new drug regimens. Subsequently, Alan joined the Defense Advanced Research Projects Agency in 2009, where he directed programs of innovative plant-protein therapeutics and biologics, as well as advancing influenza vaccine candidates into early clinical trials. Alan's diverse experiences served the malaria field well in 2010, when he participated in the Malaria Eradication Research Agenda (malERA) project. His contributions were critical to the establishment of Single Encounter Radical Cure and Prophylaxis (SERCAP) as a research priority for malaria drug development, enabling progress toward malaria eradication. His contributions as a member of this highly consultative process demonstrated leadership skills, which were to serve him well in his subsequent position at the BMGF. A listing of Alan's many management and leadership positions almost gets in the way of recognizing his enormous commitment to graduate medical education. His generosity with his time and energy placed him in a vortex of activities to advance graduate medical education of parasitology writ large, and malaria specifically. He was first recognized as an outstanding teaching resident during his internal medicine residency. This was the harbinger for what would become a life-long commitment to education, working through ASTMH, its subgroup, the American Committee on Clinical Tropical Medicine and Travelers' Health (Clinical Group) and the annual Update Course in Clinical and Tropical Medicine, as well as numerous other organizations that represent infectious diseases (Infectious Disease Society of America, American Society of Microbiology) and global health (CDC Traveler's Health and courses sponsored by the Gorgas Course in Tropical Medicine, Universidad Peruana Cayetano Heredia, and Johns Hopkins Bloomberg School of Public Health, to name a few). Alan's contributions to ASTMH began with his membership in 1991. He served as Councilor, Corporate Liaison, and on the Legislative Affairs Committee. He was a member of the American Committee on Clinical Tropical Medicine and Travelers' Health for 8 years, culminating in his service as President in 2007. He was president of ASTMH in 2014, bringing to this position his remarkable optimism, enthusiasm, and focus. He was seriously engaged in malaria elimination at this time, but during his presidential year a large Ebola outbreak in Africa became a primary focus of the tropical medicine community. He led efforts by the Society to address this epidemic, including careful attention to political challenges, scientific advances and human rights concerns. More broadly, he was greatly interested in the future of the Society, and he left a profound impact on the blueprint for future Society activities. 63rd ASTMH Annual Meeting, New Orleans, Louisiana, November 2, 2014 Alan's decision to join BMGF as Director of the Malaria Program was not made lightly. He considered the opportunity to drive the Foundation's malaria eradication strategy and its implementation as the culmination of his career. His engaging presentations at the Harvard/Barcelona/Basel Science of Eradication course over the past three years reflected his evolving framework for malaria eradication. Upon arrival at the BMGF, he worked to advance the malaria eradication strategy, applying his strong base as a malaria clinician to rethink the role of drugs as prevention, appropriate strategies to eliminate parasite reservoirs, and reshaping the vaccine development agenda to maximize impact on the eradication of malaria. His strategy was strongly endorsed by Foundation leadership and offered an enormous step forward for the field. Malaria elimination and eventual global eradication are far more achievable goals than we dreamed until very recently, in no small part because of his energy, talent, wisdom, compassion, and commitment. Through his career, Alan was a master at relating to his team and colleagues. He maintained independence of thought, but was engaged both internally and externally with those that would challenge his thinking. His passion for the history of malaria, understanding of the biological basis of disease, and unique experiences in product development of drugs and vaccines grounded his approach and cemented his credibility with the malaria research and policy communities. The integration of his program into a proactive, forward looking agenda, has resulted in a framework from which it is possible to believe, as he did, that “Malaria Delenda Est”—malaria must be destroyed. This was the inscription on the medal that he awarded, in the military tradition, to the members of his team at the BMGF. The medal given by Dr. Magill to his team at the BMGF. What is extraordinary is that since Alan's death many people have individually noted how he connected with them personally, giving whatever time was needed. This includes his staff, colleagues, and grantees. Moreover, he managed to do this while also being extraordinarily well-read, a voracious learner, a generous teacher, a malaria expert, a leishmaniac, an historian, a leader, and above all a family man. He certainly came across as smart and hardworking, but he didn't seem extraordinary. As David Brandling-Bennett noted, “After last week, I had to conclude that he was truly extraordinary, but he disguised it so well that individually we didn't realize it.” An avid outdoorsman, Alan's favorite activities included climbing mountains and hiking, activities which he enjoyed with family and friends, in the Seattle area and beyond. He is survived by his wife Janiine Babcock, daughter Lara Magill and her spouse Jonathan Krynitsky, daughter Sarah Magill, and brother Donald Magill. We thank his family for sharing him with us.

The Food and Drug Administration recently approved the use of palivizumab (palē-vizhū-mäb), an intramuscularly administered monoclonal antibody preparation. Recommendations for its use are based on a large, randomized study demonstrating a 55% reduction in the risk of hospitalization attributable to respiratory syncytial virus (RSV) infections in high-risk pediatric patients. Infants and children with chronic lung disease (CLD), formerly designated bronchopulmonary dysplasia, as well as prematurely born infants without CLD experienced a reduced number of hospitalizations while receiving palivizumab compared with a placebo. Both palivizumab and respiratory syncytial virus immune globulin intravenous (RSV-IGIV) are available for protecting high-risk children against serious complications from RSV infections. Palivizumab is preferred for most high-risk children because of ease of administration (intramuscular), lack of interference with measles–mumps–rubella vaccine and varicella vaccine, and lack of complications associated with intravenous administration of human immune globulin products. RSV-IGIV, however, provides additional protection against other respiratory viral illnesses and may be preferred for selected high-risk children including those receiving replacement intravenous immune globulin because of underlying immune deficiency or human immuno-deficiency virus infection. For premature infants about to be discharged from hospitals during the RSV season, physicians could consider administering RSV-IGIV for the first month of prophylaxis. Most of the guidelines from the American Academy of Pediatrics for the selection of infants and children to receive RSV-prophylaxis remain unchanged. Palivizumab has been shown to provide benefit for infants who were 32 to 35 weeks of gestation at birth. RSV-IGIV is contraindicated and palivizumab is not recommended for children with cyanotic congenital heart disease. The number of patients with adverse events judged to be related to palivizumab was similar to that of the placebo group (11% vs 10%, respectively); discontinuation of injections for adverse events related to palivizumab was rare.

This decade is witnessing a renaissance in the research, development and control of infectious diseases of global importance. Starting with the availability of some existing tools (such as drugs for mass drug administration to treat communities for helminths) and fueled by the potential application of science to develop novel tools (such as vaccines for malaria and hookworm), the possibilities of what can be done across the research, development and implementation spectrum to achieve a global health impact is beginning to be realized. Crucial factors for this dramatic shift in attention and the potential for impact include the following:(i) Cross sector partnerships. Originally labeled ‘public–private partnerships’ to signify the synergy from engaging industry, research institutes and not-for-profit sectors in product development, in reality, the concept reflects engagement of resources and knowledge across industry, research communities, governments, non-profit organizations and disease-endemic countries. At the disease control phase, such partnerships include pharmaceutical commitments that enable governments to make the marginal investments required to deliver interventions.(ii) Impact and other data for decision making. From research to national priorities, the emphasis on data for appropriate investment and policy setting can help to focus resources for maximum impact. Evidence on the best way to use drugs in national programs is crucial to the credibility that such programs can be launched rapidly, and will be generated to support the scaling-up efforts needed to take successes from a single community to national-level impact. Proving that programs are scalable and cost-efficient will be essential to their ultimate sustainability.(iii) Leadership and champions. As reflected in the articles in this special issue of Trends in Parasitology and in a recent analysis by the Center for Global Development, both experienced and emerging leaders are essential elements in the process of leading to the potential success of global health programs.(iv) Industrial sector engagement. This renaissance is not owned by the public sector alone, and this perhaps signals the important transitions from ‘public health’ to ‘global health’. Industry is itself exploring a variety of engagement models, from the classical drug donation so vital to the onchocerciasis program, to the active participation in product development for malaria drugs and vaccines.(v) Increasing resources. A vital ‘necessary but not sufficient’ factor, the money that drives the global health renaissance comes from an impressive array of sources. Philanthropy has been important in starting and driving the product development partnerships. Commitments from the private sector have been crucial to that greatest of the global health challenges for this decade – the eradication of polio, a cause to which Rotary International, for example, is fully committed. Government resources are the most important driver of the biggest investments being made in the implementation of control and treatment of HIV, tuberculosis and malaria globally. Obviously, these resources include the donor community (the Global Fund for AIDS, Tuberculosis and Malaria, and national commitments such as the President's Emergency Plan for AIDS Relief) but also include endemic government as the principal funder of country-specific health systems and implementation programs. However, innovative financing mechanisms are still needed to generate additional monies to meet the promises of global health.This is an auspicious beginning, and one that we are incredibly fortunate to be able to participate in. The goals of global health – driven by the commitment to equity and the vision of what is possible given these aforementioned essential elements – will not be met if we do not rise to meet that challenge as a world community. The causal pathway between a healthy family and national development is certainly more than a hypothesis, although the evidence linking these is often based on macroeconomic projections. However, there is little doubt of the opposite: that individuals and communities weakened by the impact of disease find it difficult to reach their promise. Thus, the progress documented in this special issue on global health is important not only for what researchers are achieving, but also for what they tell us is possible in the decade to come. These are worthy goals indeed and ones that are absolutely reachable.

BACKGROUND: Malaria programmes use Plasmodium falciparum histidine-rich protein-2 (PfHRP2) based rapid diagnostic tests (RDTs) for malaria diagnosis. The deletion of this target antigen could potentially lead to misdiagnosis, delayed treatment and continuation of active transmission. METHODS: Plasmodium falciparum isolates (n = 1162) collected in Southern Mozambique were assessed by RDTs, microscopy and/or 18SrRNA qPCR. pfhrp2 and pfhrp3 deletions were investigated in isolates from individuals who were negative by RDT but positive by microscopy and/or qPCR (n = 69) using gene-specific PCRs, with kelch13 PCR as the parasite DNA control. RESULTS: Lack of pfhrp2 PCR amplification was observed in one of the 69 isolates subjected to molecular analysis [1.45% (95% CI 0.3-7.8%)]. CONCLUSIONS: The low prevalence of pfhrp2 deletions suggests that RDTs will detect the vast majority of the P. falciparum infections. Nevertheless, active surveillance for changing deletion frequencies is required.

A major failure of our global society in the 21st century is that many people in developing countries are not only born and live without any official record of their existence--a flagrant deprivation of an essential human right--but also die without having been seen by medically qualified personnel. The resultant uncertainty about the real burden of specific causes of death is being increasingly recognised by international health and funding agencies as a crucial limitation in the prioritisation of effective public health programmes and assessment of their effect. Recently published estimates of the main causes of global and cause-specific mortality have stirred a profound debate about the validity and adequacy of existing methods used to estimate cause of death.