Malaria situation.Malaria remains a significant public health problem worldwide, particularly across low- and middle-income regions. Although the disease is both preventable and curable, it currently threatens nearly half of the world’s population living in 90 malaria-endemic countries.1 Over the last two decades, the large-scale implementation of preventive strategies, as well as the improvements in the diagnosis and treatment of the disease, has led to an 18% global drop in incidence rates between 2010 and 2017.1 Vector control with insecticide-treated nets (ITNs) and indoor residual spraying (IRS) is considered the main driver of these malaria gains (i.e., ITNs and IRS accounted for 78% of the malaria cases averted between 2000 and 2015).2 Despite these advances, in 2017, there were 219 million cases and 435,000 malaria deaths estimated globally, with 93% of deaths occurring in Africa.1 After over a decade of downward trends, the 2017 and 2018 World malaria reports have shown that progress has stalled, especially in high-burden countries. This poses a great challenge in achieving the morbidity and mortality targets of the WHO Global Technical Strategy (GTS) for Malaria 2016–2030.1,3

Among the challenges currently weakening vector control are mosquito resistance to insecticides and residual transmission. Residual transmission is defined as the persistence of malaria transmission after universal coverage with effective ITNs and/or IRS to which the local vectors are fully susceptible.4 Through behavioral adaptations, mosquitoes are able to avoid the standard vector control measurements by biting while humans are not protected by ITNs and/or outdoor, as well as feeding on peri-domestic livestock. Thus, research and product development are critical to mitigate the existing protection gaps. Along these lines, the GTS5 and the research agenda for malaria control proposed by the malERA consultative group6 reflect the need for improved ITNs and innovative ways of controlling residual transmission.

The potential role of ivermectin as a complementary vector control tool against malaria.Ivermectin is a long-established veterinary endectocide, first approved for human use for its antiparasitic activity against onchocerciasis in 1987.7 In 2018, global health authorities celebrated 30 years of ivermectin mass drug administration (MDA) campaigns against two neglected tropical diseases (NTDs), onchocerciasis, and lymphatic filariasis (LF).8 Besides its broad antiparasitic activity, ivermectin can kill mosquitoes that feed on treated humans and livestock during a dose-dependent period.9–12 This occurs because ivermectin binds selectively to the glutamate-gated chlorine channel of invertebrates and produces paralysis.7 By exploiting this mosquitocidal activity, ivermectin MDA to humans and/or livestock could complement the malaria toolbox, reducing mosquito survival regardless of their biting patterns.

The notion of repurposing ivermectin for malaria control originally emerged in 1985 when in vitro tests showed that the drug killed the malaria vector Anopheles stephensi.13 Additional data appeared slowly thereafter. A study in Papua New Guinea in 1999 demonstrated that even a single-standard dose of ivermectin affected vector survival in the field.14 A randomized controlled trial further supported the killing effect on mosquitoes feeding on treated people.15,16 More recently, the results of several modeling, pharmacological, and insectary-based research studies, as well as several clinical and field MDA trials, have positioned ivermectin as a first-in-class tool to enhance malaria control.17–19

After recognizing the potential for endectocides to tackle the issue of residual transmission, the WHO held a technical consultation on ivermectin in 2016. Subsequently, preferred product characteristics (PPCs) for endectocides against malaria were published with ivermectin as a reference product.20 The meeting report, endorsed by the Malaria Policy Advisory Committee (MPAC), also established the requirement for a WHO policy recommendation on ivermectin for malaria control. This requirement is that a minimum 20% decrease in malaria incidence should be achieved for at least 1 month posttreatment after a single round of ivermectin MDA when added to the standard vector control tools.20 Given this momentum, several funders began supporting the evaluation of endectocides against malaria, reflecting the new guidance and broad interest in this innovative approach (current and planned trials are discussed in section Ongoing/planned trials).

The malaria Ivermectin Roadmap.The objective of the Ivermectin Roadmap is to define a clear pathway for the evaluation of ivermectin as a vector control tool against malaria and for its subsequent implementation. Specifically, this analysis has carefully considered: 1) product development (e.g., dose and regimen), 2) evidence to support a global policy recommendation (e.g., safety and efficacy), and 3) access and deployment at scale (e.g., procurement and delivery mode). Throughout the different sections of this article, key research and development (R&D) questions have been identified so as to outline an R and D agenda for the development of ivermectin as a complementary vector control tool.

Over the past 4 years, experts in relevant fields have defined the critical aspects of repurposing ivermectin as a complement to current malaria vector control tools. In 2014, the Ivermectin Research for Malaria Elimination Network,21 began shaping the concept. The Ivermectin Roadmappers were assembled in 2017 after funding was granted by the Bill & Melinda Gates Foundation. A launch meeting took place at the 2017 Annual Meeting of the American Society of Tropical Medicine and Hygiene (ASTMH) in Baltimore (US). The multidisciplinary team included global health experts whose backgrounds encompassed entomology, infectious diseases, vaccines, veterinary, environmental sciences, ethics, financing systems, clinical trials, supply chain management, and scaling-up of interventions, among others (see full list of contributors on pages 18–19).

The process to develop this roadmap consisted of literature reviews by the participants, as well as discussions with regulatory agencies, policy and funding bodies, drug manufacturers, and future implementing partners, including the WHO and Unitaid. A synthesis meeting was held in Sitges (Spain) in May 2018, where key aspects were discussed and refined. The outcomes of the gathering were publicly presented during the symposium “A Roadmap for Ivermectin as a Complementary Vector Control Tool for Malaria” at the 2018 ASTMH Annual Meeting (https://mesamalaria.org/resource-hub/astmh-2018-session-30-roadmap-ivermectin-complementary-vector-control-tool-malaria) and are now reflected in this roadmap.