Establishment of the Ivermectin Research for Malaria Elimination Network: updating the research agenda

The meeting also provided the momentum to update the ivermectin for malaria research agenda, published in 2013 [21]. In that document, seven areas of knowledge gaps were identified, and several studies were proposed to address them. As recent publications have added additional information, an update to the agenda by categories is provided here.

Ivermectin is extremely lipophilic, it is found in higher concentrations in dermal and adipose tissue than venous plasma [22], the resulting tissular concentration gradient may lead to higher concentrations in capillary than venous blood. This may be relevant as mosquitoes imbibe blood from subdermal capillaries and thus may ingest higher concentrations of ivermectin than would be predicted from determining the drug concentration in venous samples. Circulation of drugs at higher concentrations in capillary than venous blood has already been observed for other drugs, such as piperaquine [23,24]. An ongoing clinical trial will address whether capillary and venous blood impart different mosquito-lethal effects by performing both membrane and direct skin feeding assays at the same time [Feiko ter Kuile personal communication]. Importantly, it was recently demonstrated that the ivermectin mosquito-lethality lasts longer in females than males and in volunteers with a higher body mass index, possibly due to a higher body fat proportion [14], which could potentially imply differential dosage based on gender or expected body fat.

Since 2013, new vectors have been characterized for their susceptibility to ivermectin including: Anopheles funestus, a primary vector in Africa [14], Anopheles dirus, Anopheles minimus, Anopheles campestris, and Anopheles sawadwongporni, important primary and secondary vectors in the GMS [25], and Anopheles culicifacies, a primary malaria vector in Asia [26]. Additionally, there is ongoing work to characterize Anopheles aquasalis [Marcus Lacerda, personal communication] and Anopheles darlingi [Gissella Vasquez, personal communication], both important Latin American malaria vectors. To date, all Anopheles tested have been susceptible at concentrations of ivermectin commonly found in humans or animals after a single standard dose.

Mosquito survival assessments done after annual ivermectin MDAs in Senegal demonstrated that IVM MDA reduces wild An. gambiae survivorship for up to six days and reduces the proportion of P. falciparum infection among caught mosquitoes for up to two weeks following MDA [27,28]. Recently published work by Alout et al. [11] provided new evidence on the survival, sporozoite rate and parity rate of wild An. gambiae captured after IVM MDA campaigns in Senegal, Liberia, and Burkina Faso. Following ivermectin MDAs, survival of An. gambiae was reduced by more than 33% for the next six days, the sporozoite rate was reduced by over 77% in the following two weeks, and a reduction in parity (i.e., population age structure) was also observed. This provides ample evidence that IVM MDA can reduce entomological indices of Plasmodium transmission; however, there is a knowledge gap in the expected clinical and public health impact that can be expected after IVM MDA.

Recent work by Slater et al. [16] highlighted the potential impact of combining artemisinin-combination therapy (ACT) and IVM in MDA campaigns. In the model, the addition of IVM is predicted to increase the impact of ACT MDA and reduce the time needed to interrupt transmission. Slater’s model allows for a range of scenarios to be explored, including the impact of long-lasting IVM formulations and the impact of IVM MDA across varied transmission settings, seasonality profiles and vector species. Current work also includes extending the model to track the entomological parameters measured in the field and validating the model against data collected by Alout et al. [11]. Results from this validation will be used to predict the optimal time to commence MDA and the optimal spacing between rounds.

Previous work using in vitro parasites showed that sub-lethal concentrations of IVM reduce sporogony of P. falciparum in An. gambiae [29]. The in vivo clinical trial conducted by Ouédraogo et al. found no effect in naturally infected humans treated with ivermectin but this study was not powered to examine this and may have been confounded by the use of ACT. Field studies suggest that the primary driver of the approximate two week drop in sporozoite rates following IVM MDA is an equally lasting shift in mosquito population age structure as measured by parity rates [11]. Modelling indicates that the primary driver of ivermectin MDA effect is caused by a reduction in mosquito survivorship with mosquito-sublethal sporontocidal effects only having a small impact on parasite transmission [16].

Ouédraogo et al. [14] showed it is safe to administer a single standard dose of IVM (200 μg/kg) in combination with artemether-lumefantrine and in two standard doses spaced 48 hours apart, both supportive of a pathway towards implementation of IVM MDA within a malaria elimination strategy. Artemether-lumefantrine is an effective frontline anti-malarial drug in Africa, however, the six dose requirement raises the challenge of adherence with the full course for MDA. Slater’s model indicates that there is minimal additional transmission suppression effect to adding ivermectin during individual malaria treatment but the addition of ivermectin MDA to anti-malarial MDA could accelerate time to elimination and allow for elimination in settings where anti-malarial MDA alone would not achieve it [16]. The next step, being undertaken by ter Kuile and collaborators, is to determine the safety, tolerability, and potential drug-drug interaction of ivermectin with dihydroartemisinin-piperaquine, a more appropriate ACT for MDA given the longer half-life of the partner drug and three dose regimen. The same trial will explore safety and dose ranging of ivermectin applied on a daily basis for three days [18].

Recent animal model work [12] shows it is technically possible to safely sustain stable ivermectin blood concentrations at levels toxic to the mosquito by modifying the formulation to achieve prolonged sustained drug levels. Theoretically, this could be achieved by a number of existing technical and/or novel approaches. This becomes increasingly relevant, since increasing the duration of the mosquitocidal effect of the drug (i.e. time above mosquito-killing levels) is the parameter that has shown the greatest potential for impact in the model [16].

Selection of Anopheles mosquitoes resistant to IVM to understand induction and mechanisms of resistance is ongoing in the Foy lab. First, mosquitoes respond to IVM exposure mainly by up-regulation of non-canonical transcripts. Second, older mosquitoes that have ingested a prior blood meal are more sensitive to a second IVM-containing blood meal than young mosquitoes ingesting their first blood meal containing IVM, this has important implication for possible IVM MDA since it is only the older Anopheles that can transmit the parasite. In addition, IVM-sensitive wild An. gambiae collected from the IVM MDA studies had a high prevalence of the Kdr 1014 F mutation associated with pyrethroid and DDT resistance, which suggests that potential ivermectin resistance is independent of pyrethroid resistance [Haoues Alout, personal communication].

The 2013 research agenda [21] proposed three studies to provide evidence in support of this new vector control strategy.

Although none of the suggested trials has taken place in full yet, recent work has provided partial answers to the questions originally posed. Alout et al. [11] has confirmed reduced survivorship after IVM MDA in different transmission settings, one of the key questions of the first study proposed. Ouédraogo et al. [14] have proven IVM safe in two repeated doses and in combination with artemether-lumefantrine in P. falciparum carriers, with no significant PK interactions between the drugs. Ongoing work by ter Kuile and collaborators aims to determine the safety of IVM at higher doses and co-administration with dihydroartemisinin-piperaquine.

In summary, the two main key decision nodes that can be addressed by new data are: 1) the feasibility of using IVM MDA as an additional vector control tool while determining its effectiveness across different scenarios and the comparative costs with other new or existing interventions, and 2) the viability of the product development and regulatory pathways. Funding should be prioritized to help make these key decisions.

A key concept is the potential impact of the current oral formulation and standard dose of 150–200 mcg/kg on transmission dynamics. Modelling clearly shows that the time the drug remains in human blood above mosquito-killing levels is a key determinant of the epidemiological outcome of IVM MDA. There are different ways to increase the time above the target concentration: different formulations, higher or repeated doses, and PK enhancement by blocking the P-glycoprotein or metabolic pathways. Although the current formulation in repeated doses can be used to prove the concept, scalability is a concern and multiple rounds of MDA in the field might only be practical for short rainy seasons or defined outbreaks. Data addressing the minimum time above the target concentration required to interrupt transmission is needed to answer this question appropriately and chose a suitable formulation or dosage scheme into which further investment should be made.

Ivermectin lies outside the classical definition of a transmission blocking drug as it does not impart a gametocytocidal effect, and its sporontocidal effects appear modest by the minimum essential requirements for transmission blocking drug standards set forth by the Medicines for Malaria Venture [30]. Classical transmission blocking drugs (e.g. primaquine) prevent onwards transmission from the treated individual to the mosquito population, but this means that there might be a delay before any effect is seen in terms of transmission from mosquito-to-human. However, ivermectin’s mosquito lethal and sublethal effects can quickly suppress the infectious vector population following MDA and thus immediately reduce mosquito-to-human transmission.

In spite of its excellent safety profile [31], IVM does not kill asexual stage parasites at human relevant concentrations, nor does it offer prophylaxis against newly infecting malaria parasites. This is an issue faced by other transmission blocking interventions such as primaquine [32] or vaccines [33]. However, there are direct personal health benefits to taking IVM if one considers the numerous NTD parasites that often afflict people in malaria-endemic communities [13,34].

Two recent developments show promise to ease the pathway for malaria transmission blocking interventions. One is the WHO recommendation to implement low dose primaquine as a P002E falciparum gametocytocide in elimination areas and where artemisinin resistance constitutes a threat, without the need to test for G6PD deficiency, even in the absence of direct personal clinical benefits [32]. The second is the advances driven by the PATH Malaria Vaccine Initiative in framing the regulatory pathway for a transmission blocking vaccine [33].

There may be strategies, depending on dose and formulation, for targeting multiple diseases simultaneously. This possibility, along with potential safety and efficacy issues should be considered in Target Product Profile (TPP) and development/regulatory pathway proposals. These unique and complex facets of ivermectin MDA make the development and regulatory pathways for novel ivermectin applications or formulations for malaria elimination difficult to address as it requires oversight from both drug and vector control experts and regulatory agencies. Collaboration between the WHO Global Malaria Program and Neglected Tropical Diseases Program, with input from product development and regulatory experts, would be critical to decreasing perceived clinical and regulatory barriers.

A framework addressing the potential issues for the development of ivermectin for malaria control is proposed here (Table 1).

Three options for the use of IVM for malaria elimination should be evaluated:

Following the positive interaction among interested parties the “Ivermectin Research for Malaria Elimination Network”, was formed with interested partners from academia, the private sector, non-government organizations and funding agencies. The goals of the Network are:

Members of the global health community interested in the field are encouraged to join the working group by emailing mail@ivermen.org. Current members, upcoming events and supportive documents are listed in the IVERMEN website [35].