A discovery and development roadmap for new endectocidal transmission-blocking agents in malaria

Abstract

Reaching the overall goal of eliminating malaria requires halting disease transmission. One approach to blocking transmission is to prevent passage of the parasite to a mosquito, by preventing formation or transmission of gametocytes. An alternative approach, pioneered in the veterinary field, is to use endectocides, which are molecules that render vertebrate blood meals toxic for the mosquito vector, also killing the parasite. Field studies and modelling suggest that reducing the lifespan of the mosquito may significantly reduce transmission, given the lengthy maturation process of the parasite. To guide the development of new endectocides, or the reformulation of existing molecules, it is important to construct a framework of the required attributes, commonly called the target candidate profile. Here, using a combination of insights from current endectocides, mathematical models of the malaria transmission dynamics, and known impacts of vector control, a target candidate profile (TCP-6) and a regulatory strategy are proposed for a transmission reducing agent. The parameters chosen can be used to assess the potential of a new medicine, independent of whether it has classical endectocide activity, reduces the insect and parasite lifespan or any combination of all three, thereby constituting an ‘endectocidal transmission blocking’ paradigm.

Reducing malaria burden and accelerating elimination with long-lasting systemic insecticides: a modeling study of three potential use cases

“…A single round of SI-30 or SI-14, concurrently distributed with a standard SMC campaign, has minimal effect on further reducing burden even at 100% coverage. Given safety concerns surrounding the administration of this class of drugs to women of childbearing age [13] and children under 5 [16], only long-lasting systemic insecticides of duration 90 days improve burden reduction in a meaningful way. However, in the event this class of drugs is found to be safe for use in nursing and pregnant women, and children under 5 years, a single round of SI-60 in parallel with standard SMC can still further reduce burden with coverage of around 60%.…”

“…Given the high rates of burden experienced in children under the age of 15 [13], expanding an SMC campaign to include children up to the age of 10 could be highly beneficial in many high-transmission settings. If duration of systemic insecticide effectiveness is at least 60 days, long-lasting systemic insecticides further reduce burden when added to an SMC campaign.…”

“…If duration of systemic insecticide effectiveness is at least 60 days, long-lasting systemic insecticides further reduce burden when added to an SMC campaign. If malaria control programs have the capacity to distribute multiple rounds of systemic insecticides to older children and adults alongside an SMC campaign, shorter duration systemic insecticides could still be a worthwhile option [13]. Ultimately, safety and cost-effectiveness of the drugs used in systemic insecticide MDA will determine which campaign – expanded or standard SMC with regular or long-lasting systemic insecticides – is most efficacious in reducing burden for a given setting.…”

“…However, ivermectin has a short half-life of under 4 days in large mammals [10] and 12-36 hours in humans [11]. At the currently approved doses given for treating non-malarial diseases, ivermectin concentrations in human blood can maintain mosquitocidal effects for approximately 48 hours [12], which is predicted to be too short to have much impact on malaria burden [13]. While the low concentrations of ivermectin observed 28 days post-dose continue to have a small impact on mosquito survival [14], the epidemiological relevance is unknown.…”

“…Previous mathematical modeling has suggested that high-dose ivermectin can marginally improve the impact of antimalarial MDAs [15,19], a new long-lasting systemic insecticide with high efficacy lasting 30 days can substantially reduce burden when distributed with seasonal malaria chemoprevention (SMC) [13], and MDA with an isoxazoline lasting 90 days can also reduce burden in high-transmission areas [17]. However, there has not been a systematic exploration of the potential impact of long-lasting systemic insecticides across multiple use cases within the same modeling framework.…”