Chemoprevention of malaria with long-acting oral and injectable drugs: an updated target product profile

Abstract

Malaria is preventable, but the burden of disease remains high with over 249 million cases and 608,000 deaths reported in 2022. Historically, the most important protective interventions have been vector control and chemopreventive medicines with over 50 million children receiving seasonal malaria chemoprevention in the year 2023. Two vaccines are approved and starting to be deployed, bringing additional protection for children up to 36 months. However, the impact of these currently available tools is somewhat limited on various fronts. Vaccines exhibit partial efficacy, are relatively costly, and not accessible in all settings. The challenges encountered with chemoprevention are barriers to acceptability and feasibility, including frequency of dosing, and the lack of options in the first trimester of pregnancy and for women living with HIV. Also, the emergence of resistance against chemopreventive medicines is concerning. To address these limitations, a target product profile (TPP) is proposed as a road map to guide innovation and to boost the quest for novel chemopreventive alternatives. This TPP describes the ideal product attributes, while acknowledging potential trade-offs that may be needed. Critically, it considers the target populations most at risk; primarily infants, children, and pregnant women. Malaria control and elimination requires appropriate chemoprevention, not only in areas of high endemicity and transmission, but also in lower transmission areas where immunity is declining, as well as for travellers from areas where malaria has been eliminated. New medicines should show acceptable safety and tolerability, with high and long protective efficacy. Formulations and costs need to support operational adherence, access, and effectiveness. Next generation long-acting oral and injectable drugs are likely to constitute the backbone of malaria prevention. Therefore, the perspectives of front-line experts in malaria prevention, researchers, and those involved in drug development are captured in the TPP. This inclusive approach aims at concentrating efforts and aligning responses across the community to develop new and transformative medicines.

Keywords: Chemoprevention; Drug development; Malaria.

Fig. 1

Overview of current malaria prevention interventions. AL artemether-lumefantrine, AQ amodiaquine, AS artesunate, ATV atovaquone, DHA dihydroartemisinin, IPTp intermittent preventive treatment in pregnancy, IPTsc intermittent preventive treatment in school-aged children, PDMC post-discharge malaria chemoprevention, PG proguanil, PMC perennial malaria chemoprevention, PQP piperaquine, PW pregnant women, SMC seasonal malaria chemoprevention, SP sulfadoxine-pyrimethamine, T trimester, WOCBP women of childbearing potential

Fig. 2

Main attributes of existing and future interventions for malaria prevention [–68]. SOC standard-of-care, mAb monoclonal antibody, LAI long-acting injectable. ¹Chemoprevention is recommended by WHO in children up to 15 years of age and pregnant women in their second and third trimester. SMC-SPAQ has been widely adopted, as compared to PMC and IPTsc, and was therefore considered as SOC. Main attributes for IPTp are similar and are not detailed in the summary Table. ²Most likely infants and children under 5 years of age in the first product label, due to injection volume and cost limitations. ³mAbs requiring more than one dose to protect throughout the malaria season may be considered based on cost-effectiveness [63]. ⁴Preventive efficacy of SPAQ was 83% in a controlled clinical trial [64]. ⁵RTS,S/AS01 preventive efficacy was of 39% for clinical malaria over 48 months [65]. R21/Matrix-M vaccine efficacy over 12 months was 75% at the seasonal sites and 68% at the standard sites for time to first clinical malaria episode [66]. ⁶WHO mAbs for malaria prevention preferred product characteristics, 2023 [63]. ⁷Average economic cost of dispersible SPAQ—26 cents per 3-days treatment course; and 28 cents for SP doses for adults [67]. ⁸RTS,S vaccine costs a maximum of EUR 9.30 per dose. R21 vaccine currently costs US$ 3.90 per dose for a two-dose presentation. Vaccines cost may decrease in future years as additional demand materializes [68]. ⁹Vaccines require a cold-chain for transportation and storage; and there are likely to be similar requirements for mAbs

Fig. 3

Research and development projects in malaria prevention (post-candidate selection). BMG MRI Bill & Melinda Gates Medical Research Institute, CARL cyclic amine resistance locus, CSP circumsporozoite protein, mAb monoclonal antibody, MMV MMV Medicines for Malaria Venture, NIH National Institutes of Health, P.f. Plasmodium falciparum, PYN pyronaridine, PQP piperaquine, TBD to be determined