Design and selection of drug properties to increase the public health impact of next-generation seasonal malaria chemoprevention: a modelling study

Abstract

BackgroundSeasonal malaria chemoprevention (SMC) is recommended for disease control in settings with moderate to highPlasmodium falciparumtransmission and currently depends on administration of sulfadoxine-pyrimethamine with amodiaquine. However, poor regimenadherence and the increasedfrequencyof sulfadoxine-pyrimethamine resistant parasite mutations may threaten SMC’s effectiveness. We need guidance to de-risk the development of drug compounds for malaria prevention.MethodsWe combined an individual-based malaria transmission model that has explicit parasite growth with drug pharmacokinetic/pharmacodynamic models. We modelled SMC drug attributes for several possible modes-of-action, linked to their potential public health impact. Global sensitivity analyses identified trade-offs between drug elimination half-life, maximum killing effect, and SMC coverage, and optimisation identified minimum requirements to maximise malaria burden reductions.FindingsModel predictions show that preventing infection for the entire period between SMC cycles is more important than drug curative efficacy for clinical disease effectiveness outcomes, but similarly important for impact on prevalence. When four SMC cycles are deployed to children under five years with high levels of coverage (69% of children receiving all cycles), drug candidates require a duration of protection half-life of >23 days (elimination half-life >10 days) to achieve >75% clinical incidence and severe disease reductions (measured over the intervention period in the target population, compared with no intervention across a range of modelled scenarios). High coverage is critical to achieve these targets, requiring >60% of children received all SMC cycles and >90% of children at least one cycle regardless of the drug’s duration.InterpretationWhile efficacy is crucial for malaria prevalence reductions, chemoprevention development should select drug candidates for their duration of protection to maximise burden reductions, with the duration half-life determiningcycle timing. Explicitlydesigning or selectingdrug properties to increase communityuptake is paramount.FundingBill & Melinda Gates Foundation and the Swiss National Science Foundation.

Trends in Uncomplicated and Severe Malaria following Seasonal Malaria Chemoprevention Administration in Nouna, Burkina Faso

“…11 This may be attributed to the high drug e cacy of the SMC treatment combination. 11,29 Despite concerns that the e cacy of SP may be undermined by drug resistance, 10,[30][31][32] SMC continues to be proven effective in different settings. 10,12,33 The consistent rise in rates of both uncomplicated and severe malaria from the third to the fourth week post administration of each round suggests that the effect of SMC is short-lived.…”

“…35 SMC drug e cacy, coverage level and duration of protection are among the most important factors that determine its effectiveness for malaria prevention and control. 31 A modeling study found that the duration of protection of SMC has higher importance for its public health impact on preventing disease than the drug's e cacy (parasite killing effect). 38 Therefore, for chemoprevention, as opposed to treatment, preventing infection throughout the high-risk period and between cycles was found more important than high curative e cacy.…”