A model-informed target product profile for population modification gene drives for malaria control

Area of Science:

• Genetics and genomics
• Epidemiology
• Vector control

Background:

• Malaria transmission reduction in sub-Saharan Africa has stagnated.
• Gene drive-modified mosquitoes offer a novel approach for disease control.
• Target product profiles guide the development of gene drive technologies.

Purpose of the Study:

• To investigate parameter values for population modification gene drives.
• To assess if gene drives can achieve a 50% reduction in clinical malaria incidence for at least three years.
• To determine if gene drives can achieve a 50% reduction in clinical malaria incidence in under one year.

Main Methods:

• An eco-epidemiological model was used.
• Two African settings (Burkina Faso and Kenya) with varying transmission intensities were simulated.
• Key parameters explored included homing rates, resistance allele generation, fitness costs, and effector gene efficacy.

Main Results:

• Satisfying the "window-of-protection" criterion (≥3 years) also satisfied the "time-to-impact" criterion (<1 year).
• Fitness cost of the gene drive allele and effector gene efficacy were the most influential parameters.
• Low rates of functional resistance allele generation are preferred, while costly non-functional resistance alleles aid drive persistence.

Conclusions:

• Gene drive mosquito efficacy is primarily driven by fitness costs and effector gene performance.
• Existing homing rates in Anopheles gene drives are sufficient.
• A challenge for product readiness is that crucial efficacy parameters can only be reliably measured in field trials.