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

As reductions in malaria transmission in sub-Saharan Africa stagnate, gene drive-modified mosquitoes represent one of the most promising novel tools for continued disease control. In order to advance from the laboratory to the field, gene drives will be assessed against target product profiles, planning tools that list minimum criteria products should satisfy as they progress through the development pipeline. We used an eco-epidemiological model to investigate parameter values for population modification gene drives that satisfy two previously-discussed target outcomes: a 50% reduction in clinical malaria incidence for a duration (window-of-protection) of at least three years, and a time-to-impact (considering a 50% reduction in clinical malaria incidence) of less than one year. We consider two African settings, Burkina Faso and Kenya, where gene drive mosquitoes are currently being researched, and consider three transmission intensities at each. For the gene drive product, we explored rates of homing and resistance allele generation, fitness costs associated with gene drive and non-functional resistance alleles, and efficacy of the effector gene(s) at reducing mosquito-to-human transmission. We found that when the window-of-protection criterion is satisfied, the time-to-impact criterion also is. Target outcomes are most influenced by the fitness cost associated with the gene drive allele and effector gene efficacy. Resistance allele parameters are highly influential on target outcomes, determining how long the gene drive allele persists in the population after most available wild-type alleles have been cleaved. Low rates of functional resistance allele generation are preferred, while costly non-functional resistance alleles will allow the drive allele to outcompete them. Homing rates already achieved for Anopheles gene drives do not need to be improved upon. A conundrum exists whereby the most important product parameters for predicting field efficacy are those that can only be reliably measured in the field, which presents a challenge for assessment of product readiness.