Department of Life Sciences, Silwood Park, Imperial College London, London, UK.
Department of Life Sciences, South Kensington Campus, Imperial College London, London, UK.
Malar J. 2024 May 22;23(1):156. doi: 10.1186/s12936-024-04952-9.
Sustainable reductions in African malaria transmission require innovative tools for mosquito control. One proposal involves the use of low-threshold gene drive in Anopheles vector species, where a 'causal pathway' would be initiated by (i) the release of a gene drive system in target mosquito vector species, leading to (ii) its transmission to subsequent generations, (iii) its increase in frequency and spread in target mosquito populations, (iv) its simultaneous propagation of a linked genetic trait aimed at reducing vectorial capacity for Plasmodium, and (v) reduced vectorial capacity for parasites in target mosquito populations as the gene drive system reaches fixation in target mosquito populations, causing (vi) decreased malaria incidence and prevalence. Here the scope, objectives, trial design elements, and approaches to monitoring for initial field releases of such gene dive systems are considered, informed by the successful implementation of field trials of biological control agents, as well as other vector control tools, including insecticides, Wolbachia, larvicides, and attractive-toxic sugar bait systems. Specific research questions to be addressed in initial gene drive field trials are identified, and adaptive trial design is explored as a potentially constructive and flexible approach to facilitate testing of the causal pathway. A fundamental question for decision-makers for the first field trials will be whether there should be a selective focus on earlier points of the pathway, such as genetic efficacy via measurement of the increase in frequency and spread of the gene drive system in target populations, or on wider interrogation of the entire pathway including entomological and epidemiological efficacy. How and when epidemiological efficacy will eventually be assessed will be an essential consideration before decisions on any field trial protocols are finalized and implemented, regardless of whether initial field trials focus exclusively on the measurement of genetic efficacy, or on broader aspects of the causal pathway. Statistical and modelling tools are currently under active development and will inform such decisions on initial trial design, locations, and endpoints. Collectively, the considerations here advance the realization of developer ambitions for the first field trials of low-threshold gene drive for malaria vector control within the next 5 years.
可持续减少非洲疟疾传播需要创新的蚊虫控制工具。一种方案涉及在疟蚊物种中使用低门槛基因驱动，其中“因果途径”将通过以下步骤启动：（i）在目标蚊虫媒介物种中释放基因驱动系统，导致（ii）其传播到后代，（iii）其在目标蚊虫种群中的频率和传播增加，（iv）同时传播旨在降低疟原虫媒介能力的连锁遗传特征，以及（v）随着基因驱动系统在目标蚊虫种群中达到固定，目标蚊虫种群中的寄生虫媒介能力降低，导致（vi）疟疾发病率和流行率降低。本文考虑了此类基因驱动系统初步实地释放的范围、目标、试验设计要素和监测方法，这些内容是根据生物防治剂以及其他蚊虫控制工具（包括杀虫剂、沃尔巴克氏体、幼虫剂和诱捕-毒饵系统）实地试验的成功实施情况得出的。确定了初步基因驱动实地试验中需要解决的具体研究问题，并探讨了适应性试验设计，作为一种潜在的建设性和灵活的方法，以促进对因果途径的测试。对于首次实地试验，决策者面临的一个基本问题是，是否应该有选择地关注该途径的早期阶段，例如通过测量目标种群中基因驱动系统的频率和传播增加来评估遗传效力，或者更广泛地调查整个途径，包括昆虫学和流行病学效力。在最终确定和实施任何实地试验方案之前，无论初始实地试验是否专门关注遗传效力的测量，还是更广泛地关注因果途径的各个方面，如何以及何时最终评估流行病学效力都将是一个重要的考虑因素。目前正在积极开发统计和建模工具，将为初步试验设计、地点和终点的决策提供信息。总的来说，这里的考虑因素推进了在未来 5 年内实现低门槛基因驱动疟疾媒介控制首次实地试验的开发者的目标。
