Chow Jo Yi, Bansal Somya, Dickens Borame S L, Ma Pei, Hoffmann Ary, Cheong Yoon Ling, Ahmad Nazni Wasi, Lim Jue Tao
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 308232, Singapore.
Saw Swee Hock School of Public Health, National University of Singapore, Singapore, 117549, Singapore.
EBioMedicine. 2024 Dec;110:105456. doi: 10.1016/j.ebiom.2024.105456. Epub 2024 Nov 29.
Dengue remains a global health challenge with limited treatment options, highlighting the need for effective vector control strategies. The introduction of Wolbachia pipientis into Aedes aegypti populations has shown success in reducing dengue transmission across global field trials. However, the spillover effectiveness of the technology on untreated areas is not well-known. This study estimates the spillover protective effectiveness (PE) of Wolbachia-mediated introgression on dengue.
We used the synthetic control method (SCM) under assumption of partial interference to evaluate the direct and spillover PEs of Wolbachia-mediated introgression in a long-running operational trial of the intervention in Malaysia. Synthetic controls (SCs), which comprise of a weighted sum of non-spillover controls, were constructed for each directly-treated and spillover site in the pre-intervention period to account for historical imbalances in dengue risk and risk trajectories. SCs were compared to directly/spillover-treated sites to estimate the impact of Wolbachia-introgression on dengue incidence across each site, calendar year and intervention time. Robustness checks, including visual inspections, root-mean-square error (RMSE) calculations, in-space and in-time placebo checks, and permutation tests, were used to inspect the model's ability in attributing dengue incidence reductions to the Wolbachia interventions.
The direct and spillover PEs of Wolbachia on dengue incidence were expressed as a percentage reduction of dengue incidence, or the absolute case reductions, by comparing SCs to actual intervention/spillover sites. Findings indicate a direct reduction in dengue incidence by 64.35% (95% CI: 63.50-66.71, p < 0.05 using permutation tests) in directly treated areas, corresponding to 1802 (95% CI: 1768-1932) cases averted. Meanwhile, spillover effects contributed to a 37.69% (95% CI: 36.45-38.49, p < 0.05) reduction in adjacent non-intervention areas, accounting for 115 (95% CI: 104-132) absolute cases averted. Tracking PEs by intervention time revealed a dose-response relationship, where PEs increased concomitantly with Wolbachia frequency. Model checks confirmed the robustness of these results, and ascertained that these PEs were not an artefact of poor control selection, pre-trends in dengue incidence or poor predictive ability of the fitted SCs.
Wolbachia-introgression effectively diminished dengue incidence in directly-treated and surrounding spillover regions. This dual effectiveness highlights the potential of Wolbachia-infected mosquitoes as a sustainable, cost-effective strategy against dengue.
This research is hosted by CNRS@CREATE and supported by the National Research Foundation, Prime Minister's Office, Singapore, under its Campus for Research Excellence and Technological Enterprise (CREATE) program, and is funded by the Lee Kong Chian School of Medicine-Ministry of Education Start-Up Grant. The original Hoffmann et al. (2024) study was funded by the Wellcome Trust Awards 226166, 108508, 202888 and the Ministry of Health Malaysia NMRR-16-297-28898.
登革热仍然是一项全球性的健康挑战，治疗选择有限，这凸显了有效病媒控制策略的必要性。将沃尔巴克氏体引入埃及伊蚊种群已在全球实地试验中成功减少了登革热传播。然而，该技术对未处理地区的溢出效应尚不清楚。本研究估计了沃尔巴克氏体介导的基因渗入对登革热的溢出保护效果（PE）。
我们在部分干扰假设下使用合成控制法（SCM），以评估在马来西亚一项长期运行的干预试验中，沃尔巴克氏体介导的基因渗入的直接和溢出PE。在干预前阶段，为每个直接处理和溢出地区构建合成对照（SC），它由非溢出对照的加权和组成，以考虑登革热风险和风险轨迹的历史不平衡。将SC与直接/溢出处理地区进行比较，以估计沃尔巴克氏体基因渗入对每个地区、历年和干预时间的登革热发病率的影响。使用稳健性检验，包括目视检查、均方根误差（RMSE）计算、空间和时间安慰剂检验以及置换检验，来检验模型将登革热发病率降低归因于沃尔巴克氏体干预的能力。
通过将SC与实际干预/溢出地区进行比较，沃尔巴克氏体对登革热发病率的直接和溢出PE表示为登革热发病率降低的百分比或绝对病例减少数。结果表明，直接处理地区的登革热发病率直接降低了64.35%（95%置信区间：63.50 - 66.71，使用置换检验p < 0.05），相当于避免了1802例（95%置信区间：1768 - 1932）病例。同时，溢出效应使相邻未干预地区的发病率降低了37.69%（95%置信区间：36.45 - 38.49，p < 0.05），相当于避免了115例（95%置信区间：104 - 132）绝对病例。按干预时间跟踪PE显示出剂量反应关系，即PE随着沃尔巴克氏体频率的增加而增加。模型检验证实了这些结果的稳健性，并确定这些PE不是控制选择不当、登革热发病率的前期趋势或拟合SC的预测能力差的人为结果。
沃尔巴克氏体基因渗入有效降低了直接处理地区和周边溢出地区的登革热发病率。这种双重效果凸显了感染沃尔巴克氏体的蚊子作为一种可持续、具有成本效益的登革热防控策略的潜力。
本研究由CNRS@CREATE主持，并得到新加坡总理办公室国家研究基金会在其卓越研究与技术企业校园（CREATE）计划下的支持，由李光前医学院 - 教育部启动资助。最初的霍夫曼等人（2024年）研究由惠康信托基金奖226166、108508、202888以及马来西亚卫生部NMRR - 16 - 297 - 28898资助。
