Comparative epidemiology of ivermectin and vaccines against Delta variant based on real-world data and hypothesized mechanisms of ivermectin immunological action

Abstract Purpose In areas of Africa where ivermectin is widely used as prophylaxis against neglected tropical diseases, COVID-19 morbidity and mortality are markedly lower. Thus, prophylactic administration of ivermectin is expected to be as effective as vaccine administration. This study will evaluate the effect of ivermectin on Delta variant by retrospective comparative epidemiology with vaccines and estimate its mechanism of action. Methods We used the 4-month observation period during which Delta variant was prevalent. Vaccine-using countries were divided into two groups according to the presence or absence of an inactivated vaccine approval. The number of confirmed cases, deaths, and recoveries in the ivermectin-using countries and countries with full vaccination coverage of 50% or higher were corrected using adjustment factors calculated from population factors, medical care, and test systems. The median test performed statistical comparisons by adjusted values between the ivermectin group and each vaccine group. Vaccine efficacy rates against ivermectin were calculated based on odds ratios. Spearman's rank correlation coefficient examined the interaction between ivermectin and each vaccine. Results Ivermectin was statistically less effective than the non-inactivated vaccines but was not statistically significantly different from the inactivated vaccine-approved group for all items. Vaccine efficacy against ivermectin was 35% for the non-inactivated vaccines and 13% for the inactivated vaccine-approved group. The interaction between ivermectin and the non-inactivated vaccines may reduce morbidity, while the inactivated vaccines may increase morbidity and mortality. Discussion Ivermectin may have both chemical actions and immune response mechanisms against SARS-CoV-2. Ivermectin is less effective than the non-inactivated vaccine but is more effective than the inactivated one. When used in combination with a non-activated vaccine, it may further reduce morbidity. The vaccine effect of ivermectin may last approximately 5 months. The vaccine-like effects of ivermectin may activate the retinoic acid-induced gene-I pathway, leading to antibody production and autophagy.