| Summary: | A cross-sectional serological, active outbreak search and a questionnaire-based survey were carried out to investigate foot-and-mouth disease (FMD) sero-epidemiology in Ethiopia. The circulating serotype of the FMD virus (FMDV) was identified, and the knowledge regarding FMD and husbandry practices was assessed. Using the questionnaire survey, a total of 237 individuals were interviewed, and the majority responded that there is no practice of reporting disease outbreak, free in and out movement of livestock, or share pastures, and they use traditional case management as a means of controlling the disease. A total of 1938 cattle, 490 domestic small ruminants, and 426 swine were sampled randomly for serological analysis using the 3ABC non-structural protein (NSP) enzyme-linked immunosorbant assay. An overall prevalence of 25% in cattle, 5% in domestic small ruminants, and 2% in swine was recorded. Multivariable logistic regression analysis revealed that cattle from the Oromia, Tigray, and Amhara regions had the highest probability of being sero-positive as compared with Addis Ababa odds ratio(OR)(OR: 4 (95% confidence interval (CI)(CI [3–6], 3 (95% CI [2,5]), and 2 (95% CI 2 [1,3]), respectively)). Older cattle (older than three years) and domestic small ruminants (>18 months) had a higher chance of being seropositive (OR: 2, 95% CI [1.6,3]) and (OR: 6, 95% CI [2,18]), respectively). Female and older swine older than three years of age had a higher chance of being sero-positive (<i>p</i> < 0.05). Local breed cattle had the lowest chance (OR: 0.2. 95% CI [0.1–0.3]) of being sero-positive. A region, age, and breed proved to have a statistically significant association with sero-positivity (<i>p</i> < 0.05) in cattle. Swine from Bishoftu were less likely to test positive than swine from Addis Ababa (OR: 0.04, 95% CI [0.01–0.3]). From 96 herds, 72 pooled outbreak samples were analyzed by polymerase chain reaction (PCR), virus isolation, serotyping (antigen enzyme linked immunosorbant assay (ELISA)), sequencing, and phylogenetic tree analysis. Six serotype A (G-IV) FMD viruses and three serotype O east African (EA-3 and EA-4) FMDVs were identified. Thus, this study established the lack of disease outbreak reporting, poor husbandry problems, and the prevalence of FMD in three domestic species (cattle, small ruminant, and swine). In addition, continuous circulation of serotype A and O in the study area was confirmed.
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