Background Insect‐bite hypersensitivity (IBH) in horses is a chronic allergic dermatitis caused by insect bites. Horses suffer from pruritic skin lesions, caused by type‐I/type‐IV allergic reactions accompanied by prominent eosinophil infiltration into the skin. Interleukin‐5 (IL‐5) is the key cytokine for eosinophils and we have previously shown that targeting IL‐5 by vaccination reduces disease symptoms in horses. Objective Here, we analyzed the potential for long‐term therapy by assessing a second follow‐up year of the previously published study. Methods The vaccine consisted of equine IL‐5 (eIL‐5) covalently linked to a cucumber mosaic virus‐like particle (VLP) containing a universal T cell epitope (CuMVTT) using a semi‐crossover design to follow vaccinated horses during a second treatment season. Thirty Icelandic horses were immunized with 300 μg of eIL‐5‐CuMVTT without adjuvant. Results The vaccine was well tolerated and did not reveal any safety concerns throughout the study. Upon vaccination, all horses developed reversible anti‐eIL‐5 auto‐antibody titers. The mean course of eosinophil levels was reduced compared to placebo treatment leading to significant reduction of clinical lesion scores. Horses in their second vaccination year showed a more pronounced improvement of disease symptoms when compared to first treatment year, most likely due to more stable antibody titers induced by a single booster injection. Hence, responses could be maintained over two seasons and the horses remained protected against disease symptoms. Conclusion Yearly vaccination against IL‐5 may be a long‐term solution for the treatment of IBH and other eosinophil‐mediated diseases in horses and other species including humans.