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Inactivated vaccines administered with the adjuvant aluminum hydroxide (Alum) are currently the most widely used COVID-19 vaccines in the world and have been critical to responding to the SARS-CoV-2 pandemic. Although these vaccines are efficacious against homologous virus infection in healthy young adults, the emergence of novel SARS-CoV-2 variants has resulted in significant vaccine breakthrough. Pre-clinical studies with inactivated SARS-CoV-1 and MERS-CoV vaccines have reported enhanced immunopathology upon breakthrough infection, characterized by pulmonary eosinophilia and upregulation of type 2 cytokines. These previous reports therefore raise the concern that inactivated COVID-19 vaccines may cause enhanced immunopathology upon vaccine breakthrough. To investigate this possibility, we vaccinated female BALB/c mice with inactivated SARS-CoV-2 (iCoV2) prior to coronavirus challenge. Although iCoV2 protected mice from severe clinical disease and pulmonary pathology upon homologous challenge with pathogenic SARS-CoV-2, we observed increased pulmonary pathology and pulmonary eosinophilia upon challenge in mice vaccinated with iCoV2 and Alum (iCoV2 + Alum) compared to mice vaccinated with iCoV2 alone. Furthermore, to model vaccine breakthrough upon heterologous coronavirus infection, we challenged iCoV2-vaccinated mice with a zoonotic SARS-like coronavirus (SHC014). Upon SHC014 challenge, iCoV2 + Alum vaccination failed to control virus replication and caused enhanced pulmonary pathology, pulmonary eosinophilia and upregulation of pulmonary type 2 cytokines. Ongoing studies are investigating the mechanism of iCoV2-related immunopathology, including the role of specific iCoV2 antigens. Supported by grants from NIH (K01 OD026529, U19 AI100625, U19 AI109680, and MSTP T32 GM008719), Infectious Disease Drug Discovery Program (ID3), Rapidly Emerging Antiviral Drug Development Initiative (READDI), NCTraCS and Emerging Challenges in Biomedical Research COVID Pilot Award, SOM Junior Investigator Development Award, Department of Pathology and Laboratory Medicine.