Abstract
<title>Abstract</title> <p> Tick-borne <italic>Rickettsia rickettsii</italic> causes fatal Rocky Mountain spotted fever (RMSF) in humans and dogs. Canine vaccination represents a strategic approach to improve companion animal health while simultaneously reducing the broader public health burden of RMSF. In this study, we evaluated the pathogenicity of three distinct <italic>Rickettsia rickettsii</italic> strains; Iowa, Sheila Smith, and Morgan, in dogs and assessed the protective efficacy of whole-cell antigen-based vaccines (WCAVs) derived from these strains. While the Iowa strain caused only mild clinical signs, the Sheila Smith and Morgan strains induced severe clinical disease. Formulated WCAVs demonstrated robust protective efficacy, entirely eliminating mortality and severe clinical illness across all challenged groups. Vaccinated animals exhibited significantly reduced bacteremia, minimized tissue damage, and stabilized systemic biochemical markers. This robust protection correlated with strong humoral responses and antigen-specific CD4⁺ and CD8⁺ T-cell proliferation. These findings establish a foundational framework for developing safe, effective vaccine against fatal RMSF. </p>