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The protective efficacy of intranasal (IN) administration of inactivated feline calicivirus (FCV) vaccine against homologous or heterologous FCV infection was investigated. Groups of cats immunized with the experimental inactivated, non-adjuvanted FCV vaccine via either the IN or subcutaneous (SC) route were exposed to homologous or highly heterologous FCV. Both the IN and SC immunization protocols established robust protection against homologous FCV infection. Although neither immunization regimen conferred protection against the heterologous strain, clinical scores and virus titres of oral swabs were lower in cats in the IN group compared to those in the SC group, accompanying a faster neutralizing antibody response against the heterologous virus in cats in the IN group. The IN group secreted more IgA specific to FCV proteins in oral washes (lavage fluids from the oral cavity) than the SC group. IN immunization with an inactivated whole FCV particle, which protects cats from homologous virus exposure and shortens the period of heterologous virus shedding, may serve as a better platform for anti-FCV vaccine.