GM-CSF and CD40L VLPs provided stable, long-term protection with a high titer of neutralizing antibody in mice 6 months after immunization. Furthermore, VLPs increased HTNV-specific cellular immune responses via higher expression of IFN-g and CTL responses. HTNV challenge assay results showed long-term protection against HFRS. No significant pathological alteration was observed in the organs of mice after immunization. Here, CSF2 is linked to hemorrhagic fever with renal syndrome.