Jeong-Eun Kwak^1,7, Young-Il Kim^2,7, Su-Jin Park², Min-Ah Yu², Hyeok-Il Kwon², Sukyeong Eo¹, Tae-Shin Kim³, Joon Seok³, Won-Suk Choi², Ju Hwan Jeong², Hyojin Lee⁴, Youngran Cho⁴, Jin Ah Kwon⁴, Moonsup Jeong⁴, Joel N. Maslow⁴, Yong-Eun Kim⁵, Haili Jeon⁵, Kee K. Kim⁵, Eui-Cheol Shin^1,3, Min-Suk Song², Jae U. Jung⁶, Young Ki Choi^2,* & Su-Hyung Park^1,3,*

¹ Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
² Department of Microbiology, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju 28644, Republic of Korea.
³ Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
⁴ GeneOne Life Science, Inc., Seoul 06060, Republic of Korea.
⁵ Department of Biochemistry, Chungnam National University, Daejeon 34134, Republic of Korea.
⁶ Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
⁷ These authors contributed equally: Jeong-Eun Kwak, Young-Il Kim.

^*Correspondence and requests for materials should be addressed to Y.K.C. or to S.-H.P.

Although the incidence of severe fever with thrombocytopenia syndrome virus (SFTSV) infection has increased from its discovery with a mortality rate of 10–20%, no effective vaccines are currently available. Here we describe the development of a SFTSV DNA vaccine, its immunogenicity, and its protective efficacy. Vaccine candidates induce both a neutralizing antibody response and multifunctional SFTSV-specific T cell response in mice and ferrets. When the vaccine efficacy is investigated in aged-ferrets that recapitulate fatal clinical symptoms, vaccinated ferrets are completely protected from lethal SFTSV challenge without developing any clinical signs. A serum transfer study reveals that anti-envelope antibodies play an important role in protective immunity. Our results suggest that Gn/Gc may be the most effective antigens for inducing protective immunity and non-envelope-specific T cell responses also can contribute to protection against SFTSV infection. This study provides important insights into the development of an effective vaccine, as well as corresponding immune parameters, to control SFTSV infection.