Pre-existing immunity to heartland virus protects rhesus macaques from challenge with severe fever with thrombocytopenia syndrome virus.

Heartland virus (HRTV) and Severe fever with thrombocytopenia syndrome virus (SFTSV) are closely related phenuiviruses that cause similar diseases in humans. However, animal disease models for both viruses are limited. Here, we first investigated whether human disease from SFTSV and HRTV could be recapitulated in rhesus macaques. In contrast to previous studies, we challenged rhesus macaques with a Japanese isolate of SFTSV. Although Japan reports higher human case fatality rates than many other regions, only mild disease was observed in infected rhesus macaques. Moreover, since animal models for HRTV are also limited, we challenged another group of rhesus macaques with HRTV. Although the animals seroconverted, clinical disease was not observed, suggesting rhesus macaques are unsuitable disease models for HRTV. Lastly, we subsequently tested whether immune responses raised against HRTV could cross-protect against SFTSV challenge and found that prior infection with HRTV limited SFTSV replication and signs of disease. Together, our data establishes a rhesus macaque model of SFTSV infection using a Japanese isolate of SFTSV and demonstrates that pre-existing immunity to HRTV can protect against infection with SFTSV.