Development of vaccines targeting a tick-borne phlebovirus

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Principal Investigator: Paul  Bates
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2022
Award: $577,515
Funding agency: National Institute of Allergy and Infectious Diseases

Severe Fever with Thrombocytopenia Syndrome virus (SFTSV) is a pathogenic, tick-transmitted
bunyavirus that can cause a severe febrile hemorrhagic-like disease with case fatality rates of
up to 30%. Discovered during a 2009 outbreak of febrile illness in China, the geographic
distribution of SFTSV extends into Korea and Japan with recent reports of infection in Vietnam
and Russia. The tick vector for SFTSV is widespread throughout Asia. Numerous domestic and
wild animals are naturally infected by SFTSV suggesting a large reservoir with potential spillover
to humans. There are currently no vaccines or therapeutics for SFTSV. Because of its epidemic
threat the WHO included SFTSV in its 2017 recommendation “A research and development
Blueprint for action to prevent epidemics” and identified SFTSV as one of 11 pathogens most
likely to cause severe outbreaks in the near future and proposed development of vaccines. Here
we will explore two complementary and potentially synergistic strategies for an SFTSV vaccine:
a recombinant viral vector and nucleoside-modified mRNA encoding the SFTSV viral
glycoproteins. Vesicular stomatitis virus (VSV) is a cytopathic virus that has been developed as
a vaccine vector due to its ability to rapidly induce strong, protective antibody and T cell
responses to encoded foreign antigens after a single dose. Using a VSV vector expressing the
SFTSV viral glycoproteins (similar to the currently employed VSV-Ebola vaccine), we
demonstrate single dose induction of a neutralizing antibody response and protection from
SFTSV challenge in an IFNAR1 knockout mouse model. Separately, we show that vaccination
of wt mice with a single dose of nucleoside-modified mRNA lipid nanoparticles (mRNA-LNP)
encoding the SFTSV glycoproteins elicits high levels of SFTSV neutralizing antibodies that are
capable of conferring partial SFTSV protection when transferred into the IFNAR1 KO model.
Based upon these strong preliminary findings we propose to characterize antibody and T-cell
responses in rVSV and mRNA vaccinated mice when these vaccines are used alone or in a
prime-boost regimen. These studies are significant as there is limited knowledge regarding
vaccines for this highly pathogenic virus (a single report) and use of rVSV and mRNA in a
prime-boost vaccination has not been reported. Finally, current small animal models of SFTSV
infection are limited to animals with type I IFN responses knocked out. Because these animals
lack an important innate immune response mechanism that supports amplification of cellular
and humoral immune responses, we will develop an immune competent mouse vaccination
model using transient monoclonal antibody blockade of IFNAR1 during SFTSV challenge.

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