Recombinant Human Adenovirus Type 5 Co-expressing RABV G and SFTSV Gn Induces Protective Immunity Against Rabies Virus and Severe Fever With Thrombocytopenia Syndrome Virus in Mice

Abstract

Both severe fever with thrombocytopenia syndrome (SFTS) and rabies are severe zoonotic diseases. As co-hosts of rabies virus (RABV) and SFTS virus (SFTSV), dogs and cats could not only be infected but also transmit the virus to human. Hence, developing a bivalent vaccine against both SFTS and rabies is urgently needed. In this study, we generated a recombinant replication-deficient human adenovirus type 5 (Ad5) co-expressing RABV G and SFTSV Gn (Ad5-G-Gn) and evaluated its immunogenicity and efficacy in mice. Ad5-G-Gn immunization activated more dendritic cells (DCs) and B cells in lymph nodes (LNs) and induced Th1-/Th2-mediated responses in splenocytes, leading to robust production of neutralizing antibodies against SFTSV and RABV. In addition, single dose of Ad5-G-Gn conferred mice complete protection against lethal RABV challenge and significantly reduced splenic SFTS viral load. Therefore, our data support further development of Ad5-G-Gn as a potential bivalent vaccine candidate against SFTS and rabies for dog and cat use.

Animal Model of Severe Fever With Thrombocytopenia Syndrome Virus Infection

“…Therein, immunization with recombinant SFTSV NSs protein could induce a high titer of anti-NSs antibody in sera and yet it could not promote SFTSV clearance in mice (Liu et al, 2015). Two recombinant viral vectors including a recombinant rabies virus (RABV) expressing SFTSV Gn (rLBNSE-Gn) and a recombinant human adenovirus type 5 co-expressing RABV G and SFTSV Gn (Ad5-G-Gn) were designed as potential bivalent Chen et al, 2012Chen et al, , 2020Jin et al, 2012;Liu et al, 2015;Sun et al, 2015;Matsuno et al, 2017;Park S. J. et al, 2019; vaccines against SFTSV and RABV to take precaution against possibly dangerous contacts and infection between animals and humans Yamanaka et al, 2020;Zhao et al, 2020;Ando et al, 2021;Tian et al, 2021). Additionally, a recent study showed that SFTSV can be transmitted vertically across the placental barrier of the pregnant maternal mice (C57BL/6) to the fetuses, resulting in widely distributed infection in multiple organs of the fetuses (Chen et al, 2020).…”

“…For instance, by using the C57BL/6 mouse model, researchers found that SFTSV stimulated production and secretion of pro-inflammatory cytokine Interleukin (IL)-1β and further confirmed that the NLRP3 (NLR family, pyrin domain containing 3) inflammasome complex acted as an essential mediator in the process ( Liu et al, 2021 ). Several vaccine candidates based on viral vectors, expression plasmids, or the viral protein (NSs) have been evaluated in wildtype C57BL/6 or BALB/c mice ( Jung et al, 2017 ; Zhao et al, 2020 ; Tian et al, 2021 ). Therein, immunization with recombinant SFTSV NSs protein could induce a high titer of anti-NSs antibody in sera and yet it could not promote SFTSV clearance in mice ( Liu et al, 2015 ).…”

Overview of the immunological mechanism underlying severe fever with thrombocytopenia syndrome (Review)

“…It was also found that among the surviving patients, the expression of cd86 and the ratio of cd80 + cd86 + /mdcs in week 3 was significantly higher compared with that in the patients who succumbed to the disease in week 2 (90). SFTSV vaccines, such as human adenovirus type 5 (Ad5)-G-Gn (a recombinant replication-deficient Ad5 co-expressing rabies virus G and SFTSV Gn), have been reported to increase the production of neutralizing antibodies against SFTSV (91). This appeared to be mediated by the activation of additional dcs and B cells in lymph nodes to induce a Th1-/Th2-mediated immune response in splenocytes (91).…”

“…SFTSV vaccines, such as human adenovirus type 5 (Ad5)-G-Gn (a recombinant replication-deficient Ad5 co-expressing rabies virus G and SFTSV Gn), have been reported to increase the production of neutralizing antibodies against SFTSV (91). This appeared to be mediated by the activation of additional dcs and B cells in lymph nodes to induce a Th1-/Th2-mediated immune response in splenocytes (91). This suggests that dcs can serve an antigen-presenting role in the function of SFTSV vaccines.…”

Severe Fever with Thrombocytopenia Syndrome, a Viral Hemorrhagic Fever, Endemic to Japan: Achievements in and Directions for Medical Research

“…The characteristics of the vaccine candidates developed to date are summarized in Table 2. Other vaccine candidates for SFTS have been reported using the platforms of recombinant vesicular stomatitis Yuan Y, et al (87) virus (91), rabies virus (92), and human adenovirus type 5 (93). Recombinant SFTSV with artificially modified NSs, rHB2912aaNSs, recombinant SFTSV HB29 that contained a carboxyl-terminal truncated short 12 amino acid peptide, and rHB29NSsP102A, recombinant SFTSV HB29, which had a single point mutation in the NS coding sequence from proline to alanine at position 102, were attenuated (94).…”