DNA vaccination regimes against Schmallenberg virus infection in IFNAR −/− mice suggest two targets for immunization

Abstract

Schmallenberg virus (SBV) is an RNA virus of the Bunyaviridae family, genus Orthobunyavirus that infects wild and livestock species of ruminants. While inactivated and attenuated vaccines have been shown to prevent SBV infection, little is known about their mode of immunity; specifically, which components of the virus are responsible for inducing immunological responses in the host. As previous DNA vaccination experiments on other bunyaviruses have found that glycoproteins, as well as modified (i.e. ubiquitinated) nucleoproteins (N) can confer immunity against virulent viral challenge, constructs encoding for fragments of SBV glycoproteins G and G, as well as ubiquitinated and non-ubiquitinated N were cloned in mammalian expression vectors, and vaccinated intramuscularly in IFNAR mice. Upon viral challenge with virulent SBV, disease progression was monitored. Both the ubiquitinated and non-ubiquitinated nucleoprotein candidates elicited high titers of antibodies against SBV, but only the non-ubiquitinated candidate induced statistically significant protection of the vaccinated mice from viral challenge. Another construct encoding for a putative ectodomain of glycoprotein G (segment aa. 678-947) also reduced the SBV-viremia in mice after SBV challenge. When compared to other experimental groups, both the nucleoprotein and G-ectodomain vaccinated groups displayed significantly reduced viremia, as well as exhibiting no clinical signs of SBV infection. These results show that both the nucleoprotein and the putative G-ectodomain can serve as protective immunological targets against SBV infection, highlighting that viral glycoproteins, as well as nucleoproteins are potent targets in vaccination strategies against bunyaviruses.

Modeling Arboviral Infection in Mice Lacking the Interferon Alpha/Beta Receptor

“…The relation between type I IFN and viral spreading has been investigated using seve day old IFNAR(−/−) mice intracerebrally injected with SBV and an NSs deletion mutant, confirming the role of the NSs protein as a modulator, at least indirectly, of the IFN response in vivo [77]. This mouse model has been used to validate attenuated strains as potential vaccines [41], and to test protective immunity induced by the Gc-ecto1 domain and nucleocapsid protein of the virus, showing that these could be valid candidates for the development of subunit vaccines [42]. Wernike et al [43] have also demonstrated the suitability of using Gc as an efficient vaccine in this murine model.…”

“…After SBV infection, mice showed primarily decreased weight loss, ataxia, apathy, but limited mortality [41]. In recent studies, it has been demonstrated that SBV virulence occurs as early as three days post-infection (dpi) and it becomes more severe at day six post-infection as observed by the significant weight loss and viremia [42]. The relation between type I IFN and viral spreading has been investigated using seve day old IFNAR(−/−) mice intracerebrally injected with SBV and an NSs deletion mutant, confirming the role of the NSs protein as a modulator, at least indirectly, of the IFN response in vivo [77].…”

Schmallenberg Virus: To Vaccinate, or Not to Vaccinate?

“…The most promising DIVA-compatible antigen delivery systems include live attenuated vaccines, DNA-mediated, subunit or live-vectored vaccines [ 94 ]. All those preparations have been developed for SBV [ 63 , 67 , 95 , 96 , 97 ] and some of them were successfully tested in cattle, one of the major target species of SBV ( Table 1 ).…”

“…Thus, DNA-mediated subunit as well as live-vectored vaccines have been developed on the basis of Gc. While DNA-mediated vaccines have only been tested in small animal models until now [ 63 , 96 ], subunit or viral vector vaccines have proved their efficiency in the target species of SBV, specifically cattle [ 63 , 97 ].…”

“…Interestingly, when the domain was optimally presented, it provided a protective effect equivalent to that of the earlier inactivated vaccines or a live-attenuated vaccine [ 62 , 63 , 95 , 97 ]. Besides the Gc domain, further candidate targets for vaccine development were suggested [ 96 ], however, their efficiency testing in ruminants is still pending.…”