A DNA Vaccine Encoding the Gn Ectodomain of Rift Valley Fever Virus Protects Mice via a Humoral Response Decreased by DEC205 Targeting

Abstract

The Rift Valley fever virus (RVFV) is responsible for a serious mosquito-borne viral disease in humans and ruminants. The development of a new and safer vaccine is urgently needed due to the risk of introduction of this arbovirus into RVFV-free continents. We recently showed that a DNA vaccine encoding eGn, the ectodomain of the RVFV Gn glycoprotein, conferred a substantial protection in the sheep natural host and that the anti-eGn IgG levels correlated to protection. Addressing eGn to DEC205 reduced the protective efficacy while decreasing the antibody and increasing the IFNγ T cell responses in sheep. In order to get further insight into the involved mechanisms, we evaluated our eGn-encoding DNA vaccine strategy in the reference mouse species. A DNA vaccine encoding eGn induced full clinical protection in mice and the passive transfer of immune serum was protective. This further supports that antibodies, although non-neutralizing in vitro , are instrumental in the protection against RVFV. Addressing eGn to DEC205 was also detrimental to protection in mice, and in this species, both the antibody and the IFNγ T cell responses were strongly decreased. Conversely when using a plasmid encoding a different antigen, i.e., mCherry, DEC205 targeting promoted the antibody response. Altogether our results show that the outcome of targeting antigens to DEC205 depends on the species and on the fused antigen and is not favorable in the case of eGn. In addition, we bring evidences that eGn in itself is a pertinent antigen to be included in a DNA vaccine and that next developments should aim at promoting the anti-eGn antibody response.

Vaccine Efficacy of Self-Assembled Multimeric Protein Scaffold Particles Displaying the Glycoprotein Gn Head Domain of Rift Valley Fever Virus

“…Interestingly, for other targets, including SARS-CoV-2, vaccination with relatively low amounts of nanoparticle-coupled antigen showed promise [ 37 , 38 , 39 , 40 , 41 , 42 ]. The observed full protection in the presence of adjuvant also highlights that Gn head is a potent immunogen, possibly even more potent than the complete Gn ectodomain [ 21 , 43 , 44 ].…”

Genetically Modified Rabies Virus Vector-Based Rift Valley Fever Virus Vaccine is Safe and Induces Efficacious Immune Responses in Mice

“…Inducing animals to produce specific IgG antibodies but not neutralizing antibodies may be related to pathogenic characteristics (such as those of Marburg, Lassa fever, and RVF) and the vector selected for vaccine research. Although no neutralizing antibodies were produced, the vaccine may still provide protection against a challenge with RVFV; other mechanisms such as complement-dependent inhibition, antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis remain to be investigated [23,43,44].…”

“…Although formalin-inactivated and live attenuated vaccines have been licensed for veterinary use, they still have drawbacks [19,20,21,22]. There are several vaccine platforms for RVF vaccine research that have been reported, including a DNA vaccine [23,24], EHV-1 vector [25], a DNA prime with MVA boost [26], NDV-based vector [27,28] and VLP [29] has been reported. Studies have suggested that humoral immunity is sufficient for preventing RVFV, so a vaccine that can elicit rapid humoral immune responses that neutralize RVFV while being low cost, safe, stable and highly effective is urgently needed () [17,30].…”

Rift Valley Fever – epidemiological update and risk of introduction into Europe

“…No Yes Schmaljohn et al (1989), De Boer et al (2010), Kortekaas et al (2012) and (Chrun et al (2019) 3.3. Virus Like Particle (VLP) based VLPs Mice No Yes (Liu et al (2008), Naslund et al 2009 • No vaccines against RVF have been so far authorised for use in the EU.…”