A Rift Valley fever virus Gn ectodomain-based DNA vaccine induces a partial protection not improved by APC targeting

Abstract

Rift Valley fever virus, a phlebovirus endemic in Africa, causes serious diseases in ruminants and humans. Due to the high probability of new outbreaks and spread to other continents where competent vectors are present, vaccine development is an urgent priority as no licensed vaccines are available outside areas of endemicity. In this study, we evaluated in sheep the protective immunity induced by DNA vaccines encoding the extracellular portion of the Gn antigen which was either or not targeted to antigen-presenting cells. The DNA encoding untargeted antigen was the most potent at inducing IgG responses, although not neutralizing, and conferred a significant clinical and virological protection upon infectious challenge, superior to DNA vaccines encoding the targeted antigen. A statistical analysis of the challenge parameters supported that the anti-eGn IgG, rather than the T-cell response, was instrumental in protection. Altogether, this work shows that a DNA vaccine encoding the extracellular portion of the Gn antigen confers substantial—although incomplete—protective immunity in sheep, a natural host with high preclinical relevance, and provides some insights into key immune correlates useful for further vaccine improvements against the Rift Valley fever virus.

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

“…Anti-RVFV hyperimmune mouse ascitic fluid (HMAF) was obtained as previously described (16). Balb/c mice were inoculated intraperitoneally with inactivated RVFV-infected mouse brain suspensions in Freund's complete adjuvant on day 0 and 1 and in Freund's incomplete adjuvant on day 7 and 14.…”

“…A plasmid encoding Gn glycoprotein ectodomain of RVFV (peGn) was obtained as previously described (16). In order to generate targeted antigens to mouse DEC205, we used the published sequences of the variable region of the rat heavy (VH) and light (VL) chains of the anti-mouse DEC205 NLDC-145 clone, separated by a (G 4 S) 4 flexible linker (22) and at its amino-terminus, we added a signal peptide derived from a murine IgG (22).…”

“…Neutralizing Ab before challenge were measured as previously described (16). Sera were diluted 1:10–1:160 in DMEM and incubated with 100 pfu of MP-12 virus at 37°C with 5% CO 2 for 1 h. Next, the virus and the serum mix were added to VeroE6 cell monolayers which were further processed as described under the virus titration by plaque assay.…”

“…Indeed, DNA vaccine strategies based on antigen targeting to DEC205 induced strong CD4 + and CD8 + T cell responses and enhanced the antibody (Ab) responses in mice (11–14), and even in cattle (15). Based on this context, we recently compared in lambs the efficacy of a DNA vaccine encoding eGn (peGn) and eGn fused to a single chain fragment variable (scFv) directed to the ovine DEC205 receptor (pscDEC-eGn) (16). These DNA vaccine-candidates were co-delivered by intradermal injection with a plasmid encoding GM-CSF as a genetic adjuvant (17), followed by surface electroporation (SEP) to enhance in vivo transfection (18).…”

Recombinant Antibodies in Veterinary Medicine: An Update

“…In sheep, a DNA vaccine encoding a scFv fused with Rift Valley Fever Virus Gn peptide was directed at DEC205 and CD11c receptors. Compared with targeting to CD11c and untargeted treatment, targeting to DEC205 promoted IFNγ production but showed an inefficient humoral response ( 52 ).…”