Vaccines against the Rift Valley Fever bio-threat – RiftVac

We have 4 major specific objectives:
- to develop protein and DNA RVFV vaccines by targeting the SIRP- DC with anti-DEC205 or CLEC9A ScFvs fused in frame with the eGn protein, the ectodomain of the Gn RVFV glycoprotein that was shown to be protective in mouse models (ScFv-eGn). SIRP- DC subset targeting by vaccines has mainly been conducted in mice, and showed promising results in monkeys (Flynn et al., 2011). Demonstration of the efficacy of SIRP- DC targeting by vaccines in domestic animals has never been done and would extend the mouse/monkey results to a distant mammalian species, supporting the general extension of the SIRP- DC targeting concept for application in humans. In addition, this strategy is expected to be safe and DIVA (using the anti N serological response to detect infection).
- to compare protein and DNA anti-DEC205 or CLEC9A ScFvs-eGn vaccines for their immunogenicity, using a cationic lipid-based adjuvant.
- to develop a highly immunogenic RVFV recombinant pox vector based on the attenuated MVL that will encode the eGn protein.
- to test the SIRP- DC-targeted and recombinant MVL vaccines for their immunogenicity and protective properties in the sheep model, in homologous and heterologous prime/boosts, in order to eventually select the most appropriate strategy for vaccination in case of emerging or established RVFV infection, with respect to current regulatory constraints. Indeed, the conditions of usage of DNA/protein vaccines and MVL may not end up to be the same, depending of their final effectiveness, cost and safety aspects.

Ongoing

- selection of RVFV vaccines eliciting high and fast anti RVFV antibody response, strong T cell response (CD4 and CD8), and sterilizing immunity in sheep used as a target species and as a pertinent preclinical model
- develop the first anti SIRP- DC strategy in a domestic species, as a preclinical demonstration of the proof of concept for application to humans for RVFV vaccines, and leading to application to other pathogens
- develop the first combined anti SIRP- DC strategy/recombinant pox in a domestic species as a preclinical demonstration of the proof of concept for application to humans
- comparison of immunogenicity of anti SIRP- DC ScFv-eGn as DNA and protein vaccines
- the use of recombinant MVL as a vaccine candidate against RVFV in a sheep model for clinical application in humans

NOT yet

Rift Valley Fever Virus (RVFV), a zoonotic arbovirus that has steadily expanded from Eastern Africa, is under scrutiny considering its potential as bio-threat agent both in humans and ruminants. As shown recently for other arbovirus, RVFV could emerge in new areas via intentional/bioterrorist actions or by the globalization of exchanges. Introduction of RVFV in Europe and US would be dramatic for the public health and the economy, given the viral spread among insects, livestock and humans, the severity of the disease and the lack of registered vaccines and treatments. Attenuated and inactivated RVFV vaccines are commercialized for ruminants in enzootic countries. However the insufficient safety of the attenuated vaccines and the ineffectiveness and cost of the inactivated vaccines render their registration unlikely in Europe and US. Thus new, low cost, safe, broadly effective RVFV vaccines are awaited, that induce rapid onset of long term immunity. Recombinant vaccines have been recently developed but 1) they suffer from limitations such as high cost, incomplete immunological evaluation, incomplete protection and 2) they were mainly tested in the mouse model that is not predictive of effectiveness in humans. Because sheep are natural targets of RVFV and they develop similar immune responses with humans, evaluation of RVFV vaccines in sheep stands as a pertinent preclinical step before human use.
Targeting vaccine antigens to dendritic cells (DCs) is a major strategy to produce efficient and cost effective vaccines. Two main types of DCs, characterized as SIRP- and SIRP+ throughout mammals including sheep, can be differentially targeted via specific receptors. Interestingly in mice and recently in monkeys, the SIRP- DC subset targeting with DNA or protein-based vaccines to the DEC205 and CLEC9A molecules induced exceptionally high CD8 T cell and antibody responses (>100 times higher than non targeted forms). The combination of a SIRP- DC targeted vaccine with a pox vector boost gave optimal immune responses in monkeys.
The goal of our RiftVac proposal is to develop RVFV vaccines for humans and ruminants based on 1) SIRP- DC targeting with protein or DNA-based vaccines and 2) on pox viruses, either in homologous or heterologous prime/boosts, in the sheep preclinical model. RiftVac implicates 4 complementary partners (P): P1, an expert in sheep immunology and DCs, will produce single chain variable fragments directed to ruminant DEC205 and CLEC9A, in fusion with the ectodomain of the protective Gn glycoprotein (eGn). Both DNA and protein vaccine forms will be administered with cationic/lipid adjuvants, based on P1’s previous successes in sheep. P3 will produce a strongly attenuated variant of the small pox Lister strain (MVL) expressing eGn. P2, an expert in RVFV virology, will provide the virological tools and will analyse the neutralising antibody magnitude and kinetics. Together with P4, P2 will challenge the vaccinated sheep with virulent RVFV, as recently done by them in P4’s highly contained animal facilities.
The main output of the RiftVac project is the production of RVFV vaccines that trigger high and fast RVFV antibody responses, strong CD4 and CD8 T cell responses, and sterilizing immunity in sheep used as a target species and pertinent preclinical model. The RiftVac vaccines are designed to be safe and cost-effective. These new vaccines shall be used in case of deliberate or fortuitous introduction of RVFV in free countries and also in endemic areas. The RiftVac vaccine results, including the SIRP- DC targeting that has not yet been assessed in domestic animals nor humans, will bring proofs of concept for the clinical development of novel and highly efficient vaccine generations.