New Avenues for Vaccine Development

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1 New Avenues for Vaccine Development David Wallace ARC-Onderstepoort Veterinary Institute, South Africa

2 Virus structure and genomic layout S Nc NSs M NSm G2/Gn G1/Gc L L (Van Regenmortel et al., 2000) (Freiberg et al., 2008)

3 Experimental vaccines: (Clone 13) NSs-defective clone (IFN antagonist) MV P12 (ZH548) mutagen-induced changes (segments M & L) R566 (Clone 13 + MV P12 reassortment) S segment Clone 13 and L & M of MV P12 - Safer, much less chance for reversion via reassortment with virulent strains in the field

4 Experimental vaccines - alternatives : - Subunit - DNA - Reverse Genetics - Virus-vectored

5 Experimental vaccines (continued) : Subunit (Schmaljohn et al., 1989, Wallace et al., 2006) - baculovirus : Gn & Gc - good protection in mice - E. coli : tgn - good protection in mice NC - partial protection in mice DNA (Spik et al., 2006; Wallace et al., 2006; Lorenzo et al., 2008) - GPs +NSm - poor antibody response & protection - GPs -NSm - good antibody responses & protection - NC - good and long-lasting antibodies (but, low neutralising)

6 Experimental vaccines (continued) : Reverse genetics (Gerrard et al., 2007; Bird et al., 2007; Won et al., 2007; Bird et al., 2008)

RVFV genome L - 6404 M - 3885 S - 1690 RVFV genomes amplified and

7 RVFV genome L M S RVFV genomes amplified and sequenced using Roche GS technology (ARC-OVI) (Dr Christiaan Potgieter)

8 The Terry Dermody reverse genetics strategy for reovirus

9 The Terry Dermody reverse genetics strategy for reovirus (continued)

10 Experimental vaccines (continued) : Reverse genetics (Bird et al., 2008) Deleted NSs gene alone or with NSm (EGFP-tagged) fully protected rats good DIVA properties (lack of NSm antibodies)

11 Experimental vaccines (continued) : Virus-vectored: Sindbis-replicon vectored (Heise et al., 2009) (Express GP genes : 100% protection in mice, good Nab levels in sheep) Pox-vectored: VV (Collett et al., 1987) & LSDV (Wallace & Viljoen, 2005; Wallace et al., 2006)

12 Advantages of LSDV-vectored vaccines : Vector: live, attenuated, stable, immunity Dual potential: LSDV, SPV, GPV Marker vaccine - DIVA Potential human vaccine? (e.g. rlsdv- RVFV)

13 Lumpy skin disease virus-vectored RVFV experimental vaccine p7.5k RVFV GnGc E.coli gpt p7.5k EGFP p11k TK L TK R

14 X 40 X 100

15 RVFV IgG ELISA and mouse challenge studies Average PP values* /5 5/5 1/5 1/5 #1 #2 #3 #4 RVFV SB vaccine rlsdv -RVFV rlsdv -BEFV Saline control POST-CHALLENGE SURVIVAL RATE Day 0 Day 21 Day 31 * percentage positive of SB positive control

16 rlsdv-rvfv challenge trial in sheep Temperature reactions TEMPERATURE ( C ) TIME (Days post challenge) #760 (rlsdv - 7 log) #680 (rlsdv - 7log) #841 (rlsdv - 7log) #662 (PBS) #959 (OBP RVFV vac) #957 (OBP RVFV vac) #674 (PBS) #677 (rlsdv - 6log) #667 (rlsdv - 6log)

17 rlsdv-rvfv challenge trial in sheep RVFV-specific antibodies PP values TIME (days post-vaccination) #667 ( rlsdv - 6log) #677 (rlsdv -6log) #760 (rlsdv - 7log) #680 (rlsdv - 7log) #841 (rlsdv - 7log) #674 (PBS) #662 (PBS) #959 (OBP RVFV vac) #957 (OBP RVFV vac)

18 Current work : - Removal of selection marker genes (GALVmed funded) - Removal of putative immunomodulatory genes (ourselves and CIRAD) - Planning combined animal trials

19 Conclusion : - Many different types of new vaccines and delivery systems (e.g. plants, VEE, canarypox) - New technologies (e.g. nanoparticles) - New generation adjuvants - Likely that more than one will require full development due to differing needs (e.g. governmental policies etc.)

20 FIN! Acknowledgements: Dr Bjorn Reininghaus for photo in opening slide Dr Christiaan Potgieter slides and helpful discussions ARC-OVI Directorate funding for attendance at this meeting

21 POX-VECTORED VACCINES? Use of a poxvirus (e.g. LSDV) as a vehicle for the expression of immunogenic proteins of a pathogen in specific target animals to confer protection against the pathogen. LSDV expressing the F and HA genes of RPV dual protection (Romero et al., 2003)

22 Important considerations : - Efficacy (saftey in animals/humans, recombinantion/revertence) - Type and duration of immunity - DIVA (marker vaccine) - Geographical region (indigenous vs exotic)

23 3.2 million cattle with LSD in Egypt in deaths.

24 A solution: LSDV developed as vaccine vector SA OBP vaccine strain proven track-record. Good results in animal trials (e.g. rlsdv- RVFV)

25 Construct description: LSDV SA OBP vaccine Vaccinia virus p7.5k promoter Positive selectable marker gene: gpt Visual marker gene: EGFP

26 Next stage: Remove of putative immunomodulatory genes (for improving immune responses antibody levels, duration etc.)

28 RVFV genomic layout S NC NSs M NSm G2/Gn G1/Gc L L

Revision of the RVF chapter in the OIE Terrestrial Manuel D.Goovaerts, IFAH. Mombasa, November 14 th 2012

Revision of the RVF chapter in the OIE Terrestrial Manuel D.Goovaerts, IFAH Mombasa, November 14 th 2012 Meeting of OIE ad hoc group on RVF Paris meeting October 9-11 th Chapter 2.1.14 of the Manual on