Dr Hannah Kibuuka Makerere University Walter Reed Project Presentation at the Uganda Medical Association-Uganda Veterinary Association joint conference. Theme: “Disease Eradication, What Will It Take?”

 Rationale and challenges for Vaccine development  Strategies and vaccine platforms  Clinical trials on filovirus vaccines  Conclusion

 Ebola and Marburg viruses cause geographically unpredictable and sporadic highly fatal disease outbreaks  Case-fatality rates as high as 90%  Are classified as Category A Bioterrorism agents  No Known cure for infection  Uganda has experienced multiple out breaks since 2000

 Different species of Ebola virus  Sporadic and geographically diverse occurrence of outbreaks? Who is the target population for vaccination?  Fully understanding the correlates of protection  Difficulties in establishing traditional clinical trials in the setting  “Animal use” model to conduct efficacy trials  Limited Interest in industry sponsored studies

 Vaccine given in outbreak situations  Preventive vaccine( prophylactic)  Post exposure treatment  Ideally given as a single immunisation with ability to induce durable immune responses  Prophylactic vaccine platform  Given to first responders, lab personnel, military personnel, international aid workers that respond to disease outbreaks, frontline hospital staff

Replication- competent vectored vaccine  Recombinant Vesicular Stomatitis, Recombinant Human parainfluenza virus 3  Have only been tested in animal models  Have shown efficacy in animal models as prophylactic vaccine and post exposure treatment  Induction of more durable and longer lasting responses  Require fewer immunisations to confer protection  Challenge: Safety of the vaccines particularly in Immuno-compromised individuals

 DNA Vaccines  Tested in animal models and only vaccines tested in clinical trials  Safety profile in clinical trials, given in multiple doses  Ability to induce humoral and cellular immunity  Has less than desirable immunogenicity when used alone  Best used in a prime-boost strategy as a platform for prophylactic vaccine

 Combined DNA/rAd5  Offered 100% protection from ZEBOV and Marburg viremia in non-human primates  Elicits Broad immune responses  With multiple species for Ebola, a multivalent or blended vaccine is desirable  Recent report that a combination expressing ZEBOV and SEBOV provided 100% against a challenge with BEBOV in non human primates  Challenge: Long course of vaccination

 Recombinant Ad 5 vaccine  A single vaccination has provided protection and survival in non human primates therefore more suitable for outbreak response  Challenge: Effect of pre-existing immunity to vaccine efficacy  Different adenovirus serotypes are being tested.  Other modes of delivery such as oral or nasal vaccination  Venezuelan equine encephalitis virus and virus like particles

YrStudy designVaccines#Site Phase 1 Randomised double blinded, placebo controlled, dose escalation Ebola DNA plasmid -- GP from Zaire and Sudan/Gulu Species Nucleoprotein 27USA Open label Phase I Ebola DNA plasmid- WT GP from Zaire & Sudan/Gulu Marburg DNA -WT GP/ Angolan strain 20USA Phase I b Randomised placebo controlled As above, Administered separately or concurrently 108Uganda

 Although several vaccine candidates have been tested in animal studies, only a few have been tested in clinical trials.  DNA Vaccines  have immunogenicity that is less desirable when administered alone  Adding rAd boost enhances its utility  Multiple dosages of DNA/rAd are impractical for outbreaks but regimen is useful for vaccination of individuals with high exposure risk  Development of a vaccine for use in outbreaks is key for endemic countries