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VIRUS ALERT! EBOLA: Will we be safe?

One Year Ago • • 1 victim Vector Symptoms Mode of Infection

Previous Breakouts • 13, 676 • 7606 • 4910

Development • c. Ad 3 -ZEBOV – Chimp Adenovirus type 3 • VSV-EBOV – Vesicular Stomatitis Virus • ZMapp

Underlying Mechanisms

Underlying Mechanism: r. VSVEBOV • r. VSV – recombinant vesicular stomatitis virus-based vaccine • Live-attenuated • Animal virus, asymptomatic in humans • Favorable features: – Replication in all mammalian cell lines – High titres – Strong induction of innate and adaptive immunity – Low levels of pre-existing immunity to VSV in general population

r. VSV vaccine 1. Removal of VSV glycoprotein (G) gene (r. VSVΔG) 2. Insertion of Ebola virus (EBOV) glycoproteins (r. VSV/EBOV-GP) 3. Tranfection of VSV genomic plasmid and expression plasmids in cell culture 4. Production of recombinant VSV proteins N – nucleoprotein P - phosphoprotein L – polymerase

Underlying Mechanism: c. Ad 3 EBO Z • c. Ad 3 - Recombinant Chimpanzee Adenovirus Serotype 3 Vectored Ebola Vaccine • Non-replicating vector • Use of chimpanzee adenovirus—little pre-existing immunity • Two types – Monovalent (Zaire strain) – Bivalent (Zaire and Sudan strains)

c. Ad 3 vaccine 1. Removal of E 1 gene and deletion of E 4 gene 2. Insertion of Ebola virus (EBOV) glycoprotein (EBOV -GP) 3. Transfection of c. Ad 3 genomic plasmid and expression plasmids in cell culture 4. Production of recombinant adenoviral proteins

Dosage

Dosage • r. VSV – 2 x 105 PU to 2 x 107 PU has been seen to mount a strong immune response in NHP (up to 9 months) • c. Ad 3 – Monovalent - 1× 1010 vp, 2. 5× 1010 vp, and 5× 1010 vp – Bivalent – 2 x 1010 PU and 2 x 1011 PU • Boosters not possible for c. Ad 3; questionable for r. VSV • However, a single dose may confer longterm immunity

The Companies Who’s working on this?

GSK • Europe & USA: Have already started trials on human volunteers • Vaccine used: Ch. Ad 3 • Virus altered: Adenovirus • Developed by NIAID

Human Efficacy Trials • Focus countries: Liberia & Sierra Leone • Guinea also hard-hit, but trials not possible due to poorly developed infrastructure • Focus people: Healthcare workers and first-line responders • WHO estimate: 12000 healthcare workers, 17500 first-line responders in above three countries

Human Efficacy Trials • Liberia: the largest project; 12000 individuals • Randomised administration: vaccine/placebo • Sierra Leone: parallel project; 8000 individuals • No placebo • Administered to healthcare workers at different points in time

New. Link Genetics • Developed by Public Health Agency of Canada • Vaccine used: VSV-EBOV • Virus modified: Vesicular Stomatitis Virus • NLG working on human trials

Human Trials • 40 volunteers planned • Planned at: Walter Reed Army Institute of Research & National Institutes of Health Clinical Center • Phase 1 in progress • Determining drug safety and proper dosage

Johnson and Johnson • • In collaboration with Bavarian Nordic Two-step vaccine Ready for testing in early 2015 Has been announced only

Crude Cost Estimates Norwegian Institute of Public Health 27 million doses = $73 million est Campaigning = $78 million est New. Link Genetics put in $200 million to speed up the research • Could cause another spike in prices due to competition • •

Clinical Trials Race against time?

Clinical Trials: c. Ad 3 -EBO Z 1 st Trial -> August 2014. 2 nd Trial -> September 2014. 3 rd Trial -> Mali, October 2014 Phase 1 (official title describes it to be in Phase 1 -B) All studies are in early stages

Clinical Trials: c. Ad 3 -EBO Z The study that began in August was to see if the vaccine was safe for humans 2 experimental groups; both given different doses The study in Mali has begun and 3 people were infected with vaccine, people in US and 40 people from Gambia will also be taking part (2 experimental groups with different doses) The third study from September will have 3 groups of 20, given different doses

Clinical Trials: VSV-EBOV Phase 1 Clinical trial for VSV-EBOV was launched in US in September 20 vials were sent to US for testing On October 20 th 800 -1000 vials were sent to Geneva along with additional funding If this phase proves to be successful then the next phase is to be carried out in west Africa Results of this trial phase are expected in December 2014

Clinical Trials: Issues Last week of September -> meeting to discuss the best way to speed up clinical trials and overcome hurdles. Practical issues that were singled out were: Keeping the vaccine at proper temperature Getting proper staffing and funding To speed things up they changed study designs and deployed already available vaccine to workers Everything said and done—a big enough dose won't be ready till the first quarter of 2015, and Phase II trials will also begin around that time.

Questions? Prepared By GROUP 4 Aizaz Izzat Ghazia Abbas Muhammad Hassan Rizvi Rabia Anjum