Safety and Immunogenicity of a Parenterally Administered Rotavirus VP8 Subunit Vaccine in Healthy Adults

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1 Safety and Immunogenicity of a Parenterally Administered Rotavirus VP8 Subunit Vaccine in Healthy Adults Stanley Cryz 1, Clayton Harro 2, Monica McNeal 3, Nicole Meyer 3, Barbara DeNearing 2, Alicia Cage 2, Denise Adams 2, George Robertson 1, Jorge Flores 1, John Boslego 1 and Alan Fix 1 1 PATH, Washington, DC, USA 2 Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA 3 Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio, USA

2 Rationale for Non-replicating Rotavirus Vaccine (NRRV) Project Slide 2 Currently licensed oral live, rotavirus vaccines offer great benefit to developing country populations but are relatively costly and have reduced efficacy in those populations (~50%) compared to >90% in high income settings Rotavirus VP8 subunit candidate: - May provide superior efficacy in target populations - Projected to be less expensive (<$1 per dose) - May be combined with EPI vaccines, facilitating delivery and further reducing costs. Focus on the ability of immunization to elicit a rotavirus neutralizing antibody response as passive transfer of such antibodies can provide protection

3 Page 3 Characteristics of P2-VP8 Vaccine Developed at US NIH by Dr. Yasutaka Hoshino Truncated VP8 subunit from human Wa strain (G1P[8]) fused to the tetanus toxin P2 CD4 epitope Expressed in E. coli Simple 3 step purification process results in high yields No unexpected toxicity in rabbits at doses up to 60 µg Non-pyrogenic Schematic diagram of rotavirus VP4 protein ΔVP8* Fusion domain Liquid formulation, adsorbed to aluminum hydroxide Elicits homotypic and heterotypic anti-[p] antibodies that neutralize P[8] and P[4] rotavirus strains Hsc70 binding site

4 VAC 009 A Phase 1 Double-blinded, Randomized, Placebo-controlled Dose Escalation Study to Examine the Safety, Reactogenicity, Tolerability and Immunogenicity of the P2- VP8 Subunit Rotavirus Vaccine in Healthy Adult Volunteers First-in-human testing of the P2-VP8 subunit rotavirus vaccine Enrollment: Dec 2012 Feb 2013 Page 4

5 VAC 009 Study Schema Cohort Dosing Groups N Page µg vaccine with Al(OH) 3 12 Placebo 4 30 µg vaccine with Al(OH) 3 12 Placebo 4 60 µg vaccine with Al(OH) 3 12 Placebo 4 Total Vaccine Schedule: Days 0, 28 and vaccine 12 placebo

6 Highest Level of Any Reactogenicity per Subject (Local and Systemic Combined) Mild Moderate Severe Any Placebo 3 (25.0) 2 (16.7) 0 5 (41.7) 10 µg 7 (58.3) 2 (16.7) 0 9 (75.0) 30 µg 6 (50.0) (50.0) 60 µg 6 (50.0) 2 (16.7) 0 8 (67.7) Page 6

7 Anti-P2-VP8 IgG EIA Titers Vertical lines represent GMT & corresponding 95% CI Page 7 Proportion of responses >4-fold

8 Anti-P2-VP8 IgA EIA Titers Vertical lines represent GMT & corresponding 95% CI Page 8 Proportion of responses >4-fold

9 Neutralizing Antibody Response to Rotavirus Strains Expressing P4, P6, or P8 Serotypes* 10µg 30µg 60µg Strain P-type Wa P WI DS SC ST BRD *Response defined as a 4-fold rise in titer following third dose of vaccine Page 9

10 Neutralizing Antibody Response to Wa Strain by Baseline Titer Baseline Titer to Wa N Post-vaccination response (>4-fold rise) N (%) < (83) (63) > (0) Page 10

11 Antibodies in Lymphocyte Supernatant Responses (7 days post first vaccination) Treatment Arm IgA IgG Placebo µg 4 (33.3%) 3 (25.0%) 30 µg 5 (41.7%) 3 (25.0%) 60 µg 8 (67.7%) 4 (33.3%) Page 11 All baseline IgA and IgG titers were below the limit of detection

12 Conclusions from Phase 1 Trial Vaccine safe and well tolerated Vaccine elicits a robust neutralizing antibody response to several homologous P[8] strains of rotavirus modest response to P[4] strains and a meager to P[6] strains Trivalent P2- VP8-P[4/6/8] vaccine will be required to provide broad protective response against P serotypes most frequently isolated in the field Response rates lower in those with high levels of pre-existing antibody Performance of the vaccine in immunologically naïve subjects remains to be determined Slide 12

13 Additional Clinical Studies Underway Phase I/II descending-age, dose-escalation trial in South African toddlers and infants initiated March 2014 with P2-VP8-P[8] vaccine Safety Immunogenicity Impact of immunization on Rotarix shedding Progress to date Toddlers immunized with a single 10, 30 or 60ug dose of vaccine. Infants currently being immunized with 10 and 30ug dose level of vaccine Page 13

14 Future Studies Planned Trivalent P2-VP8-P[4]/P[6]/P[8] produced and undergoing toxicology testing. Clinical trials planned for mid-2015 pending positive outcome from ongoing Phase I/II monovalent trial. Page 14

15 Acknowledgments JHSPH Center for Immunization Research Clayton Harro Barbara DeNearing Alicia Cage Denise Adams JHSPH Enterics Laboratory David Sack Subhra Chakraborty Cincinnati Children s Hospital Medical Center Monica McNeal Nicole Meyer PATH Alan Fix Jorge Flores George Robertson Heather Wenzel Maureen Power Allison Stanfill John Boslego Page 15

16 Acknowledgments Medical Research Council: Respiratory and Meningeal Pathogens Research Unit, University of the Witwatersrand, Johannesburg, South Africa Funding from the Bill & Melinda Gates Foundation Michelle Groome Page 16

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18 Page 18 Backup Slides

19 Highest Level of Local Reactogenicity per Subject Severity Mild Moderate Severe Any Placebo 4 (33.3) 1 (8.3) 0 5 (41.7) 10 µg 7 (58.3) 1 (8.3) 0 8 (66.7) 30 µg 5 (41.7) (41.7) 60 µg 7 (58.3) 1 (8.3) 0 8 (66.7) Page 19

20 Highest Level of Systemic Reactogenicity per Subject Severity Mild Moderate Severe Any Placebo 1 (8.3) 1 (8.3) 0 2 (16.7) 10 µg 6 (50.0) 1 (8.3) 0 7 (58.3) 30 µg 3 (25.0) (25.0) 60 µg 5 (41.7) 1 (8.3) 0 6 (50.0) Page 20

21 Maximum Injection Site Reactogenicity per Participant Severity Pain Tenderness Itching Redness Swelling N (%) N (%) N (%) N (%) N (%) Placebo None 10 (83.3) 8 (66.7) 9 (75.0) 11 (91.7) 11 (91.7) Mild 1 (8.3) 3 (25.0) 3 (25.0) 1 (8.3) 0 Moderate 1 (8.3) 1 (8.3) (8.3) 10 µg None 7 (58.3) 5 (41.7) 11 (91.7) 11 (91.7) 10 (83.3) Mild 4 (33.3) 6 (50.0) 1 (8.3) 1 (8.3) 2 (16.7) Moderate 1 (8.3) 1 (8.3) µg None 10 (83.3) 7 (58.3) 11 (91.7) 11 (91.7) 10 (83.3) Mild 2 (16.7) 5 (41.7) 1 (8.3) 1 (8.3) 2 (16.7) Moderate µg None 8 (66.7) 11 (91.7) 9 (75.0) 10 (83.3) Mild 3 (25.0) 8 (66.7) 1 (8.3) 3 (25.0) 2 (16.7) Moderate 1 (8.3) Page 21

22 Maximum Systemic Reactogenicity per Participant Severity Page 22 Fever N (%) Nausea N (%) Vomiting N (%) Arthralgia N (%) Chills N (%) Fatigue N (%) Headache N (%) Myalgia N (%) Placebo None 12 (100) 10 (83.3) 12 (100) 10 (83.3) 11 (91.7) 10 (83.3) 10 (83.3) 11 (91.7) Mild 0 2 (16.7) 0 2 (16.7) 1 (8.3) 1 (8.3) 2 (16.7) 1 (8.3) Moderate (8.3) µg None 12 (100) 11 (91.7) 11 (91.7) 11 (91.7) 11 (91.7) 10 (83.3) 10 (83.3) 10 (83.3) Mild 0 1 (8.3) 1 (8.3) 1 (8.3) 1 (8.3) 1 (8.3) 2 (16.7) 2 (16.7) Moderate (8.3) µg None 12 (100) 12 (100) 12 (100) 11 (91.7) 11 (91.7) 11 (91.7) 10 (83.3) 11 (91.7) Mild (8.3) 1 (8.3) 1 (8.3) 2 (16.7) 1 (8.3) Moderate µg None 12 (100) 10 (83.3) 12 (100) 9 (75.0) 11 (91.7) 10 (83.3) 9 (75.0) 9 (75.0) Mild 0 2 (16.7) 0 3 (25.0) 1 (8.3) 1 (8.3) 3 (25.0) 3 (25.0) Moderate (8.3) 0 0