Dr Olga Pleguezuelos CSO and Project Manager at SEEK

Transcription

1 Dr Olga Pleguezuelos CSO and Project Manager at SEEK

2 Imutex Limited, formed in 2016, is a joint venture between SEEK Group and hvivo to accelerate the development of a Mosquito Vaccine (AGS-v) and Broad- Spectrum Influenza Vaccine (FLU-v). SEEK and hvivo each have in excess of 15 years experience in the fields of immunology, infectious diseases, vaccines, clinical trials and human models. 2

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4 No risk of genetic integration or recombination. Cost effective large scale purification Absence of infectious material Ability to exclude regions associated with toxicity or autoimmune recognition Easy characterization by well established analytical techniques (HPLC/MS) Freeze drying avoids cold-chain during storage and transport Amplify conserved and immune regions in protein

5 Aim: rapid identification of conserved immunoreactive antigens. Epitope prediction: T cell reactive epitopes predicted using 16 different parameters to assess reactivity including crystallography, charges, Van der Waals forces, shapes, length and chemical interactions. Peptide selection based on: conservation (>70%) multiple predicted T cell epitopes for several human HLAs approx <40 aa long no similarity to other human or murine proteins manufacturing feasibility

6 Complex manufacturing, limited number of doses available, only those at risk are vaccinated. Ineffective antiviral treatment due to development of resistance. Disease burden: (~1 billion cases of flu, ~3 5 million cases of severe illness and 300K 500K deaths annually worldwide) Low efficacy when circulating strains and vaccine strains are not matched Economic burden: lost work force and strained health system. Influenza virus is highly variable requiring development of a new vaccine annually. 6

7 Universal Vaccine Goals Provides cross-protection against broad range of influenza strains. Decreases symptomatology. Reduces hospitalisations. Remains the same year after year allowing all year round manufacturing. Less complex and cost-effective manufacturing so larger population can be vaccinated. 7

8 FLU-v is composed of an equimolar mix of 4 peptides (FLU-5, FLU-7, FLU-8N, FLU-10) which cover conserved T cell reactive regions in M1, M2 and NP influenza proteins. A dose of 500ug contains 50nmol of each peptide in a sterile glass vial (no excipients). The final product is a lyophilised sterile mix that will need reconstitution prior subcutaneous injection (either as emulsion in oily adjuvant (Montanide ISA-51, Seppic) or as a non adjuvanted suspension.

9 A phase I (N=32) and phase Ib (N=48) showed FLU-v was safe and well tolerated. A single dose of FLU-v induced specific dose dependent cellular immunity in humans. Vaccination with a single dose of adjuvanted FLU-v followed by challenge with live influenza H3N2 strain resulted in reduction of viral titre and clinical symptom score that correlated with IFNγ production. The immune response to FLU-v showed cross-reactivity reactivity in vitro to different influenza strains (A/Swine H1N1, A/Duck H3N8 and A/New Caledonia H1N1). Results published in Vaccine (2012) 30: , Clinical and Vaccine Immunology (2015)22: and Clinical and Vaccine Immunology (2015) 22:

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13 EU funded, UNISEC Consortium A randomised, double-blind, placebo-controlled, singlecentre phase IIb trial (healthy adults 18-60) Treatment arms: 1 dose FLU-v adjuvanted (n=74) 2 doses FLU-v non-adjuvanted 21 days apart (n=74) 1 dose Adjuvanted Placebo (n=37) 2 doses Non-adjuvanted placebo (n=37) Trial Locations: Clinical Site: Isala, Zwolle, The Netherlands, External Laboratories: RKI (Germany), NIPH (Norway), UMCG (The Netherlands)

14 5 visits: Visit 1(day -7 to day-2): screening Visit 2 (day 0): randomisation, baseline blood sample and vaccination 1 Visit 3 (day 21): vaccination 2 & review of AEs after vaccination 1. Visit 4 (day 42): review of AEs after vaccination 2 and postvaccination blood sample 1 Visit 5 (day 180): post-vaccination blood sample 2 Influenza follow up from 1 st Dec March 2017: Daily online symptom questionnaire followed by swab after sudden onset of at least one respiratory and one systemic symptom. 14

15 Immunogenicity: To evaluate the cellular immune responses at 42 and 180 days as the change in level of TH1 cytokine production from baseline (day 0) following FLU-v vaccination, given as a suspension or as emulsion (adjuvanted), compared to placebo (Flow Cytometry and ELISA). Safety: To evaluate the incidence of solicited AEs in all groups until 21 days after the last dosing of study vaccine. To evaluate the incidence and nature of unsolicited AEs and SAEs in all subjects during the whole study period. (Primary) 15

16 To compare the effects of FLU-v with placebo, given as a suspension or emulsion (adjuvanted) on immune responses as measured using TH2 cytokines (Flow Cytometry) To evaluate the IgG and IgM antibody responses specific to FLU-v at 42 and 180 days from baseline following vaccination (ELISA) 16

17 To assess the effect of previous influenza vaccinations on the immunogenicity of FLU-v. To evaluate the efficacy of FLU-v vaccine in the reduction of the incidence of RT-PCR confirmed influenza A and/or B infection in all subjects during the influenza season To evaluate the efficacy of FLU-v vaccine in the reduction of symptom scores using diary entries and a scoring system among RT-PCR confirmed influenza A and/or B confirmed infections during the influenza season To measure the titer of IgG subclasses in antibody responder samples to determine their functional role. To determine whether immune response to FLU-v is able to cross-recognise five different influenza strains (IFNg+Granzyme B ELISPOT) 17

18 Most common injection related AEs are mild to moderate in severity and include haematoma, heat, swelling, redness, pain, itching and induration at the site of injection. SAEs: Vaccine unrelated as determined by PI, study doctor, medical monitor and pharmacovigilance: Abdominal Hernia surgery: resolved Surgery for skiing shoulder fracture: resolved Surgery for myocardial infarction: resolved Hospitalisation for alcohol abuse and depression: resolved 18

19 Intention to treat: all randomised subjects independently of vaccine administration. N=175 Full Analysis Set: 2 immunisations, blood samples in prevaccination and at least 1 post-vaccination timepoint. N=167 Per Protocol: 2 immunisations, blood samples for all 3 time points, no major Protocol Deviations. N=152 Safety Population: any subject that received at least one immunisation. N=175 Protocol deviations:

20 Partial Blinded-Data was analysed to determine the quality of the data and the robustness of the statistical methods used The analysis of some samples was repeated Rules for sample acceptance under discussion and to be implemented in version 2 of the Statistical Analysis Plan Unblinding planned for 19 th February Statistical Analysis completed by (TBC by Eelko s team) Data report completed by 31 st March 20

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