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Development of Advanced Adjuvants and Immune Modulators 100 Therapeutic IDR-1018 + Anti-malarial 10 6 PbA 90 70 % Survival 40,000 p = 0.034 80 30,000 d0 4 days (Par 3-6%) 60 Anti-malarial Control Peptide Pyrimethamine + Chloroquine in drinking water 50 40 Immunize 20,000 30 10,000 20 1018 or IDR-1 d 4, 5, 6 10 No Treatment 0 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Day 0 Days post-infection R.E.W. (Bob) Hancock, Centre for Microbial Diseases and Immunity Research, University of British Columbia Day 22 Cationic Peptides Birds do it, bees do it, even educated fleas do it.... Cole Porter Important host defense mechanism in all complex species of life. >1000 peptides known. Diverse amino acid sequences and structures. 12 to 40 (or more) amino acids. Net charge +2 to +9 (Lys; Arg). Amphipathic. Role in Innate Immunity involves antimicrobial, immunomodulatory and antibiofilm activities; “Host Defence” peptides. Modulate Innate & Adaptive Immunity virulent live MTb strain H37Rv . After 2 months of infection, treatment via New immunomodulatory peptides show IT: 32 g (~1 mg/kg) peptides every 2 days. broad protection in Mouse Model Infections Groups of 5 animals sacrificed after 4 wks of treatment Invasive Staph. aureus Mouse Model and lung bacilli counted. MDR -TB Mouse Model Cerebral Malaria Mouse Model 100 PLoS One 8:e59119, 2013 p = 0.034 80 Science Transl. Med. 4:135ra64, 2012 70 % Survival Works vs. H37Rv & MDR TB strains. d0 4 days (Par 3-6%) 60 Anti-malarial Control Peptide Pyrimethamine + Chloroquine in drinking water 50 40 30 20 1018 or IDR-1 d 4, 5, 6 10 ● PBS ■ IDR-1018 Therapeutic IDR-1018 + Anti-malarial 10 6 PbA 90 IDR 1018: VRLIVAVRIWRR-NH2 No Treatment 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Days post-infection Science Transl. Med. 4:135ra64, 2012 Also protects vs. E. coli, Salmonella, Klebsiella, Pseudomonas, MRSA, In mice & pigs VRE, Pox & HSV viruses Bruno Rivas Rogelio PLoS One and 7:e39373, 2012 Hernandez Pando, UNA de México IBD, CF, Sterile inflammation; Time (days) LPS/hypoxia-ischemia Wound Healing Lars Steinstraesser, Louis Schofield, Ariel Achtman, Bruno Rivas, Rogelio Hernandez Pando, Carina Mallard Intranasal delivery (Single dose) Pseudomonas aeruginosa lung infections * (p = 0 .0 1 7 ) T N F a ( p g /m l) in B A L F 6 4 2 80 Harmful Inflammation 60 40 20 ) g ) /k g g m g (4 2 (2 0 1 0 0 1 0 1 0 0 2 + 1 0 0 2 2 u e s P m m (1 o d o d u e s P /k /k g a n o m g r te s a s a n o m ) 0 0 W L o g 1 0 C F U /m l Protective Immunity 100 8 Peptides work by stimulating protective immunity while suppressing potentially harmful inflammation Adjuvants and Immunity Adaptive immunity is antigen-specific, requires gene rearrangements and thus is slow to develop (days to weeks) and can discriminate between self and non self. Exploited with Vaccines Innate immunity fast acting and relatively non-specific. Exploited using immune modulators and adjuvants But “Innate immunity instructs adaptive immunity” & effectors TLR4 to NFB interactome overlap Mechanisms still not well understood but: Adjuvants can either Act as a depot (focus) Recruit Immune cells Activate Immune Cells Node Interaction Need for affordable adjuvants Adjuvant platform should cost pennies per dose! Roadblocks to Effective Vaccines Need for multiple dosing (e.g. 3-5 doses for DPT); Reduces compliance; Delays protection. Maternal interference Current adjuvants like Alum are biased to Th2 responses Neonates respond poorly Vaccination Site Ivory Coast New prime boost regimens show only partial protection Volker Gerdts, Lorne Babiuk, Bob Hancock and many others Triple adjuvant combination gives the potential for single dose protection vs. pertussis 40,000 30,000 20,000 High Titre Mixed Th1, Th2 Single Dose Protective Pigs, Cattle, Mice Immunize Works in Neonates Long duration PTd & PP & CpG-C & HH2 PTd & PP & CpG-C & HH2 Ptd = pertussis toxoid e.g. Vaccine 31:3148-55, 2013 Also works with RSV, Flu, Chlamydia prime-boost PTd & PP & CpG-C PTd & PP PTd & CpG-C PTd & HH2 PTd (pertussis toxoid alone) 10,000 0 Activate Day 0 CpG ODN Depot Mouse dose Day 22 Polyphosphazene; PP Recruit IDR Peptide 0.6 g CpG, 1.2 g HDP, 0.6 g Polyphosphazene Antigen Sparing Features of the Adjuvant Formulation Duration of immunity > 2 years (mice) >10 months in pigs Comparison to Alum (2 different doses) 1.0×10 6 IgG2a Antibody Titre IgG2a Antibody Titre 1.0×10 6 1.0×10 5 1.0×10 4 1.0×10 3 1.0×10 2 1.0×10 1 * 1.0×10 4 * 1.0×10 3 2 4 8 12 16 19 22 26 30 34 38 42 52 61 68 76 85 90 1.0×10 2 Weeks Bacterial burden day 2 Protective – Neonatal pigs 2 4 6 8 10 12 14 200000 150000 100000 50000 bo Tr ip le co m ra ce l ua d Q on tr ol 0 C 19 Weeks * 250000 16 Works mucosally at very low doses * cfu per total lung lesion 1.0×10 5 Vaccination OVA plus 0.6 g CpG, 1.2 g HDP, 0.6 g Polyphosphazene Acknowledgements Lab: Ana Nijnik, Neeloffer Mookherjee, Evan Haney, Ashley Hilchie, Kelli Wuerth, Melisssa Elliott, IDR peptide Team; Bioinformatics Team Collaborators: Volker Gerdts, VIDO crew, Scott Halperin, Jun Wang