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Development of Advanced Adjuvants and Immune Modulators

This research focuses on the development of advanced adjuvants and immune modulators to enhance innate and adaptive immunity. The study investigates cationic peptides and their role in host defense mechanisms, with a diverse range of peptides known to have antimicrobial, immunomodulatory, and anti-biofilm activities. New immunomodulatory peptides show broad protection against various infectious diseases in mouse models. The research also explores the use of adjuvants to stimulate protective immunity while suppressing harmful inflammation.

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Development of Advanced Adjuvants and Immune Modulators

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  1. Development of Advanced Adjuvants and Immune Modulators R.E.W. (Bob) Hancock, Centre for Microbial Diseases and Immunity Research, University of British Columbia

  2. 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, immunomodulatoryand anti-biofilm activities; “Host Defence” peptides. • Modulate Innate & Adaptive Immunity

  3. New immunomodulatory peptides show broad protection in Mouse Model Infections Invasive Staph. aureus Mouse Model MDR -TB Mouse Model Cerebral Malaria Mouse Model PLoS One 8:e59119, 2013 Science Transl. Med. 4:135ra64, 2012 IDR 1018: VRLIVAVRIWRR-NH2 ● PBS ■ IDR-1018 Science Transl. Med. 4:135ra64, 2012 Also protects vs. E. coli, Salmonella, Klebsiella, Pseudomonas, MRSA, VRE, Pox & HSV viruses IBD,CF, Sterile inflammation; LPS/hypoxia-ischemia  Wound Healing In mice & pigs PLoS One 7:e39373, 2012 Time (days) Lars Steinstraesser, Louis Schofield, Ariel Achtman, Bruno Rivas, Rogelio Hernandez Pando, Carina Mallard

  4. Protective Immunity  Harmful Inflammation  Intranasal delivery (Single dose)Pseudomonas aeruginosa lung infections Peptides work by stimulating protective immunity while suppressing potentially harmful inflammation

  5. 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 overlap • Mechanisms still not well understood but: • Adjuvants can either • Act as a depot (focus) • Recruit Immune cells • Activate Immune Cells TLR4 to NFB interactome

  6. Need for affordable adjuvants Adjuvant platform should cost pennies per dose!

  7. 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 • New prime boost regimens show only partial protection Vaccination Site Ivory Coast Volker Gerdts, Lorne Babiuk, Bob Hancock and many others

  8. IDR Peptide CpG ODN Polyphosphazene; PP Triple adjuvant combination gives the potential for single dose protection vs. pertussis High Titre Mixed Th1, Th2 Single Dose Protective Pigs, Cattle, Mice 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) Depot Mouse dose 0.6 g CpG, 1.2 g HDP, 0.6 g Polyphosphazene Antigen Sparing Activate Recruit

  9. Features of the Adjuvant Formulation Duration of immunity > 2 years (mice)>10 months in pigs Comparison to Alum (2 different doses) Protective – Neonatal pigs Works mucosally at very low doses Vaccination OVA plus 0.6 g CpG, 1.2 g HDP, 0.6 g Polyphosphazene

  10. Acknowledgements Lab: Ana Nijnik, NeelofferMookherjee, Evan Haney, Ashley Hilchie, Kelli Wuerth, Melisssa Elliott, IDR peptide Team; Bioinformatics Team Collaborators: Volker Gerdts, VIDO crew, Scott Halperin, Jun Wang

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