2.3 Vaccine adjuvants (1).pptx

2.3 Vaccine adjuvants Overview Definition and history Mode of action of old and novel adjuvants Safety  see lecture on vaccine safety Which adjuvant to use when? Some examples 2 What is an adjuvant? “An adjuvant is any substance (or a mixture of substances) that enhances the immune response to...

2.3 Vaccine adjuvants Overview Definition and history Mode of action of old and novel adjuvants Safety  see lecture on vaccine safety Which adjuvant to use when? Some examples 2 What is an adjuvant? “An adjuvant is any substance (or a mixture of substances) that enhances the immune response to an antigen with which it is mixed” Janeway, Immunobiology, 7th Edition “The immunologist’s dirty little secret” C.A. Janeway ‘Approaching the asymptote? Evolution and revolution in immunology’, Cold Spring Harb Symp Quant Biol, 54 Pt 1:1-13, 1989. Polling question Which of the following vaccine types exerts an adjuvant effect? A. Protein vaccine with alum B. Live attenuated vaccine C. Nucleic acid-based vaccine D. All of these E. None of these Polling question Which of the following components has not been evaluated as an adjuvant in the 1920s-1930s? A. Aluminium (Al) B. Lead (Pb) C. Bread crumbs D. Tapioca E. I don’t know From alchemy to rational design 1883 – William Coley Killed bacteria to treat cancer MPL CpG 1925 - Gaston Ramon Inulin Starch, tapioca, agar Fish oil Bark extracts Squalene QS21 1926 - Alexander Glenny Aluminium hydroxide Used ever since… 6 Aluminium salts, the most widely used adjuvant • • • • • Most widely used adjuvants for > 80 years No adjuvant Low cost Aluminium salt Well established safety profile Indirect benefit on antigen stability Do not “work” with all antigens HPV (DNA recombinant) Invasive pneumococcal disease Invasive meningococcal disease DTPa combination based vaccines Hepatitis A (inactivated) Hepatitis B (DNA recombinant) Pertussis (Subunit) Polio (Inactivated) Diphtheria (Toxoid) Tetanus (Toxoid) Pertussis (Inactivated) Yersinia pestis Vibrio Cholerae Salmonella Rabies Smallpox (1789) 19 00 1 19 Aluminium salts 0 2 19 0 3 19 0 4 19 0 5 19 0 19 60 7 19 0 8 19 0 9 19 0 0 20 0 20 10 Adapted from Garçon N, et al. Understanding Modern Vaccines, Perspectives in vaccinology, Vol 1, Amsterdam: Elsevier; 2011; chapter 4: p89-113 7 Why do we need adjuvants? Replicating (live attenuated pathogen) The loss of endogeneous adjuvanticity necessitates the addition of exogenous immune stimulatory agents live attenuated pathogen killed pathogen or fraction of pathogen Subunit Purified antigens Non-replicating (various antigens, (whole inactivated pathogen) (toxoids, split virus, fragments of pathogens) recombinant proteins) immunogenicity Tolerability Immunogenicity Dougan G & Hormaeche C. Vaccine 2006; 24S2:13–19; Garçon N & Van Mechelen M. Expert Rev Vaccines 2011; 10:471–486. What is the desired impact of an adjuvant on a vaccine-induced immune response? Immune response Adjuvanted formulation Stronger/ broader immune response Ideally induced with lower antigen doses Longer-term immune response Non-adjuvanted formulation Earlier immune response Time Modified from Pulendran B & Ahmed R. Cell 2006; 124:849–863. Potential benefits of adjuvants … to fill crucial gaps in modern vaccine development Reed et al. Nature Med 2013; 19: 1597-1608 Challenges for vaccine development Challenges Strategies to overcome these challenges Pathogens Pathogens or or diseases: diseases: Malaria, Malaria, HIV, HIV, tuberculosis, tuberculosis, CMV, CMV, dengue, dengue, RSV, RSV, HCV, HCV, … … Challenging Challenging populations: populations: Hard-to-reach Hard-to-reach individuals, individuals, infants, infants, pregnant pregnant women, women, older older adults, adults, immunocompromised immunocompromised persons, persons, … … Challenging Challenging circumstances: circumstances: Emerging Emerging infections, infections, epidemics, epidemics, pandemics pandemics (MERS, (MERS, Ebola, Ebola, Lassa, Lassa, avian avian influenza, influenza, coronavirus,..), coronavirus,..), therapeutic therapeutic vaccination vaccination New New antigens antigens New New antigen antigen presentation presentation (e.g. (e.g. DNA, DNA, mRNA) mRNA) New New delivery delivery strategies strategies (e.g. (e.g. live live vectors) vectors) New New adjuvants adjuvants Polling question An adjuvanted protein vaccine is least successful in stimulating the following immune cells/mediators A. Antibodies B. CD4 T cells C. CD8 T cells D. Dendritic cells E. I don’t know General mode of action of adjuvants Site of injection (Muscle) Without adjuvant Macrophage Draining lymph node Activated CD4+ Tcell APC Immature DC Periphery/site of infection Naïve B-cell Plasma cell Granulocyte Blood vessel Monocyte With adjuvant Antibodies MHC Antige n Cytokines Pro-inflammatory signals CD4+ T-cell Adjuva Cytokines (improved nt pattern) Memory CD4+ Tcell Memo ry Bcell CD4+ T-cell (diversity impacted) APC, antigen-presenting cell; MHC, major histocompatibility complex; DC, dendritic cell Garçon et al. Chapter 4 in: Garçon et al. Understanding Modern Vaccines, Perspectives in vaccinology, Vol 1, Amsterdam. Elsevier 2011;p89-113 Antibodies (wider profile) General mode of action of adjuvants Site of injection (Muscle) Without adjuvant Macrophage Draining lymph node Activated CD4+ Tcell APC Immature DC Periphery/site of infection Naïve B-cell Plasma cell Granulocyte Blood vessel Monocyte With adjuvant Antibodies MHC CD4+ T-cell Adjuva Cytokines (improved nt pattern) Memory CD4+ Tcell Memo ry Bcell CD4+ T-cell (diversity impacted) APC, antigen-presenting cell; MHC, major histocompatibility complex; DC, dendritic cell Garçon et al. Chapter 4 in: Garçon et al. Understanding Modern Vaccines, Perspectives in vaccinology, Vol 1, Amsterdam. Elsevier 2011;p89-113 Antibodies (wider profile) Model of innate control of adaptive immunity Innate immunity Adaptive immunity Antigen-specific B- and T-cell responses ‘Inflammatory responses’ Min Hours Days Months–Years Naive lymphocytes receive 3 signals upon interaction with APC 1. An antigen signal through the T- or B-cell receptor 2. A co-stimulatory signal - Naive T cells: B7.1 or B7.2 on APC binds to CD28 on T cells - Naive B cells: CD40L on activated T cells binds to CD40 on B cells 3. A cytokine signal Nat Rev Immunol 2014; 14: 719-30 Toll-like receptors: location and ligands Frontiers in Psychiatry. DOI:10.3389/fpsyt.2015.00015 Polling question How many different vaccine adjuvants (incl. alum) are present in licensed vaccines today? A. 7 B. 17 C. 70 D. I don’t know Trade names FYI GSKsystems Bio Adjuvant Systems Novel adjuvant (AS) combine formulation and immune-enhancers Type of formulation/delivery system Aluminium salts AS04 o/w emulsions Hepatitis B virus (in pre-haemodialysisFendrix®) Human papilloma virus (Cervarix®) CpG 1018 TLR-9 agonist Hepatitis B (Heplisav-B) Liposome AS03 Pandemic Influenza (Pandemrix ®, Arepanrix ®) Seasonal Influenz (Fluad®) Immune-enhancers MPL (TLR-4 agonist) AS01 QS-21 (saponin) Plasmodium (Mosquirix ®) VZV (Shingrix ®) RSV preF3 (Arexvy®) Tocopherol (AS02) AS adjuvant systems are registered trade marks of the GlaxoSmithKline group of companies MF59 (Plasmodium (Malaria)) Matrix-M SARS-CoV-2 (Novavax®) Polling question What is the mechanism of action of alum as a vaccine adjuvant? A. A depot effect B. Better uptake of the antigen by APC C. Induction of danger signals D. All of the above E. I don’t know Mechanism of action of aluminium salts slow antigen release  maintains antibody levels 2. Uptake of particulate matter - - 3. Induction of danger signals • Alum induces cell death • The damaged host cells release genomic DNA and uric acid as DAMPs • Alum stimulates macrophages and DCs to produce NLRP3 inflammasome-dependent IL-1β and IL-18 • These cytokines contribute to acute inflammation DAMP: danger-associated molecular pattern DC: dendritic cell NLRP3: NOD-like receptor family pyrin repeat 3 Adapted from Kuroda et al. Int Rev Immunol 2013;32:209 + + -+ -+ --+-++ + -+ + -+ ++ +-- ++ + -- 1. DEPOT effect  desorption by acids - Lactic acid Citric acid Malic acid ++ + ++ - ++ + - ++ + Characteristics of aluminium salts PRO’s Induction of antibodies and type 2 helper T cells (Th2) humoral immune responses to bacterial toxoids and other antigens Good track record of safety Low cost CON’s Do not show adjuvant effect with all antigens Generate only limited CMI, limits their usefulness Freezing destroys alum-containing vaccines. Kool et al. J Med Microbiol 2012; 61: 927-34 All vaccines have adjuvant effect, either exogenous or “built in” Modulation of the innate immune system: Via pattern recognition receptors but also through tissue damage, cell death and various metabolic and nutrient sensors Pulendran B. Nature Rev Drug Discov 2021; 20: 454-75 FYI: Mode of action of adjuvants is being unravelled (‘known knows’), but many aspects remain poorly understood (‘known unknowns’) Pulendran B. Nature Rev Drug Discov 2021; 20: 454-75 The elucidation of the adjuvant effect of mRNA vaccines (1/2) 47% vaccine efficacy Unmodified mRNA vaccine, 12 µg per dose - Rcognized by TLR 3, 7, 8, RIG-I  strong induction of Type I interferon - Consequences: - High reactogenicity - Low immunogenicity due to low translation efficiency Kobiyama et l. Nat Immunol 2022; 23: 472Li et al. Nat Immunol 2022; 23: 543-55 The elucidation of the adjuvant effect of mRNA vaccines (2/2) Modified mRNA vaccines, 30 µg per dose (Pfizer) or 100 µg (50 µg for booster) per dose (Moderna) - mRNA: - Modification: methylation of cytosine, adenine, uridine in the mRNA  ↓ innate immune recognition of the mRNA - - Adjuvant effect: e.g. recognized by MDA-5  Type I IFN  CD8+ T cells LNP: - Nanoparticle that mimics the virus’ size and behaviour - Delivery into the cells and protection of mRNA - Adjuvant effect: e.g. IL-1, IL-6  TFH and BGC cells TFH : follicular helper T cells BGC : germinal center B cells Kobiyama et l. Nat Immunol 2022; 23: 472Li et al. Nat Immunol 2022; 23: 543-55 Among all the possibilities, how is an adjuvant selected? Understand: Understand: •• Type Type of of response response needed needed (knowledge (knowledge on on the the targeted targeted disease) disease) •• Antigen Antigen to to be be produced produced •• Optimised Optimised immunological immunological tools tools to to follow follow the the vaccine vaccine response response Identify Identify need need for for adjuvant adjuvant In In case case classical classical aluminium aluminium not not sufficient, sufficient, consider consider other other adjuvants adjuvants based based on: on: Compatibility Compatibility with with antigen? antigen? Stability Stability over over time? time? Expected Expected immune immune response? response? Safety Safety and and reactogenicity? reactogenicity? Leroux-Roels et al., in: Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1, Amsterdam, Elsevier, 2011, chapter 5 pp. 115–50 26 Comparative study of several adjuvant systems versus alum = ½ AS01B 291 healthy HBV-naïve individuals 18-45 years old HBs Ag + 1 of 5 adjuvants (1:1:1:1:1) Burny et al. Front Immunol 2017; doi: 10.3389/fimmu.2017.00 Challenges for vaccine development Pathogen-related challenges Population-related challenges Older adults immunosenes cence Immune evasion, intracellular infection Complex life cycle, latent disease Multiple sero/genoty pes Induce protection Reduce dose Overcome weakness Short duration of protection Immunosuppressed: reduced response/live vaccines contraindicated Induce Increase Broaden Prolong Chronic disease reduced response Antigenic drift Moderate, limited efficacy Pregnant women Infants – immate immune system Adapted from Nathalie Garçon Example: pandemic influenza vaccine Seasonal influenza vaccine: 15 mg/strain 1 vaccine = >1 egg per person Pathogen related challenges Population related challenges Older adults immunosenes cence Immune evasion, intracellular infection Complex life cycle, latent disease Multiple sero/genoty pes Induce protection Reduce dose Overcome weakness Short duration of protection Immunosuppressed: reduced response/live vaccines contraindicated Induce Increase Broaden Prolong Chronic disease reduced response Antigenic drift Moderate, limited efficacy Pregnant women Infants – immate immune system H5N1 avian influenza virus was a pandemic threat ~15 years ago AS03: Oil in water (o/w) emulsions Two vaccine doses on day 0 en 21 (H5N1 A/Vietnam/1194/04 split virus) + Squalene + a-Tocopherol Selected formulation 3.8 mg + AS03 100 3.8 µg H5N1 Seroconversion rate (%) 7.5 µg H5N1 15 µg H5N1 75 50 40 30 µg H5N1 EMA registration criterion 0 Post dose 1 • Droplets of oil in water, stabilized with surfactant • Most contain squalene, a 7.5 µg H5N1/AS03A natural organic oil, the 15 µg H5N1/AS03A precursor for the biosynthesis of several 30 µg H5N1/AS03A steroid hormones, vitamin D and cholesterol • Surfactant used are polysorbate 80 (Tween) and Span 85 • a-tocopherol is a Vit E derivative which exerts an immune enhancing effect Leroux-Roels I et al. Lancet 2007; 370 (587): 580–89. 3.8 µg H5N1/AS03A 25 Post dose 2 Antigen sparing capacity of AS03 demonstrated Oil in water (o/w) emulsions Effect of AS03 adjuvant on H5N1 heterologous antibody titers Two vaccine doses on day 0 en 21 (H5N1 A/Vietnam/1194/04 split virus) A/Indonesia/5/05 Clade 2.1 A/turkey/Turkey/1/05 Clade 2.2 A/Anhui/1/05 Clade 2.3 100 Day 21 Seroconversion rate (%) Day 42 80 Day 180 60 40 20 0 3.8 µg 3.8 µg + AS03A 3.8 µg 3.8 µg + AS03A 3.8 µg 3.8 µg + AS03A Broad clade 2 cross-reactive immunity induced by an adjuvanted clade 1 H5N1 influenza vaccine Leroux-Roels I et al. PLoS ONE 2008; 3 (2): e1665 This knowledge led to the rapid development in 2009 of Pandemrix®, an AS03-containing pandemic influenza with 3,8 µg of H1 haemagglutinin The AS03 adjuvant was also present in 2 SARSCoV-2 candidate vaccines but due to the slower production of the recombinant spike protein and some other hurdles these vaccines have just recently been licensed (but not broadly used) Example: varicella zoster vaccine Pathogen related challenges Population related challenges Older adults immunosenes cence Immune evasion, intracellular infection Complex life cycle, latent disease Multiple sero/genoty pes Induce protection Reduce dose Overcome weakness Short duration of protection Immunosuppressed: reduced response/live vaccines contraindicated Induce Increase Broaden Prolong Chronic disease reduced response Antigenic drift Moderate, limited efficacy Pregnant women Infants – immate immune system Adapted from N. Garçon VZV vaccine Shingrix Antigen Antigen Adjuvant Adjuvant System System Glycoprotein Glycoprotein E E (gE) (gE) AS01 AS01 MPL from microbial membrane (gE) LPS Saponin QS21 purified from plant extract Liposome Illustration by Franz Eugen Köhler MPL 34 Varicella zoster virus (VZV) infection During VZV reactivation the virus replicates in the sensory ganglia with potential nerve damage and neural pain as a consequence4 VZV migrates via the sensory nerve to the skin and causes herpes zoster or shingles4  Symptomatic reactivation: Herpes Zoster Skin  VZV-specific T cells keep virus latent   Spine  Primo-infection: Varicella 1. 2. 3. 4. After primo-infection VZV migrates to the dorsal ganglia (sensory nerve)2 Oxman MN JAOA 2009 Johnson et al. Drugs Aging 2008; 25: 991-1006 Weaver A. J AOA. 2009;109:S2-S6 Kimberlin DW et al. N EnglJ Med 2007  VZV is latently present in the dorsal ganglia and persists lifelong3 Latency Crucial role of CMI in the protection against VZV # VZV specific CD4 T cells decreases with age Overview of VZV vaccines Varicella – chicken pox Name Manufacture r Provarivax SP-MSD (Merck) GSK Varilrix (Priorix-Tetra: MMR-V) Type Strength Route Live attenuated, Oka strain > 1350 PFU SC Live attenuated, Oka strain > 3300 PFU SC Herpes zoster – Shingles Name Zostavax Shingrix Brand and manufacturer names are FYI Manufactur er Merck SP-MSD GSK Type Strength Route Live attenuated, Oka strain > 19400 PFU SC Recombinant protein (gE) + AS01B adjuvant 50 µg gE IM PFU: plaque forming unit; SC: subcutaneous; IM: intramuscu gE+AS01B (HZ/su) induces a robust CMI (CD4 T cells) VZV-specific CD4 T cells induced by HZ/su vaccine >> Oka vaccine in adults 50-70 yr Dose 1 Dose 2 Leroux-Roels I et al. J Infect Dis 2012; 206: 1280-90 and this translates into very high vaccine efficacy in older adults 97,2% vaccine efficacy 6 cases HZ in vaccine group vs 210 cases in placebo group Design: Randomized placebo-controlled phase 3 study in 15 411 participants (50+), 2 vaccine doses with 2 months interval, 3.2 years FU As a comparison: Zostavax (Oka vaccine): 51.3% VE overall and age-related decline (69.8% VE in 50-59 yrs vs 37.6% in 70+ yrs) (Oxman et al. N Engl J Med 2005; 352: 2271-84) Conclusion: AS01-adjuvanted VZV vaccine induces very high protective efficacy against shingles in an older population. It can overcome immunosenescence. Shingrix received FDA approval in 2017 and EMA approval in 2018 Lal et al. N Engl J Med 2015; 372: 2087-96 Cunningham et al. N Engl J Med 2016; 375: 1019-32 BIO/ADJ/0007/12 Date of preparation: July 2012 Impact of vaccination Slide 40 Novel approaches to vaccine design New New antigens antigens •• Multiple Multiple immunodominant immunodominant epitopes, epitopes, conformationally conformationally accurate accurate recombinant recombinant proteins, proteins, antigens antigens in in VLPs VLPs construction, construction, reverse reverse vaccinology, vaccinology, … … Delivery Delivery strategies: strategies: DNA, DNA, mRNA mRNA and and live live vectors vectors •• Genetic Genetic material material coding coding for for antigens antigens contained contained in in aa nonnonreplicating replicating DNA DNA plasmid plasmid or or A A combination combination mRNA mRNA of of these these •• Antigens Antigens expressed expressed by by cells cells of of vaccine Novel vaccine recipient recipient Novel adjuvants adjuvants • •• Substances • Targeted Targeted antigens antigens incorporated incorporated Substances to to enhance enhance the the into quality into the the vector’s vector’s genetic genetic material material quality and and strength strength of of the the •• Antigens immune Antigens expressed expressed by by aa nonnonimmune response response induced induced by by pathogenic the pathogenic vector vector the vaccine vaccine antigen(s) antigen(s) Nathalie Garçon, Adjuvants today and tomorrow, Human Vaccines Project (YouTube, 27/06/2019) Nathalie Garçon, Adjuvants today and tomorrow, Human Vaccines Project (YouTube, 27/06/2019) A new framework for adjuvant development Pulendran B. Nature Rev Drug Discov 2021; 20: 454-75 Nanishi et al. Curr Opin Pediatr 2020; 32: 125-138 Conclusion • Vaccine = antigen + adjuvant (endogenous or exogenous) • Mechanism of action is still being elucidated, but innate immune response is key • to induce the desired adaptive immune response (nAbs, sIgA, CD4 T cells, CD8 T cells, …) • Choice of adjuvant/delivery system depends on many factors, e.g. • Pathogen-related factors: severity of disease, correlate of protection, … • • Host-related factors: target population, reactogenicity profile, … Future: • Novel antigens, delivery systems and adjuvants • Not only the pathogen is important, but also the host • Systems vaccinology