Mucosal Immunityor immunity at the mucosa Robin Shattock
What’s special about mucosal Immunity.• Most pathogens enter the body via mucosal surfaces.• Local immunity (specific IgA/IgG, cellular immunity) is an important first line of defense vs. pathogens.• Mucosal immunity may be able to provide sterilizing immunity (influenza)• Particularly important for pathogens that evade subsequent immune clearance.
What’s problematic about mucosal Immunity.• Most mucosal responses are often short lived.• Systemic immunization is generally considered poor at inducing local immunity.• Mucosal adjuvant and delivery strategies are less developed than parenteral approaches• Combined route strategies have been under explored in human studies
Adaptive mucosal effector functions Mucosal antibody•Neutralization•Aggregation•Mucus penetration•Epithelial interaction•Transcytosis•ADCC•Fc inhibition Mucosal cellular response •Rapid elimination (or containment) of the initial foci of infection preventing secondary dissemination – typically require high numbers of effector and/or effector memory cells
Antibodies are actively secreted at mucosal surfaces - both local and systemic Neonatal Fc receptor (FcRn) -Polymeric- immunoglobulinimmunoglobulin -mediatedreceptor- secretion ofmediated antibodies (IgG –secretion of pH dependent).antibodies (dIgA). And transudation…. Strugnell & Wijburg Nat Rev Micro 2010
Immune exclusion Intracellular neutralization Antigen excretionProtection of the mucosal surface by secretory immunoglobulin throughimmune exclusion, intracellular neutralization or antigen excretion. Strugnell & Wijburg Nat Rev Micro 2010
Tissue-specific imprinting leads to programmed trafficking to mucosal sites –concept of tissue specific prime/boost Urogenital Kunkel et al 2003
Expression of mucosal immune responses after different routes of vaccination – local/distal
Human mucosal Immunology has suffered much from over reliance on non-primate models •Rodents and domestic animals constitutively express dimeric IgA in the systemic compartment •Induction of dIgA in any compartment will lead to expression in any distal compartment expressing pIgR •In humans (and NHP) systemic IgA is predominantly monomeric, produced in bone marrow and cannot interact with pIgR •Binding of pIgM to pIgR is strong in man, but weak in rodents •TLR expression patterns and function differ significantly between rodents and humansNeed for greater emphasis on experimental human immunology
Expression of mucosal immune responses after different routes of vaccination – local/distal – in humans•Vaginal and nasal immunization induces Cholera vaccine-specific cervical responses after vaginal immunization duringthe midfollicular menstrual cycle phase. - Kozlowski et al Journal of Immunology, 2002, 169: 566–574.
Do mucosal and systemic B-cell repertoires overlap? VH3 segment frequencies from B cells of each isotype isolated from cervix and PBMC Summary of networks formed between VH sequences (No. of unique sequences) Gaudet et al MAbs. 2011
Can intramuscular vaccination induces detectablemucosal responses? Intramuscular induces vaginal and cervical IgG responses to Papilloma virus antigens – but 3 logs below that of systemic levels Intramuscular SublingualMean serumneutralizingtitre: 25461 SystemicMean vaginalneutralizingactivitydetectable 3/6 Vaginalsubjects Huo, Lewis PLoSOne 2012
Stimulating sustained mucosal responsesProteins• Mucosal delivery strategies/formulations• Mucosal adjuvants• Repeat boostingVectors• Mucosal tropism• Replicating mucosal vectorsRoutes of immunization• Which route is optimal for which mucosal surfacesHeterologous routes• Prime-Boost, Prime-Pull NIH IP/CP
Live Attenuated Vectors.• Concept: antigen delivery as a recombinant gene in live vector mimicks natural infection, giving rise to strongly protective immunity.• Vectors: bacteria (commensals, attenuated Salmonella spp., BCG), viruses (poliovirus, vaccinia, canarypox, etc.)• Replicating vectors enhance immune response.• Induce strong cellular (TH1) response (CTLs) and antibodies.• May provide sustained mucosal immunity through persistence.
Licensed vaccines against mucosal infectionsInfection Vaccine Route of Imm ProducerPolio Inactivated Subcutaneous/int Salk vaccine ramuscularPolio Live attenuated Oral ManyCholera rCTB+ Oral Dlcoral (SBL inactivated Vc. vaccine)Cholera Live attenuated Oral Orochol (Bern)Typhoid Vi polysacharide Subcutaneous/int typhimVi ramuscular (Aventis)Typhoid Live attenuated Oral Vivotif (Bern)Rotavirus Live attenuated Oral RotaRix (GSK) monovalentRotavirus Live attenuated Oral RotaTeq (Merck) pentavalentInfluenza Live attenuated Nasal Flumist (medimmune)Influenza Split/inactivated Intramuscular Many
Solving problems with mucosal anti-antigen/anti- vector immunity Immune exclusion/antigen Gp140 IgG Titres in Plasma at Week 10 excretion 10 8 IM 7 10 IN 10 6 IV 10 5 IR Titre 10 4 10 3 •Heterologous route regimes 10 2 •Prime boost/prime and pull 10 1 •Vector combinations IM IN IR IV •Protein encapsulation •Vector encapsulationSelf limiting antibody response
Comprehensive Approaches to Vaccination Approaches Route AntigensPrior to Exposure Delivery (prime/boost) Point of Transmission •DNA (+/-EP) •TrancutaneousSubunit •Vector •Intradermal •Replicating vector •Subcutaneous •Mucosal tropic •IntramuscularInactivated •VLP •Nasal •Protein •Lung •Protein scaffold •RectalAttenuated •Peptide •Vaginal •Oral Combined or sequential
Summary.• Mucosal immunity provides the best opportunity for vaccine induced prevention• Mucosal responses may be enhanced or modulated by route, adjuvant and/or delivery strategy (vector).• Adaptive mucosal effector functions must be maintained at sufficient levels to be effective (persistence/boosting).• Human mucosal immunity as it relates to vaccine strategies has been poorly defined in humans with an over reliance on small animal models