immunity to microbes principles of vaccination€¦ · immune evasion by bacteria (examples) 17....
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CLINICAL IMMUNOLOGY 4540-FS2019-0
Immunity to MicrobesPrinciples of Vaccination
Christoph Hauser, MDUniversitätsklinik für InfektiologieInselspital
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Aims – immunity to microbes
> Understand the responses of the innate, adaptive, humoral and cellular immune system to the major classes of microbes— Extracellular bacteria— Intracellular bacteria— Fungi— Viruses— Parasites
> Mechanisms of immune evasion by microbes
> Understand key concepts of immunological pathogenicitymediated by microbes
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Figures from 6th/8th Ed.
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Innate and adaptive immunity
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Innate immune response to extracellularbacteria
> Complement activation (alternative pathway) through> -Peptidoglycan in the cell wall of Gram-positive bacteria
-Lipopolysaccharide in Gram-negative bacteria by-by mannose on bacterial surface
Leads to
> Opsonization and enhanced phagocytosis> Lysis of susceptible bacteria by membran attack
complex> Activation of phagocytes and inflammation
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Adaptive immune response to extracellular bacteria
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CD4 response
Antibody production
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Bacterial superantigen may lead toinjurious effects of the immune response
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Immune response to intraacellularbacteria
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Dynamic of the immune response tointracellular bacteria
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Adaptive immune response to intracellularbacteria: CD4+/CD8+ cooperation
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Granulomatous reaction – pathologicresponse to persistent intracellular bacteria
> Example Mycobacterium spp> With T-cell help (IFN-gamma) macrophages are activated
and have enhanced ability to kill intracellular bacteria> Cell wall components inhibit fusion of phagocytic
vacuoles with lysosomes> Some mycobacteria persist> Granulomatous reaction: central necrosis, multinucleated
giant cells, walled off by lymphocytes contains «latent» infection in 90% of patients
> Genetic polymorphism or any kind of immunosuppressioncan lead to loss of control either shortly or years after infeciton
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Nunez et al Nature Reviews 2014
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Importance of TH1 and TH2 response
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LeprosyMycobacterium leprae
TH1 Tuberculoid leprosy TH2 Lepromatous leprosy
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Immune evasion by bacteria (examples)
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Immune evasion by bacteria(schematic, example N. gonorrhoeae)
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Immunity to fungi: innate response
> Innate response mainly by phagocytes (neutrophils andmacrophages)
> Liberation of radical oxygen species, lysozyme, intracellulardigestion
Romani 2011
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Adaptive Immunity to fungi
> Adaptive response to fungi— Intracellular: mainly CD4/CD8 cooperation (similar as
for bacteria); Th1 responses; tendency to chronicgranulomatous inflammation
— Antibodies may exert some protection> Immune evasion (inhibition of cytokine production in
phagocytes)
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Romani 2011
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Innate and adaptive immune responses against viruses
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Innate immune responses against viruses
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Viral immune evasion: overview
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Evasion from immune response:Inhibition of antigen processing by viruses
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Immune response to protozan parasites
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TH1
TH2
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Helminth infection induces TH2 response
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Helminths to big for«normal» immune response (phagocytosis, CTL)
But basic protein ofeosinophils can destroyhelminths and mast cellmediarors lead toexpulsion of helminths
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TH2 effector functions
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Immune evasion by parasites
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Immunological pathogenicity mediatedby microbes
> Direct killing of host cells infected> Killing or functional impairment of host cells by toxins
— Endotoxins: liberated by lysis of the microbe, component of cellenvelope or cytoplasm
— Exotoxins: secreted> By stimulating immune responses damaging infected and
uninfected (innocent bystander) host cells> Immunological sequelae: molecular mimicry, immune
complexes…
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Aims – Principles of Vaccination
Introduction
The federal vaccine program
Types of vaccines currently in use, including theiradvantages and disadvantages
The impact of the route of administration of a vaccine
Important effectors of vaccine response
Importance of adjuvant / examples
Introduction to the term „herd immunity“
„New“ vaccines
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Introduction to vaccines
> Continuous race between host and pathogen> For exclusive human pathogens: important co-evolution> Different pathogens – different strategies> Co-existence may be desired or not> Vaccine efforts exert evolutionary pressure
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Introduction to vaccines
> 1796: First vaccination by Jenner
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Basic principle of vaccination
- Active: expose individual with attenuated, killedor split organisms that leads to the development of an immune response withoutthe risk of (severe) disease
vs.- Passive: adoptive transfer of specific effector
mechanisms from other, previously activelyimmunized individuals
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Federal vaccine program
www.ekif.ch, www.infovac.ch
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Swiss routine vaccine program 2016
www.ekif.ch, www.infovac.ch
Additional vaccines for special indications:- Travel: Yellow fever, Japanese encephalitis, etc..- Special exposures: FSME, Rabies, etc ..- Patients at risk: Influenza
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„THE GOOD OLD DAYS….“ some examples
Morbidity/Mortality per year in CH
Disease without vaccine with vaccine
Diphtheria 4‘000 cases Last case 1983
Poliomyelitis 800 cases Last case 1982
Invasive H. influenzae type b 180 cases 17 (<17 yrs old)
Tetanus 50 cases 16 (none <20 yrs old)
Congenital Rubella 30-50 cases 1? (not complete)
Pertussis 140 deaths ?
Zimmermann HP et al. Rev Med Suisse Romande 1998; www.bag.admin.ch
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GOALS OF A VACCINE
Protect individual: infection(disease)(clear disease)
By mimicking infection in terms of long lasting immune responsewithout doing harm
“Optional”: Give indirect protection (herd immunity)Support global eradication of pathogen
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Types of vaccines
Passive: antibodies
Active: live, attenuated
Active: inactivated
Active: component
Newer technologies
- Vector based (e.g. lactobacilli)
DNA vaccines
- Recombinant (e.g. VSV-ZEBOV)
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Types of vaccines
Vaccine Advantage Disadvantage
Passive (antibodies) Rapid protectionMinimal side effects
Short durationNo memory
Active
Whole cell/virus Variety of antigens Side effects
Live, attenuated Replicates: antigen↑ May cause disease
Inactivated Does not replicate pot. less immunogenic
Component Target antigen knownLess side effects
Restricted immune response to target antigen
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Passive immunisation
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Route of administration
Parenteral:- Intradermal- Subcutaneous- Intramuscular
Mucosal:- Ingestion- Aerosol
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Poliomyelitis vaccines: oral-live vs. parenteral inactivated
Whole virusInactivatedParenteral
Whole virusLiveOral
++ Serum antibody titres
+
Duration of protection ↑(+) Pharyngeal
viral excretion+
(+) Prevent intestinal infection
+
- Spread of vaccine virus
+
- Vaccine disease +
-Interference with other enteroviral infection in
the intestine+
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Immunologic interactions in successfulVaccines NATURE BIOTECHNOLOGY 2007; 25 :303
4540-FS2017-0: Selected topics in Clinical Immunology
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Adaptive B cell
Innate
Adaptive T Help
adjuvant
Pollard et al 2009
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Vaccines against bacterial polysaccharidese.g. Streptococcus, pneumoniae, Haemophilus influenzae, Neisseria meningitidis
Pollard et al 2009
UN-conjugated
Vs
conjugated
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Primary immune response to vaccines
What have we learned (in retrospect) Early protection: antibody-dependent Quality (e.g. avidity) → efficacy Mucosal vaccines: IgA response Duration: B-cell memory
persis. Ab prod. (early response)
T-cell response: importantless well described
Complicating: antigenic variationstrain diversityinfluence of age
Lambert PH, Siegrist CA. Nature Medicine. 2005;11:S54.
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Boosting, affinity maturation
→ favors short term responseRapid vaccine schedules(several, closely spaced doses)
→ support immune memoryLower antigen doseAntigen persistence? (animal models)“Nature of antigen”Booster dose
Lambert PH, Siegrist CA. Nature Medicine. 2005;11:S54.
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Adjuvant
Goal: enhance Ab affinity maturation process
mostly by enhancing innate response
specially important for inactivated andcomponent vaccines
Adjuvant:Aluminium salt
Experimental- CpG oligos- (mod.) E. coli heat labile toxin
Lambert PH, Siegrist CA. Nature Medicine. 2005;11:S54.
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Importance of early response: depends on infectious agent etc.
Example: Tetanus-Toxin (TeNT)
Neutralization before up-take into neuron !!
Example: Hepatitis B virus
Memory → long lived protection= anti-HBs Ag titer ever >100 U/L
Incubation period 4-12 wksTime to recruit memory cells
Role of T-cell response??
Lambert PH, Siegrist CA. Nature Medicine. 2005;11:S54.
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Passive/active immunisation after exposure?
Need to know natural history of infectionOften narrow time window (48-72-96h after first exposure)
Example: Varizella-Zoster virus:
Days
7 10 210
ContactInfection
Vesicles Crusts
8
Contagious
28
Viraemia
IgVaccine72 h
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Can vaccine protection be measured in the individuum?
Importance: Surrogate for clinical efficacy studiesDocument individual protection for high risk situations
Surrogate: Vaccine record!! (= empiric), e.g. 2 doses MMR vaccine
Measurement of antibody titres in serum:- Threshold defined for relatively few vaccines, examples:
Hepatitis BTetanus toxinFSMERabiesetc.
- Cannot extrapolate to wild-type infection (e.g. measles)- Quantity ≠ quality (e.g. avidity of antibodies, route of administration)
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Antigen variation / strain diversityExample: influenza virus / vaccine
Hemagglutinin (H, n=15)Neuraminidase (N, n=9)
RNA, segmented→AG drift / shift
Seasonal vaccines- Four strains - Yearly up-date (WHO)
Reverse genetics for new strains??
Get away from egg embryos?
H5N1 vaccine: conserved epitopecrossreactive?
“Pandemic vaccine”
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Antigenic sin
Lambert PH, Siegrist CA. Nature Medicine. 2005;11:S54.
Vaccine efficacy might be modulated by prior vaccination
“Original antigenic sin”
Cross-reactive epitopes preferentially reactivate high-affinity memory B-cells rather than lower affinity naive B-cells.
Individuals exposed 50 yrs earlier to H1N1Influenza virus strain respond differentlyto a new H1N1 vaccine strain than adultsthat had never been exposed to H1N1
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Herd immunity= indirect protection of susceptibles by reduced circulation of pathogen
Vaccine was given to <2 yrs old!!
Kyaw MH et al. NEJM 2006;354:1455.
Conjugated pneumococcalpolysaccharide vaccines → Reduce colonisation→ Reduce transmission
X
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Vaccination at the extremes of age
Newborns to 1 year of life
Immature immune systemPoor response to T-cell indep. ag- IgM to IgG2 switch ↓- Complement-mediated reaction ↓- Splenic marginal zone organ ↓
Response to T-cell dep. ag ↓- IFN-γ by CD4+TH1 cells ↓
Inhibiting maternal antibodiesAffects B-cell response - mechanisms? - Inhibition of live virus vaccines- FcR mediated inhibition of B-cell activation
- Specific epitope neutralization/ competition with antigen specific B-cell receptors→ ratio maternal ab : vaccine antigen(impact of adolescent immunization?)
Siegrist CA. Vaccine 2003;21:3406
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Vaccination at the extremes of age
Elderly: impaired immune response – very late in lifeNot well investigated
Not all vaccines are equally affected by immune senescence:- Pneumococcal poylsaccharid vaccine: +++- Tetanus-Toxoid booster: (+)
Immunology:- Rapid waning of antibody response- Relativ restriction of T-cell repertoire
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Evidence for the importance of T-cell response for vaccine immunity
Lambert PH, Siegrist CA. Nature Medicine. 2005;11:S54.
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DNA vaccines
Vaccine = - naked DNA on plasmid
with strong promoter- Enters cell nucleus → antigen production
Current problems- Limited immunogenicity- Various strategies for enhancement
proposed
Hung C-F et al. Exp. Mol Med 2007; 39:679
http://www.brookscole.com/
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The future: Viral vector vaccines ?-> Example rLCMV
Principle: - commensal / «attenuated» pathogen*- biological property of interest:
e.g. compartmentalization to intestinal mucosa)- genetic engeneering: vaccine antigen(s)
Pinschewer et al, SMW 2017
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The future: Viral vector vaccines ?-> Example rLCMV