vaccine and immunisation

week 11 immunology

vaccination controversy

• vaccination ethics

• fears of iatrogenic diseases

• preferences for natural lifestyles

• religious opposition to vaccines

• increased sense of responsibility for small risks of vaccines vs. responsibility for risks of exposing children to infectious diseases

active and passive immunisation

active immunisation	passive immunisation
long term	short term
induced by using inactivated or attenuated live organisms or their products	administration of human iGs or immune cells
vaccines induce humoral/ cell mediated immunity	immediate protection

passive immunisation

• human normal immunoglobulins (HNIG): derived from pooled plasma of donors and containing AB to infectious agents

• specific immunoglobulins for tetanus, hep B, rabies

  • obtained from pooled blood donors recently immunised with relevant vaccine

mammalian humoral response to infection

• viral infection induces at least 3 classes of ABs: IgG, IgM, IgA

requirements for an effective vaccine

active immunisation strategies

inactivated vaccines

• chemical procedure

• ineffectivity is eliminated, antigenicity not compromised

• relatively stablem carrying little or no risk of vaccine-associated virus infection

• denaturation of virus proteins may lead to loss of antigenicity

• possible contamination with viral components

polio virus

• enterovirus of picornaviridae

• 3 antigenic types

• minor illness: aseptic meningitis

• major illness: flaccid weakness of various muscle groups

• IPV: inactivated polio vaccine

  • enhanced potency inactivated polio vaccine contains polio viruses of all 3 types

influenza virus

• acute viral infection of respiratory tract

• symptoms: fever, chills, headache, myalgia

• secondary bacterial infections (chronic respiratory and cardiac diseases can aggravate illness)

• formalin-inactivated or detergent or chemically disrupted

• prepared each year using virus strains considered most likely to be circulating in winter

• purified viruses grow in embryonated hen’s eggs and chemically inactivated

• live attenuated vaccine given by aerosol may soon be licensed

attenuated vaccines

• viral replication occurs, stimulates immune response

• infection induces mild or inapparent disease

• viruses traditionallt attenuated by sleeting for growth in non human cells

sabin oral poliovirus vaccine

• virs must first be isolated by growing it in cultured human cells

• adaptation to growth in cultured human cells mat cause some attenuation

• virus adapted to grow in cells of a different species until it grows poorly in human cells (adaptation result of mutation)

• life attentuated viral vaccines pose particular risk to immunodeficient recipients

• risk of reversion

safer live-attenuated viral vaccines using recombinant DNA technology

• if a gene that is required for virulence but not growth or immunogenicity can be identified, this gene can be mutated or deleted from genome using recombinant DNA

• creates an avirulent (non pathogenic) virus that can be used as vaccine

• usually large mutations in virulence gene, making it difficult for virus to revert to wild type

subunit vaccines

• consist of only some components of virus, sufficient to induce a protective immune response but not enough to allow danger of infection

• antigen usually a capsid or membrane protein

subunit vaccines categories

several categories of subunit vaccines:

• synthetic vaccines

  • short, chemically synthesied peptides

• recombinant vaccines

  • produced by genetic engineering

• virus vectors

  • recombinant virus genomes genetically manipulated to express protective antigens from pathogenic viruses

hep B virus vaccination

• cancer vaccine

• HbsAg protein produced in yeast

• currently prepared from yeast cells using recombinant DNA technology

action of HBV vaccine

1. injected HBV vaccine containing HbsAg proteins are engulfed and processed by APCs

2. APCs process antigen and attach the same to the surface of the APCs

3. APCs present antigen to the Th cells, leading clonal expansion, of T cells as well as production oof memory T cells

4. antigen recognised directly from B cells → weak immune response

   • Ag binding to Fab region on weak B cell receptor, secondary signalling from cytokines released by Th cells

   • B cells begin somatic hypermutation at the Fab region, further increases corresponding fit between the Fab and the antigen

5. B cells mature to plasma cells to produce neutralising ABs

   • also undergo clonal expansion and memory cell formation for future defence

recomb

recombinant zoster vaccine

• herpes virus

• causes chickenpox in childhood

• later reactivates causing shingles

• recombinant gE produced in mammalian

• adjuvanted with AS01

• injected

adjuvants

• enhance immunogenicity of vaccines but few are approved for use in humans

• adjuvants are tested in combination with specific vaccines and are approved for use in that configuration

adjuvants are diverse

• particulates

  • liposomes

  • microparticles

  • virus-like particles

• bacterially derived adjuvants

• natural/synthetic surfactants

• oil/water emulsions

adjuvants enhance immunogenicity of vaccines

• vaccines without adjuvants inhance modest production of Th polarising cytolines, ABs and activated T cells

• vaccines with adjuvants promote maturation of more APCs increase interaction between APCs and T cells

  • promotes production of greater numbers and more types of Th polarising cytokines, multifunctional T cells and ABs

core of mechanism of action of adjuvants

• classified as immunostimulants and delivery systems

  1. immunostimulants such as PAMPs, DAMPs, chemically synthesised small molecules agonists provide danger signals to activate PRRs on APCs

  2. enhance antigen presentation on MHC molecules

  3. activation of PRRs lead to upregulation of cytokines/co-stimulatory molecules

  4. enhance co-stimulatory signalling

  5. delivery systems such as LNPs, PGLA and self loaded protein nanoparticles act by facilitating presentation of antigens on MHC molecules

molecular targets of adjuvants: toll-like receptors

TLR1/TLR6: heterodimerise with TLR2 and signal through myeloid differentiation primary response 88

• activated NF-κB and MAP kinases, leading to secretion of pro-inflammatory and anti-inflammatory cytokines

TLR4/TLR5: function as homodimers and signal to MyD88 pathway

TLR7/TLR9: also use MyD88 pathway, rapidly activate IRF7 to induce type I interferons

TLR3: uses TIR domain-containing adapter inducing IFNβ (TRIF) signalling to induce type I interferons through IRF3

molecular targets of adjuvants: cytosokic pattern recognition receptors

• nucleotide binding oligomerisation domain (NOD like receptors) are cytosoic sensors of bacterial PAMPs but also recognise multiple cellular products including ATP, uric acid and K+

• activate NF-κB pathway and induce cytokines driving Th 2 differentiation

• retinoic acid inducible gene I and melanoma differentiation associated protein 5 are intracellular viral sensors that drive type I interferon response through IRF3 and IRF7

• cGAS stimulator of interferon genes STING pathway recognised double stranded DNA to induce NF- κB pathway

molecular targets of adjuvants: C type lectin receptors

• CLR are cell surface molecules expressed on multiple myeloid cell subsets

• dectins 1 and 2/MINCLE recruit SYK1 and activate NF-κB through the CARD9-BCL-10-MALT1 complex

• dectin 1 has been shown to induce NFAT and AP1 pathways in macrophages and dendritic cells and in vitro experimental models

• dectins are also specialised in inducing antifrugal immunity

• dendritic cell specific ICAM3 DC SIGN activates NF-κB via p65 acetylation

• resulting gene expression is poorly understoof but IL-10 expression ahs been shown to be induced

• DEC205 and DNGR1 are known to induce cross presentation but signalling pathways are unknown

SARS-CoV-2

• causes COVID-19

• divided into 3 phases

  1. asymptomatic state (1-2 days of infection)

  2. upper airway and conducting airway response (next few days)

  3. hypoxia, ground glass infiltrates and ARDS progression

SARS-CoV-2 virion structure

• lipid membrane includes 3 transmembrane proteins

• spike protein is trimer of identical subunits (2 small proteins, transmembrane protein and envelope protein)

platforms of COVID 19 vaccines

• schemaric diagram of SARS CoV 2 structure including ssRNA genome and 4 structural proteins: spike protein (S), envelope protein (E), membrane protein (M) and nucleocapsid protein (N)

• diverse vaccine platforms including:

  • inactivated vaccine

  • live attenuated vaccine

  • viral vector vaccine DNA vaccine

  • RNA vaccine

  • recombinant subunit vaccine

  • virus-like particles vaccine

COVID-19 inactivated whole virus vaccines

• inactivated whole virus vaccines are made using old technology, which delivers an inactivated version of SARS-CoV-2 virus if it later infects body

• virus-like particle

COVID-19 adenoviral vaccines

• adenoviral vector vaccines are made using common cold virus to deliver genetic instructions for human cells to make SARS-CoV-2 spike protein, priming immune system to attack SARS-CoV 2 virus if it later infects host

COVID-19 DNA vaccines

• DNA vaccine consists of plasmid produced in bacteria that encodes protein of interest

• antigen is transcribed and translated in transfected human cells

• vaccine antigen is presented to APCs, via MHC pathways which will present to activate naive T cells

• CD8+ T cell immunity is predominantly activated by endogenously expressed antigens presented on MHC class I molecules

• active CD8+ T cells stimulated release of cytokines that inhibit viral replication and increase expression of MHC I molecules

• macrophages are also activated to support cell mediated immune responses

• CD4+ Th cell activation via MHC class II from APC

• if vaccine proteins are secreted, these are recognised by BCRs in naive B cells, which also use ,MHC-II to get activated

• activated B cells produce Abs to protect against disease

COVID-19 mRNA vaccine

• mRNA vaccines are made using nanoparticle to deliver genetic instructions for human cells to make SARS CoV 2 spike protein, priming immune system to attack virus if it later infects host

autoimmune haemolytic anaemia (AIHA) of COVID-19 mRNA vaccination

• AIHA may be considered as a very rare complication of COVID 19 vaccination that occurs following vaccination

• direct casual relationship between COVID-19 and AIHA is still ambiguous

• AIHA is caused by IgG and IgM autoABs that react with RBC related surface antigens

  • warm ABs (mainly IgG type)

    • detectable by direct antiglobulin test positivity for IgG, Abs can activate complement

  • cold autoABs (usually IgM class)

    • binds at cold temperatures and rapidly activate complement, causing IV RBC lysis

COVID-19 protein-based vaccine

• made using older technology, which deliver CoV spike protein directly into body, with adjuvant, priming immune system to attack virus later

vaccine challenges

• difficult to develop single vaccine to target all strains and mutations

• immune escape

• vaccination hesitancy

• issues of distribution, affordability, accessibility and acceptability

dendritic cell based vaccines

• CD14+ monocytes are isolated from leukapheresis products, differentiated into immature MoDCs with IL-4 and GM-CSF

• adult dermal fibroblasts are directly reprogrammed to conventional type I DCs by lentiviral transduction of TFs without need of leukapheresis

• resulting DCs are then loaded with tumour associated antigens

• mature, TAA loaded DCs are reinfused to pt