13 IPPH Immunology 2013 JPS

7/28/2019 13 IPPH Immunology 2013 JPS

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Slide&1&

IPPH 1: Immunology

Phone: 8344 4441

Room Number: 103

Email: [email protected]

Lecture 13

Vaccines and vaccine development

A/Prof Jean-Pierre Scheerlinck

Semester'1,''2013 ' ' ' ' ' ''''''''''''''''''''''''''''''VETS70005&


2/26

Slide&2&

The'most'important'ba9les'did'not'occur'in'Verdun'or'the'rainforests'of'South?East'

Asia'

'but'occur'in'our'body'every'day'of'our'lives.'

My'name'is'Jean?Pierre'Scheerlinck And'I'will'tell'you'about'

these'ba9les

1. Overview&of&the&immune&system&2. Ab&effector&mechanisms&3. Recogni?on&of&An?gen&by&B&&T&Cells&4. Thymus&development&5. B&cell&development&6. MHC&Restric?on&7. Cytokines&8. An?gen&Processing&&9. T/B&Collabora?on&10. Cell&mediated&immune&effectors&11. Complement&system&12. Tolerance&&autoimmunity&13. Vaccines&and&vaccine&development&


3/26

Slide&3&

The&power&of&vaccines:&Rinderpest&

South&Africa&1900&rinderpest&epidemic.&(New&York&Times)&

Disease& Signs:&fever,&oral&erosions,&diarrhea&and&lymphoid&necrosis& 95%&mortality&within&1Z2&weeks& Fragile&virus&quickly&deac?vated&by&heat&and&sunlight&

Control& Movement&control& Slaughter&of&affected&ca]le& Vaccina?on&1994Z2006& Last&case:&Kenya&2001& Eradica?on&declared&

8th&&August&2011&

doesn't last for a long time unlike food and mouth disease

which can spread via water.


4/26

Slide&4&

WHOs&statement&on&ideal&vaccines&

Affordable&worldwide& Heat&stable& Effec?ve&aer&a&single&dose& Applicable&to&a&number&of&diseases& Administered&by&mucosal&route&

Suitable&for&administra?on&early&in&life&

Source: Goldsby et al, Immunology 5th edition!!

Yen, Kenya 2010

lonelyplane?mages.com&

how T and B cell epitopes relate to this


5/26

Slide&5&

Future&and&underu?lized&vaccines&

HIV&

TB&Malaria&

Dengue&

Meningococcus&HPV&Rotavirus&Pneumococcus&Cholera&

Typhoid&Hib&(conj)&

Hep&B&Rubella&

Jap&enc&

Influenza&Yellow&Fever&

Measles&Tetanus&

Polio&Pertussis&

Diphtheria&1960& 1980& 2000&

Future&

Vaccines&

Underu?lized&

Vaccines&

Widely&used&Vaccines&

Save&3&106&lives/year&

(WHOZIVR&August&2006)&

Note:&the&halos&represent&deaths&currently&being&averted,&and&solid&circles&represent&deaths&es?mated&to&occur.&

immuniza?onbasics.jsi.com&


6/26

Slide&6&

&Speed& &Magnitude& &Persistence& &Increased&avidity&

Immunobiology&5,&Janeway&et&al&

Most&vaccines&induce&immune&memory&

Prime&

Boost&or&infec?on&

0&&&&&&&&&&&2&&&&&&&&&&&&4&&&&&&&&&&&&6&&&&&&&&&&&&8&

&&&&&&&&&&&&&Weeks&postZpriming&

Second encounter -> immune memory,

second immune response with these

4 characteristics.


7/26

Slide&7&

Most&Vaccines&Rely&on&Immune&Memory&

Vaccination

Infection

Vaccination or

primary infection

Infection

after vaccination

vaccination 'tricks'

animal into thinking

it already encountered the

disease.

2nd time: big igG response


8/26

Slide&8&

Comparing&Primary&and&Secondary&Immunity&

T cells direct what type

of antibodies are made

Higher affinity because

of maturation of antibody

response


9/26

Slide&9&

The&Persistence&of&Memory&

Memory&B&cells&live&much&longer&than&Ab&secre?ng&cells&

Immune&memory&last&a&long&?me&(some?mes&as&long&as&

animal&lives)&

Ab&response&diminishes&over&?me&in&a&ma]er&of&months&

Persistence&of&memory&may&require&the&con?nuous&presence&

of&an?gen&(uncertain)&&

Persistence&of&memory&(S&Dali&Z&1931)&

retain high level of antibody in the serumbut declines after several years

t and b cells remain at high level of memory


10/26

Slide&10&

Antigen

MHC II

Dendritic cell

T helper cell

TCR

CD4

Cytotoxic T cell

MHC I

T helper cell

IFN-"

Antigen

MHC II

TCR

CD4

B cell

Antibody

T helper cellCD4

CD8

InfectionCytotoxic T cell

CD8

Induc?on&of&immune&responses&&second infection

t cell in periphery

Ab binds to Ig, taken up and presented

to T cell


11/26

Slide&11&

Vaccines&Against&Hidden&An?gens&

Vaccine&against&gut&an?gen&of&ca]le&?ck&(BM86)& Tick&feeds&on&ca]le&blood& An?bodies&bind&gut&an?gen&in&?ck& Tick&gut&damaged&

Animal&not&exposed&to&an?gen&during&infec?on& No&boost&of&immune&response&during&

infec?on&

Relies&on&presence&of&preZexis?ng&Ab& Requirement&for&regular&booster&

Ab&levels&in&serum&decline& Memory&is&present&but&is&of&no&use&since&

infec?on&does&not&result&in&exposure&to&

an?gen&

h]p://www.moa.gov.zw/&

dependent on the presence of antibodies in the serum.

ticks - bite through skin. require regular booster to

keep serum levels high.


12/26

Slide&12&

Types&of&vaccines:&Life&a]enuated&&

Minor&P,&Nat&Rev&Microbiol.&2004&Jun;2(6):473Z82.&

Passage&of&disease&in#vitro#or&in&nonZnatural&species&& Mutants&occur&that&are&no&longer&as&

pathogenic&(i.e.&a]enuated)&

Oen&unknown&what&has&changed& Random&process& For&example&poliomyeli?s&vaccine&&

Ra?onal&muta?on&of&pathogenicity&genes&

Need&to&be&iden?fied& Each&is&single&muta?on&so&poten?al&for&

reversion/complementa?on&most used. loses pathogenicity in culture

if single point mutation -> could

potentially revert back to pathogenicity


13/26

Slide&13&

A]enuated&vaccines&

Have&many&of&the&characteris?cs&of&the&pathogen& Oen&provides&good&immunity&& Some&induce&diseaseZlike&symptoms& Can&cause&disease&in&immunoZcompromised&animals&

since live attenuated can still get sick

with the same symptoms. lasts for a

long time


14/26

Slide&14&

Issues&with&life&a]enuated&vaccines:&Recombina?on&

Two&vaccine&strains&can&recombine&to&form&a&pathological&strain& Recent&research&from&Melb&Uni&Veterinary&School& Infec?ous&Laryngotrachei?s&Virus&(ILTV)& Two&poultry&vaccine&strains&in&Australia&

SA2/A20&produced&by&Pfizer& Serva&produced&by&Intervet&

Recombina?on&event&leads&to&virulent&strain&

SangZWon&et&al,&Science,&2012,&337:188&

Vaccine&strain&A20/SA2& Vaccine&strain&Serva&

Virulent&strain&

do not use both vaccines at the same time


15/26

Slide&15&

Types&of&vaccines:&Inac?vated&

Killed&whole&organisms&(viruses,&bacteria)& For&example&influenza&vaccine&produced&

&in&eggs&

Toxoid&vaccines&(i.e.&inac?vated&toxin,&for&&&&&&&&example&tetanus)&&

Very&commonly&in&veterinary&medicine& Majorly&induce&an?body&responses&

&

Advantages:& Safe& Standardized&successful&technology&

Disadvantages:&

reduced&immunogenicity&>&mul?ple&vaccina?ons,&adjuvants&


16/26

Slide&16&

Types&of&vaccines:&Recombinant&protein&

Cloned&protein&from&pathogen& For&example&Hepa??s&B&vaccine&

Surface&protein&of&Hepa??s&B&produced&in&yeast& Spontaneous&assembly&into&a&par?cle&

Majorly&induce&an?body&responses& Advantages:&

Safe& Standardized&successful&technology&

Disadvantages:& Reduced&immunogenicity&>&mul?ple&vaccina?ons,&

adjuvants&

Expensive&>&few&veterinary&applica?ons&


17/26

Slide&17&

Types&of&vaccines:&DNA&

Injec?on&of&DNA&>&animal&produces&the&vaccine& Fish&vaccine&is&only&commercial&DNA&vaccine& No&purifica?on&of&protein& No&classical&adjuvants& Can&use&immunoZmodulators&incorporated&into&DNA&vaccine&

Advantages:& Can&induce&cytotoxic&T&cell&responses&

Disadvantages:& Very&low&level&of&DNA&expression& Generally&not&very&efficacious& Expensive&>&few&veterinary&applica?ons&

genengnews.com&animal muscle cell makes its own protein

goes into mhc1 pathway good for inducing cytotoxic t cell response.

mhc2 presentation as well..?


18/26

Slide&18&

Vaccine&formula?ons:&summary&

DNA&vaccine&

Immune&response&

Humoral&

Cellular&

&

Memory&

&

Manufacturing&

&

&

&

Safety&

Live&a]enuated& Killed/protein&subunit&

&

+&+&+&

+&+&+&Th1&

+&+&

+&+&+&

+&+&

&

+&+&+&+&

+&+&+&

+&+&+&

+&+&+&

&

B&cells&

CD4+&

CD8+&

Humoral&

Cellular&

&

Ease&of&produc?on&

Cost&

Transport/storage&

&

+&+&+&

+&/&&Th1&

+&+&+&

+&+&+&

+&+&+&

&

+&

+&

+&

+&+&

&

+&+&+&

+&/&&Th1&

&

+&+&+&

+&/&&

&

+&+&

+&

+&+&+&

+&+&+&+&

Source: Gurunathan et al, Annu. Rev. Immunol., 2000


19/26

Slide&19&

Vaccine&components&

An?gen&=&Adap?ve&immune&response&

Specific&molecule&from&pathogen&against&which&immune&response&is&induced&

Need&to&be&neutralising& Oen&on&surface&of&pathogen&(an?body&accessible)&

Adjuvant&=&Innate&immune&response& Increases&immune&response&to&an?gen&

Increase&in&terms&of&be]er&memory&response&not&necessarily&primary&response&

Longer&term&immune&response/memory& Defines&TYPE&of&immune&response&induced& No&an?gen&specific&response&to&adjuvant& Oen&works&through&TollZlike&receptor& Vaccine&vector&can&be&seen&as&adjuvant& An?gen&dose&sparing&

keficat.site88.net&

ISCOMATRIX:&

&&&&&&&&&cholesterol,&lipids,&saponin&

determines which specific antigen is recognised.

^ e.g if used as

live attenuated vaccine


20/26

Slide&20&

Choice&of&an?gen& Trial&and&error&with&some&ra?onal&&

If&an?bodyZmediated&needs&to&be&on&cell&surface& If&T&cell&mediated&no&requirement&to&be&on&surface& Preferably&boostZable&during&infec?on&

An?gen&varia?on&and&selec?on& Trypanosome&(sleeping&sickness),&successive&waves&of&

parasites&with&dis?nct&surface&an?gens&

HIV&>&rapid&muta?on&and&selec?on&&

www2c.cdc.gov&

Male&and&female&Schistosoma&mansoni&in&copula,&

transverse&sec?on&

ncbi.nlm.nih.gov&microbiologybytes.com&

pressure on pathogen -> mutation to try and evade immune system


21/26

Slide&21&

Choice&of&adjuvant& Define&immune&response&required&

CTL&

Th&(which&type,&Th1/Th2/Th17)& Ab&(which&isotype,&IgG,&IgE,&IgA)&

Choices&are&limited& Alum&is&most&widely&used&in&humans&and&&

animals& Good&Th2&but&poor&Th1&adjuvant&

MF59&(Squalene)&approved&for&human&use&in&Europe&but&not&US& Novar?s,&Influenza&vaccine&

AS04&(monophosphoryl&lipid&A&(MPL))&a&TLR4&ligand,&licensed&in&Europe& Combined&with&alum,&in&GlaxoSmithKlines&Cervarix&and&Hepa??s&B&vaccines&

Quil&A&approved&for&animals&but&not&humans& Good&mixed&response&Th1/2&but&side&effects&make&it&unsuitable&for&human&use&

dpi.qld.gov.au&

cytotoxic response, hypersensitivity

mucosal - want iga

large parasite - want mast cells, ige

compliment fixation - igg best one


22/26

Slide&22&

Current&adjuvants&and&how&they&work&

Depot&for&Ag&& alum,&incomplete&Freunds&adjuvant&

Induce&inflamma?on& Inflammasome&(alum)& A]ract&cells&to&the&site&of&injec?on&(Alum,&complete&Freunds&adjuvant)& Target&Ag&to&dendri?c&cells&(CTLAZ4&targe?ng)& Ac?vate&dendri?c&cells&(see&TLR&below)&

Target&Ag&to&specific&Ag&processing&pathways& ISCOMs&

Increase&access&of&immune&system&to&Ag& Nanobeads&

Ac?vates&Toll&like&receptor&(TLR)&pathways& &complete&Freunds&adjuvant& CpG&mo?ves&in&DNA&vaccines&


23/26

Slide&23&

Vaccine&delivery&

visualphotos.com&

Depends&on&species& 10,000&chicken&in&shed&

In&water,&aerosol& Ca]le&on&outback&property&

Single&delivery!& Injec?on&OK&

Humans& No&needles&(thank&you!)&

Different&vaccine&vectors& Delivery&depends&on&vector&used& Need&for&cold&chain&

Route&of&immunisa?on&affects&immune&response&induced& TH1/Th2&balance&

organidad.com&


24/26

Slide&24&

Mucosal&vaccines&

Mucosal&surfaces&are&important&pathogen&entry&points& Lung,&gut,&vagina,&mouth,&nose& Very&large&area&exposed&to&many&poten?al&

pathogens&

Early&destruc?on&of&pathogen&prevents&infec?on&of&other&organs&&

Mucosal&immunity&requires&mucosal&vaccina?on& Lymphocyte&recirculate&to&mucosal&surface& Some&degree&of&protec?on&between&mucosal&

surface&

Vaccina?on&at&one&mucosal&site&may&protect&other&mucosal&sites&

Specific&adjuvants&are&oen&very&important& Oral&vaccina?on&requires&specific&adjuvants&

otherwise&we&would&mount&immune&responses&to&

food&an?gens&

Lung&surface&area&=&area&of&a&tennis&court&

myoo.com&

mucosal surfaces weak point

mucosal administration -> more likely

to give mucosal response


25/26

Slide&25&

Vaccine&efficacy&

Protec?on&from&disease&symptoms& Animal&is&a&carrier&and&can&s?ll&transmit&disease&

but&is&not&sick&

Reduc?on&in&transmission& Animal&has&a&reduced&risk&of&passing&on&infec?on& Effect&can&be&sufficient&to&bring&R01 disease will die out.


26/26

Slide&26&

Effect&of&vaccina?on&on&herd&immunity&

When&sufficient&animals&within&a&popula?on&are&immune,&so&that&disease&can&not&become&established&

Gene?cally&resistant&popula?on& Vaccina?on&of&large&propor?on&of&animals&

Even&if&some&animals&are&not&protected&they&are&unlikely&to&be&exposed&to&disease&because&

the&disease&is&absent&from&popula?on&

Some&parents&do&not&vaccinate&their&children&against&whooping&cough&because&herd&immunity&makes&this&

disease&so&rare&

If&too&many&people&do&this&whooping&cough&will&become&prevalent&again&

www.niaid.nih.gov&

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13 IPPH Immunology 2013 JPS