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7/28/2019 13 IPPH Immunology 2013 JPS
1/26
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&
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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&
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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.
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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
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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¤tly&being&averted,&and&solid&circles&represent&deaths&es?mated&to&occur.&
immuniza?onbasics.jsi.com&
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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.
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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
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Slide&8&
Comparing&Primary&and&Secondary&Immunity&
T cells direct what type
of antibodies are made
Higher affinity because
of maturation of antibody
response
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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
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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
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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¬&exposed&to&an?gen&during&infec?on& No&boost&of&immune&response&during&
infec?on&
Relies&on&presence&of&preZexis?ng&Ab& Requirement&for®ular&booster&
Ab&levels&in&serum&decline& Memory&is&present&but&is&of&no&use&since&
infec?on&does¬&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.
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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
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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
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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
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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&
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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&
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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¬&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..?
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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
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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¬&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
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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.govµbiologybytes.com&
pressure on pathogen -> mutation to try and evade immune system
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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¬&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¬&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
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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&
7/28/2019 13 IPPH Immunology 2013 JPS
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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&
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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°ree&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
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Slide&25&
Vaccine&efficacy&
Protec?on&from&disease&symptoms& Animal&is&a&carrier&and&can&s?ll&transmit&disease&
but&is¬&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.
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Slide&26&
Effect&of&vaccina?on&on&herd&immunity&
When&sufficient&animals&within&a&popula?on&are&immune,&so&that&disease&can¬&become&established&
Gene?cally&resistant&popula?on& Vaccina?on&of&large&propor?on&of&animals&
Even&if&some&animals&are¬&protected&they&are&unlikely&to&be&exposed&to&disease&because&
the&disease&is&absent&from&popula?on&
Some&parents&do¬&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&