Mimm 465: Lecture 09/10 Ward

Front 1

What is the etymology of vaccine?

Back 1

Vacca (latin for cow)
Vaccinia (latin for cow pox virus)
Used to prevent smallpox
(Vaccine --> Vaccinate --> Vaccinee ----------> Victim of Vaccination)

Front 2

What are characteristics of the ideal vaccine?

Back 2

Inexpensive
Single dose
Simple administration (i.e. oral)
Stable for long periods (at cold and hot T)
100% effective
Immediately effective
Durable immunity
100% safe

Front 3

What were the millenium development goals?

Back 3

1) ** Eradicate extreme poverty and hunger
2) Achieve universal primary education
3) Promote gender equality and empower women
4) **Reduce child mortality
5) ** Improve maternal health
6) ** Combat HIV/AIDS, malaria and other diseases
7) Ensure environmental sustainability
8) Develop a global partnership for development

Front 4

What are DALYs?

Back 4

Disability Age Lost Years

Front 5

What are some of the leading causes of lost DALYs?

Back 5

1) Lower Respiratory infection
2) Diarrheal disease
...
Ischaemic heart disease, cerebrovascular disease, TB, Measeles, malaria, iron-deficiency anemia, ptn-E malnutrition, tetanus, pertussis, osteoarthritis, liver cirrhosis, HIV, diabetes mellitus, asthma

Front 6

Describe the distribution of the global disease burden.

Back 6

99.9% of the disease in devlopping world
Amt of disease in developed/western countries is very little
->Have a vaccine for quite a few of them

50% of developing world DALYs lost are lost due to infection diseases (vs <4% in the developed world)

Front 7

Look at tables/graphs

Back 7

Look at tables/graphs

Front 8

Describe the differential access to vaccines.

Back 8

2002: Vaccines only 1.7% of total worldwide pharmaceutical costs
2004: ~34 million children didn't have access to childhood vaccines (UNICEF)
10-15 year delay in universal access for most vaccines in developing countries (vs devloped countries)

Front 9

How much would provision of all vaccines to all children by 2014 cost?

Back 9

$30 billion USD

Front 10

Why does full access to vaccines make good global sense?

Back 10

Lowers burden of disease in poorest countries
Helps to reduce population growth
Removes human "fuel" for epidemics and pandemics (ppl bring diseases with them when they move)
Essential to achieve global goals of control or eradication (ie smallpox, measles, polio)

Front 11

How is technology development related to development (security)?

Back 11

95% of global vaccine market controlled by 5 companies (GSK, Wyeth (Pfeizer), Merck, Sanofi Pasteur, Novartis)
Cost to build capacity for cGMP flu vaccine: ~60-100 million

Front 12

What has happened recently in technology development?

Back 12

Developping countries such as Brazil, India, Indonesia etc are starting to develop vaccines as well
*BUT, 93% of it is still in the Western World**

Front 13

What happens to the map of world happiness during a pandemic?

Back 13

It shifts

Front 14

Why does it shift?

Back 14

The countries that make the vaccines have a hold on them
Their citizens get the vaccine first, before it is sent to other countries
EX: Mostly Developed countries that have influenza vaccines available

Front 15

When was the OKA vaccine developed?

Back 15

Late 1960's in Japan

Front 16

What happened to the vaccine industry during the development of varicella vaccines (vs chicken pox)?

Back 16

2 major vaccine companies bought the right to the OKA vaccines
They agreed to divide the world in 2 (western and eastern hemispheres)
NO ONE WANTED AFRICA

Front 17

What did Company A try and do?

Back 17

Rushed to market a thermo-labile vaccine (needed -80 C)
Licensed vaccine in Canada in 1999

Front 18

What did company B do?

Back 18

Spent more time and developed a thermo stable vaccine that only needed to be stored at -20 C

Front 19

What was the agreement upon which the 2 companies had decided to market their products?

Back 19

10 years exclusive market agreement for each company in their half of the world

Front 20

What is the sequence of events leading to varicella licensure in Canada?

Back 20

1999: Company A licenses vaccine in Canada
1999: Canadian consensus conference recommmends universal use of varicella vaccine as soon as the thermo stable product is available
2000: Company B licenses thermo-stable vaccine in Canada
2001: Company A sues Company B in US court to prevent sales of vaccine in Canada (wins)
2003: 10 year exclusive market aggreement expires
2003: Company B begins to sell vaccine in Canada
2003: Company A licenses "thermo-stable" vaccine in "Canada

Front 21

What has the goal of vaccination been in the past? (1600-2000)

Back 21

Eradicate organism: smallpox, measles, polio
Prevent infection/colonization:
-Age restriction: BCG, H influenza
-Sex limited: Rubella
Prevent consequenes of infection
-Colonization OK: S. pneumoniae
-Antitoxin: Tetanus, diphtheria
Modify disease: Measles vaccine + IgG

Front 22

Why don't we want a vaccine that prevents colonization of strep?

Back 22

It's part of many ppl's natural flora
Resides in the thoat
-> Only a problem when it colonizes the lungs

Front 23

What is sterile immunity?

Back 23

Protects you for life

Front 24

What were the vaccine types up to the mid-2000s?

Back 24

-Black box: Put in pathogen in animals, mutate them, get animal AB
-Kill the bugs/attenuate them
-Recombination of path DNA

Front 25

Milestones in human development
Cross Species protection

Back 25

Exposure to one species can protect you from another
-Credited to Edward Jenner for treating smallpox with cowpox, but already done in China, Turkey and Middle East

Front 26

Milestones in human development
Animal Passage of Defined Pathogen (18th century)

Back 26

Found rabies could be passed from one animal to another
Dev'p first vaccines for rabies
-> Dried spinal cord taken from rabbits with rabbies
-> Crushed and used to make a vaccine

Front 27

Milestones in human development
Germ Theory
Broth Cultures
(19th century)

Back 27

Germ Theory developed by Pasteur
Galtier: worked with Pasteur
- Isolated bacteria on fruit/potatoes
-Grow something in pure culture
-Heat treat these bacteria and give to ppl
-Dev'p vaccines for plague, typhoid and cholera

Front 28

Milestones in human development
Toxin Isolation
Egg as crude cell culture
(early 20th C)

Back 28

Eggs are sterile env't
Can do tissue culture
Inject virus in egg/grows in large number
Kill virus in egg
Make vaccines
Give toxins of the path
-> Diphtheria, Pertussis, Tetanus
-> Also BCG, Yellow Fever and Influenza (latter 2 are egg based)

Front 29

Milestones in human development
DNA/RNA
Attenuation of Organism
Basic Immunology
Cell Culture
(post-WWII)

Back 29

Dev'p of tissue culture
Vaccines vs viruses, etc

Front 30

Milestones in human development
Molecular Biology

Back 30

Almost all new vaccines use this
->Hep B etc

Front 31

What are the factors that drive vaccine development?

Back 31

Fear and Massive Human Suffering
Germ theory and Sterility
Egg-culture
Tissue culture (1950s)
Molecular Biology (1980s)
Modern Immunoloy (1980s)
Fear (Bioterrorism) and Massive Human Suffering (TB/AIDS)
Profit

Front 32

What did Pasteur target?
Why?

Back 32

Chicken cholera: Economic interest, chickens were the poor man's ptn
Rabies: Infected animals and adults (mostly males)

Front 33

What are the factors driving vaccine development?

Back 33

Fear and Massive Human suffering
Germ theory and sterility
Egg culture
Tissue culture (1950s)
Molecular Biology (1950s)
Modern Immunology (1980s)
Fear (bioterrorism) and Massive human suffering (TB/AIDS)
Profit

Front 34

What has happened to the vaccine industry lately?

Back 34

Booming
Big pharma companies realized they can make billions of dollars

Front 35

What are the new tools in vaccine development?

Back 35

New Ag
Adjuvants
Delivery systems
New Routes
New Schedules

Front 36

What are the new Ag?

Back 36

Subunit vaccines- multivalent vaccines
Peptide vaccines (chimeric peptides)
Epitope vaccines: looked at 30,000 epitopese for HIV
Conserved ptns for cross-protection:
-multiple serotypes (eg pneumococcus: now have 7,9 &13 valent vaccines, but there are 90 valencies. Can we find a shared epitope betweeen them?)
-Genetically labile organisms (HIV/HCV)
Unique life stages to block transmission
-Malaria gametocytes (blood sterilize parasite in insect so bug can't infect anyone else after)
-Lyme disease: meant to work in tick's gut. Have a vaccine to target Ag in tick's gut.
Cellular vaccines (personalized vaccines)

Front 37

What are the adjuvants?

Back 37

-Aluminum salts (alum): has been used for a long time
-PAMPS (ex: TLR ligands like LPS, porins and CpG)
-Cholera toxin B (other toxins, superAg)

Front 38

What are the new delivery systems?

Back 38

DNA vaccines (CpG + intracellular delivery)
Vesicles (eg: Liposomes, ISCOMS, proteosomes)
Chimeric viruses and bacterial vectors

Front 39

What are the new routes for vaccination?

Back 39

Aerosol
Nasal
Oral
Vaginal
Intradermal

Front 40

What are the new schedules?

Back 40

Prime-boost strategies

Front 41

Where can vaccines be administered?

Back 41

Intranasal
Oral
Intramuscular
Subcutaneous
Cutaneous (intadermal, epicutaneous, transdermal)
Per rectum/vagina

Front 42

Describe skin

Back 42

Largest "immune organ" in the body
Massive Ag exposure
Critical barrier vs invasion
Active surveillance:
-benign vs aggressive
-carefully regulated
High concentraion of Langerhans cells, dermal DCs and macrophages

Front 43

How can an immunization be given subcutaneously?

Back 43

Liquid jet: can even get to the muscle
Vaccine Powder: send sugar coated vaccine as a powder
Hair follicle:
Tape stripping: Rip hair off (arm) and rub vaccine there
Micropore
Colloidal carrier
Ultrasound
Adjuvant patch
Electroporation
Microneedle: give the injection to yourself, cut out the middleman, save a lot of the cost

Front 44

What are the immunologic concepts driving vaccine devlopment?

Back 44

Th1/Th2 paradigm (Th0 and Th17)
DCs
Immunologic priming
Innate immune response

Front 45

Describe the Infectious disease "Paradigm" (leishmania Animal Model)

Back 45

Infect BALBc (sensitive mice)
-> If you add Anti-IL4 or IFN-y: mouse survives (if not, mouse dies)
B56BL/6 (resistant mice)
-> Don't add anything, mouse lives
-> Add Anti-IFNy or IL-4: mouse dies

Front 46

What did this show?

Back 46

Genetically competent mice had genetically shifted
Genetically sensitive mice could have changed their phenotype

Front 47

What is alum?

Back 47

Powerful Th2 adjuvant
Drives Immune response away from what we need (Th1 response because viruses are intracellular)

Front 48

What is DC cross-priming/cross presentation?

Back 48

Under the right circumstances, DCs can route inactivated Ag to MHC-I presentation --> CTL

Front 49

What role does DC cross presentation play in vaccination development?

Back 49

Use dead Ag
-> No longer need to use live virus to have an IR vs intracellular path

Front 50

What does immune priming do?
Example?

Back 50

Directs IR
Example:
If you give kids a polysac vaccine, they only make Abs
If you give kids a DNA vaccine, you won't initially see anything. But then when you give them the polysac vaccine, you see that you get a more balanced response (Th1/Th2))

Front 51

What is the problem with immunology in the past?

Back 51

Was focused on Adaptive response
-> Now starting to look at the role of innate immunity

Front 52

What is involved in innate immunity pattern recognition?

Back 52

PAMPs (pathogen ass't molecular patterns)
PRRs (pathogen recognition receptors)

Front 53

What are some PAMPs?

Back 53

LPS
Lipoptns
P/g
Lipoarabinomanna
Oligosacs

Front 54

What are some PRRs?

Back 54

Formyl peptide resceptors
Mannose and glycan receptors (i.e. MBP)
Lipopolysac binding ptn (LBP) and CD14
TLRs

Front 55

What does TLR3 recognize?

Back 55

dsRNA

Front 56

What are the adjuvants of the future?

Back 56

PRRs

Front 57

Why are PRRs good adjuvants?

Back 57

Some PAMPs are intrinsic
Others can be added (classic adjuvants)
Others can be engineered (chimerics)

This can take advantage of in/extrinsic innate responses
Take same adjuvant
Depending on which ligand used, can generate a humoral or cellular response

Front 58

Why try to deliver the Ag as a package?

Back 58

I.S. evolved to see array type structures (not just a little particle)
The Ag pkg does this
Best way to deliver pkg: Bolus of Ag w/ structural array and a TLR stimulant

Front 59

What are the new uses for vaccines?

Back 59

Many more targets:
-Intracellular organisms (TB, H pylori etc)
-More complex organisms (dengue, malaria etc)
-Therapeutic approaches (HBV, HPV etc)
Completely new uses:
-Cancer vaccines (preventative, therapeutic)
-Inflammatory conditions
-Contraception (sterility vaccines)

Front 60

What are the new targets concerning cancer?

Back 60

Prophylactic vaccines:
-population based or targeted
-p53 or known familial TAA
Therapeutic vaccines:
-TAAs
-Adjunctive therapy, mop-up
-Primary therapy
Potential for double-deged sword is massive

Front 61

What is the double edged sword problem?

Back 61

Some vaccines target aggressive cells: NK, CTL
Risk increases as new vaccines are developed
ex: Melanoma: get a vaccine vs it but now they have another problem -> thelioma
->Autoimmune attack on the skin
=>But what if the tumour is in the brain or heart?
Much larger problems

Front 62

What is required to make a vaccine?

Back 62

Idea
Pre-clinical
Phase I-IV

Front 63

What happens during the pre-clinical stage?

Back 63

Can you make the target (culture, molec bio)?
Is there an animal model
Are the correlates of immunity established?
Toxicity studies
Cost: $1 million

Front 64

What happens in phase 1?

Back 64

First in humans
Focus on safety (sneak some immunogenicity: want to see what could happen)
15-50 adult subjects
Intensive monitoring
Cost: $1-2 million

Front 65

What happens in phase II?

Back 65

Larger numbr of subjects (300-3000)
Dose escalation (immunogenicity)
First look at efficacy (sometimes) (want to see if some ppl get the disease)
Studies in special populations (kids, elderly etc)
Cost: $10-50 million

Front 66

What happens in phase III?

Back 66

The pivotal studies
Field efficacy trials
Large numbers (up to 60,000)
Sometimes challenge studies
Expanded populations
~100s millions

Front 67

What is a challenge study?

Back 67

Example:
Give ppl malaria vaccine you're working on
Grow some malaria in a colony
Infect the insects with malaria
Let the insects bite the ppl

Front 68

What happens in phase IV?

Back 68

Post-licensure
Highly variable (depends on uptake and market forces
Often done to address specific needs in one or another market)
Cost: variable, but millions

Front 69

What are new vaccines that will come out in the future?

Back 69

Easy ones to introduce: RSV, TB, HIV, malaria
Harder: H. pylori, Gp B strep, HSV I/II, EBV
Ones that won't be easily received: UTI vaccines, "common cold" vaccines

Front 70

Why are some harder to introduce?

Back 70

Some bacteria are part of our immune system, part of the normal flora
Probably not a good idea to try and get rid of them entirely

Front 71

What type of vaccines are the big pharmaceutical companies working on?
Why?

Back 71

UTI/Common cold ones
-Because they are very common, everyone gets them
.: makes them very profitable

Front 72

What happens if you kill bacteria that are part of the normal flora?

Back 72

Those areas can be colonized with pathogens
Multiresistance "intensive care" organims (cystic fibrosis)
Antibiotic ass't colitis (C. dificil, started in hospitals because ppl given too many antibiotics)
Vaginal yeast infections

Front 73

What happens if EBV is targeted?

Back 73

EBV has a copy of human IL-10
Potent immunosuppresive agent
-EBV always there at an early age
If we knock out EBV, we'll KO IL-10 copy of EBV
Can be very dangerous

Front 74

Are vaccines safe?

Back 74

Depends on the definition
Defined as harmless: then no vaccine is safe
Defined as "prevention from some other danger": then yes, very safe
Need to weigh risk vs benefit

Front 75

Are vaccines safe enough?

Back 75

Different q's
Rabies vaccines ---> Encephalomyetis
-rabbbit spinal cord vaccine (1:200) (autoimmune T-cell mediated destruction of the brain)
-Duck embryo vaccine (1:1000s)
-tissue culture vaccine (none:millions)
Smallpox-------> death, dissemination, ocular infection
-Smallpox gone ---> vaccine too dangerous
-first new case ----> vaccine ok
IPV (inactive polio vaccine) ---> OPV (ocular polio vac)
-Oral vaccine has live virus, causes problems, Canada has switched to IPV

Front 76

What is the problem with MMR (measles, mumps, rubella) vaccine?

Back 76

Problem with measles part
Can result in major platelet decrease
Cause bleeding
->1-2 kids die from this each year in Canada

Front 77

What is going on with the anti-vaccination sentiments?

Back 77

People are thinking of vaccines more and more as bad (but not a new sentiment, has been happening since the timeof Jenner)

Front 78

What's going to happen to anti-vaccination sentiment?
Why?

Back 78

Probably going to get worse
Every reason to expect the next generation of vaccines targeting prganisms that require CMI for prevention or clearane will be at least as problematice as the prior generations
-> When something goes wrong and it ends up in the headlines, all ppl are going to see is Vaccine and Sudden death

Front 79

Why is the vaccine world rapidly changing?

Back 79

Plethora of new tools
Political will + philanthropy to vaccinate all
Pharma suddenly engaged ($$$)
Vaccines to target cancer, chronic illness
Many new players (countries, small biotechs)
Regional vaccines