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79 Cards in this Set

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  • Back
What is the etymology of vaccine?
Vacca (latin for cow)
Vaccinia (latin for cow pox virus)
Used to prevent smallpox
(Vaccine --> Vaccinate --> Vaccinee ----------> Victim of Vaccination)
What are characteristics of the ideal vaccine?
Single dose
Simple administration (i.e. oral)
Stable for long periods (at cold and hot T)
100% effective
Immediately effective
Durable immunity
100% safe
What were the millenium development goals?
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
What are DALYs?
Disability Age Lost Years
What are some of the leading causes of lost DALYs?
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
Describe the distribution of the global disease burden.
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)
Look at tables/graphs
Look at tables/graphs
Describe the differential access to vaccines.
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)
How much would provision of all vaccines to all children by 2014 cost?
$30 billion USD
Why does full access to vaccines make good global sense?
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)
How is technology development related to development (security)?
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
What has happened recently in technology development?
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**
What happens to the map of world happiness during a pandemic?
It shifts
Why does it shift?
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
When was the OKA vaccine developed?
Late 1960's in Japan
What happened to the vaccine industry during the development of varicella vaccines (vs chicken pox)?
2 major vaccine companies bought the right to the OKA vaccines
They agreed to divide the world in 2 (western and eastern hemispheres)
What did Company A try and do?
Rushed to market a thermo-labile vaccine (needed -80 C)
Licensed vaccine in Canada in 1999
What did company B do?
Spent more time and developed a thermo stable vaccine that only needed to be stored at -20 C
What was the agreement upon which the 2 companies had decided to market their products?
10 years exclusive market agreement for each company in their half of the world
What is the sequence of events leading to varicella licensure in Canada?
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
What has the goal of vaccination been in the past? (1600-2000)
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
Why don't we want a vaccine that prevents colonization of strep?
It's part of many ppl's natural flora
Resides in the thoat
-> Only a problem when it colonizes the lungs
What is sterile immunity?
Protects you for life
What were the vaccine types up to the mid-2000s?
-Black box: Put in pathogen in animals, mutate them, get animal AB
-Kill the bugs/attenuate them
-Recombination of path DNA
Milestones in human development
Cross Species protection
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
Milestones in human development
Animal Passage of Defined Pathogen (18th century)
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
Milestones in human development
Germ Theory
Broth Cultures
(19th century)
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
Milestones in human development
Toxin Isolation
Egg as crude cell culture
(early 20th C)
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)
Milestones in human development
Attenuation of Organism
Basic Immunology
Cell Culture
Dev'p of tissue culture
Vaccines vs viruses, etc
Milestones in human development
Molecular Biology
Almost all new vaccines use this
->Hep B etc
What are the factors that drive vaccine development?
Fear and Massive Human Suffering
Germ theory and Sterility
Tissue culture (1950s)
Molecular Biology (1980s)
Modern Immunoloy (1980s)
Fear (Bioterrorism) and Massive Human Suffering (TB/AIDS)
What did Pasteur target?
Chicken cholera: Economic interest, chickens were the poor man's ptn
Rabies: Infected animals and adults (mostly males)
What are the factors driving vaccine development?
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)
What has happened to the vaccine industry lately?
Big pharma companies realized they can make billions of dollars
What are the new tools in vaccine development?
New Ag
Delivery systems
New Routes
New Schedules
What are the new Ag?
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)
What are the adjuvants?
-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)
What are the new delivery systems?
DNA vaccines (CpG + intracellular delivery)
Vesicles (eg: Liposomes, ISCOMS, proteosomes)
Chimeric viruses and bacterial vectors
What are the new routes for vaccination?
What are the new schedules?
Prime-boost strategies
Where can vaccines be administered?
Cutaneous (intadermal, epicutaneous, transdermal)
Per rectum/vagina
Describe skin
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
How can an immunization be given subcutaneously?
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
Colloidal carrier
Adjuvant patch
Microneedle: give the injection to yourself, cut out the middleman, save a lot of the cost
What are the immunologic concepts driving vaccine devlopment?
Th1/Th2 paradigm (Th0 and Th17)
Immunologic priming
Innate immune response
Describe the Infectious disease "Paradigm" (leishmania Animal Model)
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
What did this show?
Genetically competent mice had genetically shifted
Genetically sensitive mice could have changed their phenotype
What is alum?
Powerful Th2 adjuvant
Drives Immune response away from what we need (Th1 response because viruses are intracellular)
What is DC cross-priming/cross presentation?
Under the right circumstances, DCs can route inactivated Ag to MHC-I presentation --> CTL
What role does DC cross presentation play in vaccination development?
Use dead Ag
-> No longer need to use live virus to have an IR vs intracellular path
What does immune priming do?
Directs IR
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))
What is the problem with immunology in the past?
Was focused on Adaptive response
-> Now starting to look at the role of innate immunity
What is involved in innate immunity pattern recognition?
PAMPs (pathogen ass't molecular patterns)
PRRs (pathogen recognition receptors)
What are some PAMPs?
What are some PRRs?
Formyl peptide resceptors
Mannose and glycan receptors (i.e. MBP)
Lipopolysac binding ptn (LBP) and CD14
What does TLR3 recognize?
What are the adjuvants of the future?
Why are PRRs good adjuvants?
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
Why try to deliver the Ag as a package?
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
What are the new uses for vaccines?
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)
What are the new targets concerning cancer?
Prophylactic vaccines:
-population based or targeted
-p53 or known familial TAA
Therapeutic vaccines:
-Adjunctive therapy, mop-up
-Primary therapy
Potential for double-deged sword is massive
What is the double edged sword problem?
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
What is required to make a vaccine?
Phase I-IV
What happens during the pre-clinical stage?
Can you make the target (culture, molec bio)?
Is there an animal model
Are the correlates of immunity established?
Toxicity studies
Cost: $1 million
What happens in phase 1?
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
What happens in phase II?
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
What happens in phase III?
The pivotal studies
Field efficacy trials
Large numbers (up to 60,000)
Sometimes challenge studies
Expanded populations
~100s millions
What is a challenge study?
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
What happens in phase IV?
Highly variable (depends on uptake and market forces
Often done to address specific needs in one or another market)
Cost: variable, but millions
What are new vaccines that will come out in the future?
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
Why are some harder to introduce?
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
What type of vaccines are the big pharmaceutical companies working on?
UTI/Common cold ones
-Because they are very common, everyone gets them
.: makes them very profitable
What happens if you kill bacteria that are part of the normal flora?
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
What happens if EBV is targeted?
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
Are vaccines safe?
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
Are vaccines safe enough?
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
What is the problem with MMR (measles, mumps, rubella) vaccine?
Problem with measles part
Can result in major platelet decrease
Cause bleeding
->1-2 kids die from this each year in Canada
What is going on with the anti-vaccination sentiments?
People are thinking of vaccines more and more as bad (but not a new sentiment, has been happening since the timeof Jenner)
What's going to happen to anti-vaccination sentiment?
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
Why is the vaccine world rapidly changing?
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