Transcript BME 301 - Rice University

BME 301
Lecture Nine
Summary of Lecture 8
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Pathogens: Bacteria and Virus
Levels of Immunity:
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Barriers  First line of defense
Innate  Inflammation
Phagocytes
 Complement
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Adaptive  Immunologic memory
Antibody mediated immunity
 Cell mediated immunity  Pathogens within cells
 Diversity to recognize 100 million antigens
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Class Activity 2
The Immune System
Q3: How can technology
solve health care problems?
CS1: Prevention of
infectious disease
Outline
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Pathogens: How They Cause Disease
The Immune System: How We Fight Disease
How Vaccines Work
The Power of Vaccines: Childhood Illnesses
Designing a New Vaccine: HIV/AIDS
Roadmap of CS 1
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Science
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Engineering
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Organisms that cause disease
Immunity
How to make a vaccine
Vaccines: From idea to product
Societal Impact
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Health and economics
Ethics of clinical trials
Developed world/Developing world
Viruses
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Three basic problems each must solve
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How to reproduce inside a human cell
How to spread from one person to another
Inhale
 Eat
 During birth
 Intimate physical contact
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How to evade the immune system
Influenza
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Viral Reproduction - 1
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Must get inside human
cell to use cell’s
biosynthetic machinery
Influenza virus binds to
cell receptor
Induces receptor
mediated endocytosis
Influenza
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Viral Reproduction - 2
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pH slowly reduced in
endosome, virus releases
its single stranded RNA
and polymerase proteins
RNA segments and
polymerase proteins enter
nucleus of infected cell
Cell begins to make many
copies of the viral RNA
and viral coat proteins
Influenza
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Viral Reproduction - 3
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New viral particles exit
nucleus and bud from cell
Viral polymerase proteins
don’t proofread
reproduction
Nearly every virus
produced in an influenza
infected cell is a mutant
Influenza
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Viral Spread
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Infected person sneezes or coughs
http://students.washington.edu/grant/rand
om/sneeze.jpg
Micro-droplets containing viral particles inhaled by
another person
Penetrates epithelial cells lining respiratory tract
Influenza kills cells that it infects
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How does it evade immune extinction?
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Can only cause acute infections
Cannot establish latent or chronic infections
Antigenic drift
Caused by point mutations
Yearly vaccination
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http://www.bme.utexas.edu/faculty/richardskortum/BME301/thisweek/archives.htm
Influenza
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How does the virus cause symptoms?
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Cells of respiratory tract are killed by virus or
immune system
Resulting inflammation triggers cough reflex
to clear airways of foreign invaders
Influenza infection results in production of
large quantities of interferon
Fever
 Muscle aches
 Headaches
 Fatigue
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MMR Weekly
Genetic Shift and Flu Pandemics
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Genetic Shift
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Animals co-infected by different strains of virus
Viral gene segments randomly reassociate
Reassortment of virus segments from birds, pigs, etc is
source of new strains that infect humans
How does this happen?
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Virus shed in bird feces, gets into pigs' drinking water
Humans handle and/or cough on the pig
New virus - segments from humans, birds & pigs
China:
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Breeding ground for new influenzas strains
Proximity of humans, pigs, and ducks in China
Asian flu, Hong Kong flu, etc.
http://www.cdc.gov/flu/avian/facts.htm
Vaccines
How Are They Made?
Vaccination
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Vaccination:
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Practice of artificially inducing immunity
Goal of vaccination:
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Make memory T helper cells, memory killer T
cells, and memory B cells that will protect the
vaccinated person against future exposure to
pathogen
Want the vaccine to have:
Maximum realism
 Minimum danger
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What is needed to make memory cells?
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Memory B Cells & Memory Helper T Cells:
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B and T cell receptors must see virus
debris
or viral
Memory Killer T Cells:
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Antigen Presenting Cells must be
with virus
infected
Types of Vaccines
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Non-infectious vaccines
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Live, attenuated bacterial or viral vaccines
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DTaP
Pneumococcus
Chicken Pox
Carrier Vaccines
DNA Vaccines
Non-infectious vaccines
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Killed bacterial or inactivated viral vaccines
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Subunit vaccines
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Use part of pathogen OR
Use genetic engineering to manufacture pathogen protein
No danger of infection
Hepatitis A & B, Haemophilus influenza type b, pneumonoccocal
conjugate vaccines
Toxoid vaccines
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Treat pathogen with chemicals (like formaldehyde)
Impossible to guarantee that you have killed all the pathogen
Salk (inactivated) Polio vaccine, rabies vaccine
Bacterial toxins that have been made harmless
Diphtheria, tetanus and pertussis vaccines
This approach will make memory B cells and memory
helper T cells, but NOT memory killer T cells
Booster vaccines usually required
Live, attenuated vaccines
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Grow pathogen in host cells
Produces mutations which:
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Weaken pathogen so it cannot produce disease in
healthy people
Pathogen still produces strong immune response that
protects against future infection
Sabin Polio vaccine (oral Polio)
Measles, mumps, rubella, varicella vaccines
This approach makes memory B cells, memory
helper T cells, AND memory killer T cells
Usually provide life-long immunity
Can produce disease in immuno-compromised host
Cell Culture: Live, Attenuated Vaccine
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Grow cells:
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Removed from tissue
In vitro (in glass)
By supplying nutrients and other factors
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Specific O2 and CO2 (pH level)
Glucose, ions
Serum from blood: proteins
Passaging Cells
Organ
Dissection/
Primary
Breakdown…
Cell Line
Add media for growth
Incubate
Divide -> transferred
Secondary
Cell Line
Carrier Vaccines
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Use virus or bacterium that does not cause disease to
carry viral genes to APCs
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e.g. vaccinia for Smallpox vaccine
http://www.bme.utexas.edu/faculty/richardskortum/BME301/thisweek/thisweek.htm
This approach makes memory B cells, memory helper T
cells, AND memory killer T cells
Does not pose danger of real infection
Immuno-compromised individuals can get infection from
carrier
Carrier must be one that individuals are not already
immune to
Cannot make booster vaccines with carrier (must use
different carrier for booster)
DNA Vaccines
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DNA injections can produce memory B
cells and memory T killer cells
Reasons are not fully understood
Make a DNA vaccine from a few viral
genes
No danger that it would cause infection
Types of Vaccines
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Non-infectious vaccines
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Live, attenuated bacterial or viral vaccines
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Makes memory B cells, memory helper T cells, AND memory
killer T cells
Usually provides life-long immunity
Can produce disease in immuno-compromised host
Carrier Vaccines
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No danger of infection
Does not stimulate cell mediated immunity
Usually need booster vaccines
Makes memory B cells, memory helper T cells, AND memory
killer T cells
Does not pose danger of real infection
Immuno-compromised individuals can get infection from carrier
DNA Vaccines
Effectiveness of Vaccines
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Vaccination Effectiveness
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About 1-2 of every 20 people immunized will not have
an adequate immune response to a vaccine
Herd Immunity
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Vaccinated people have antibodies against a
pathogen
They are much less likely to transmit that germ to
other people
Even people that have not been vaccinated are
protected
About 95% of community must be vaccinated to
achieve herd immunity
Does not provide protection against non-contagious
diseases – eg tetanus
Vaccines
How Are They Tested?
Vaccine Testing
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Laboratory testing
Animal Model
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Animal must be susceptible to infection by
agent against which vaccine is directed
Animal should develop same symptoms as
humans
Vaccine Testing
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Human Trials
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Phase I
Small number of volunteers (20-100)
 Usually healthy adults
 Last few months
 Determine vaccine dosages that produce levels of
memory B or T cells that are likely to be protective
 Evaluate side effects at these dosages
 FDA must approve the vaccine as an
Investigational New Drug (IND)
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NPR Story – Ebola Vaccine Trials
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http://www.npr.org/rundowns/segment.php?wfId=
1513230
Vaccine Testing
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Human Trials
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Phase II
Larger number of volunteers (several hundred)
 Last few months to few years
 Controlled study, with some volunteers receiving:
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Vaccine
Placebo (or existing vaccine)
Endpoints: Effectiveness, safety
Vaccine Testing
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Human Trials
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Phase III
Large number of volunteers (several hundred to
several thousand)
 Last years
 Controlled double blind study, with some
volunteers receiving:
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Vaccine
Placebo (or existing vaccine)
Neither patients nor physicians know which was
given
Vaccine Testing
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Role of the FDA:
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Licensure by FDA required before a company can
market the vaccine (about a decade)
Each batch of vaccine must be tested for safety,
potency, purity and sample lot must be sent to FDA
Post-licensure surveillance
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Doctors must report adverse reactions after
vaccination to FDA and CDC
Vaccine Adverse Events Reporting System (VAERS)
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As many as 12,000 reports per year, 2,000 serious
Most are unrelated to the vaccine
Vaccine Testing
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Recommendations by health departments and
expert physician groups
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When should vaccine be used
Who should receive it
Weigh: risks and benefits of the vaccine, costs of
vaccination
Legislation:
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States determine which vaccines are required by law
All 50 states have school immunization laws
Can be exempted based on:
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Medical reasons (50 states)
Religious reasons (48 states)
Philosophical reasons (15 states)
Vaccine Schedule
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Birth
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DTap #1
Polio #1
Hib #1
Hepatits B #2
Pneumococcus #1
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DTaP #2
Polio #2
Hib #2
Pneumococcus #2
6 months
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DTaP #3
Hib #3
Pneumococcus #3
12 months
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Hib #4
Polio #3
Hepatitis B #3
Pneumococcus #4
DTap #4
By age two:
20 shots!!
Single visit:
Up to 5
shots!!
4-6 years
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MMR #1
Varicella
15 months
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4 months
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Hepatitis B
2 Months
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MMR #2
Polio #4
DTaP #5
11-12 years
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Tetanus, Diphtheria
http://www.christianpoint.org/inspirati
on/images/crying_baby.jpg
Recommended Vaccine Schedule
History of the Rotavirus Vaccine
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Withdrawn from the market after post-licensure
surveillance indicated small number of adverse
effects
Vaccines
Are They Effective?
History of Vaccination
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Seventh Century
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Second millennium
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Indian Buddhists drank snake venom to
induce immunity (through toxoid effect)
Variolation against smallpox
Central Asia, China, Turkey
1721
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Variolation against smallpox moves from
Turkey to England
History of Vaccination
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History: 1798 - Edward Jenner noted:
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Smallpox and Cowpox:
Milkmaids frequently contracted cowpox which
caused lesions similar to that smallpox
 Milkmaids who had cowpox almost never got
smallpox
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Jenner’s (unethical) experiment:
Collected pus from cowpox sores
 Injected cowpox pus into boy named James Phipps
 Then injected Phipps with pus from smallpox sores
 Phipps did not contract smallpox
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First to introduce large scale, systematic
immunization against smallpox
History of Vaccination
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1885: Attenuation
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Early 1900s: Toxoids
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Influenza
1950s: Tissue Culture
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Diphtheria, tetanus
1936
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Louis Pasteur - first vaccine against rabies
Polio (Nobel Prize for Enders, Robbins, Weller)
1960s:
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Measles, Mumps, Rubella
Effects of Vaccination in US
Disease
Max # of Cases # Cases in 2000
Diphtheria 206,929 (1921)
%D
2
-99.99
Measles
894,134 (1941)
63
-99.99
Mumps
152,209 (1968)
315
-99.80
Pertussis
265,269 (1952)
6,755
-97.73
Polio
21,269 (1952)
0
-100
Rubella
57,686 (1969)
152
-99.84
Tetanus
1,560 (1923)
26
-98.44
HiB
~20,000 (1984)
1,212
- 93.14
Hep B
26,611 (1985)
6,646
-75.03
Effects of Vaccination
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Smallpox
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1974
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First human disease eradicated from the face
of the earth by a global immunization
campaign
Only 5% of the world’s children received 6
vaccines recommended by WHO
1994
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>80% of the world’s children receive basic
vaccines
Each year: 3 million lives saved
Smallpox
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One of world’s deadliest diseases
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Vaccine available in early 1800s
Difficult to keep vaccine viable enough to deliver in
developing world
Elimination of smallpox
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1950: stable, freeze dried vaccine
1950: Goal  Eradicate smallpox from western
hemisphere
1967: Goal achieved except for Brazil
1959: Goal  Eradicate smallpox from globe
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Little progress made until 1967 when resources dedicated,
10-15 million cases per year at this time
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Strategies:
 Vaccinate 80% of population
 Surveillance and containment of outbreaks
May 8, 1980: world certified as smallpox free
Childhood Immunization
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1977:
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Goal to immunize at least 80% of world’s
children against six antigens by 1990
rtsp://audio.npr.org/me/20021120.me.10.smil
Vaccines
What is Still Needed?
What Vaccines are needed?
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The big three:
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HIV
Malaria
Tuberculosis
Summary of Lecture 9
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How do vaccines work?
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How are vaccines made?
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Non-infectious vaccines
Live, attenuated bacterial or viral vaccines
Carrier Vaccines
DNA Vaccines
How are vaccines tested?
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Stimulate immunity without causing disease
Lab/Animal testing
Phase I-III human testing
Post-licensure surveillance
Impact of vaccines
Assignments Due Next Time
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Two reading assignments:
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WTIND - p. 147, 172, 182-185, 311-315
CPS - 767-782
WA5 (Vaccines)