1. Lecture 26. Prevention and Control -- Vaccines
Flint et al., chapter 19, pp

2. How do we acquire immunity?
HOW LONG LASTING???
aby from other human beings - a few weeks to a few months
IgG from mom 3-6months
used for: botulism
diphtheria
hepatitis
measles
rabies
snake/spiders bites

3. Passive Immunity in Infants

4. Artificial Passive Immunity
Gamma globulin
Ig’s from pooled blood of at least 1,000 human donors
variable content
non-specific
Specific immune globulin (SIG)
higher titers of specific antibodies
Antisera and antitoxins of animal origin

5. Antibody and effector T-cells are the basis of protective immunity
Primary infection stimulates an initial immune response.
A second infection is “inapparant” because it provokes no symptoms.
However, it does re-stimulate and fine tune the immune response.
Years later, memory B- and T-cells can become reactivated upon infection, protecting the individual from disease

6. Artificial Active Immunity
Vaccination (Immunization)
exposing a person to material that is antigen but NOT pathogenic.
Regardless of the nature of the immunizing substance, the mechanism of active immunization is the same:
When administred, the immune system recognizes it as foreign and produces antibodies or cytotoxic Tcells or both AND memory cells. The immune response is the same as the one that occurs during the course of a disease. The disease doesn’t occur because whole organisms aren’t used or (if whole orgare used) they have been weaked so that they are no longer virulent.

7. History of Vaccination: Smallpox
Smallpox killed or maimed 10% of humankind.
Killed > 300,000,000 people in the 20th century alone
Ancient Chinese history: a once in a lifetime disease.
11th century China and India: “Variolation”
Scratch a healthy person with pus from infected person
If they don’t die, they are immune for life

8. Vaccination May 14, 1796, Edward Jenner
Noted that milkmaids got cowpox, but not smallpox.
Injected pus from a cowpox lesion under the skin of a child
Waited 2 weeks
Deliberately infected the child with smallpox.
The boy survived
(Today, Jenner would be majorly sued, would lose his license, be put on trial, get a good lawyer, write a book, and do the talk show circuit…Just like Michael Jackson’s doctor!)

9. History of Vaccination
Despite Jenner’s success, it took 100 years til the next vaccine.
1881, Louis Pasteur: coined the word Vaccine.
Used dried spinal cord from rabid rabbit to create a rabies vaccine.
Also developed vaccines to fowl cholera and anthrax
July 6, 1885: 9 year old Joseph Meister who was badly bitten by a rabid dog.
Although Pasteur was not a licensed physician and faced legal risks, the boy would most certainly have died without treatment like many before him.
Pasteur decided to treat the boy nevertheless and inoculated Joseph with rabies vaccine that had been tested only on dogs previously.
The risk paid off and the boy recovered dramatically.

10. Large scale vaccination programs
Fig. 19.1
Dramatic improvements in public health.
Nobody in this room has had…
Smallpox, Polio, Measles, Chickenpox
Mumps, Rubella
…Because of vaccination
Smallpox is the only human disease to ever be eradicated

11. Characteristics of a good vaccine
Safe
Few side effects
Give long lasting, appropriate protection
Low in cost
Stable with long shelf life (no special storage requirements)
Easy to administer
Inexpensive
Public must see more benefit than risk

14. Types of vaccines whole agent subunit recombinant
individual parts alone

15. Whole agent vaccines -- Killed using heat or formaldehyde
Killed virus
Live virus
epitopes
epitopes
Problem: These microbes are dead! Living organisms, b/c they replicate in the body, usually elicit a more robust immune response and are more likely than killed organisms to cause production of memory cells. Living organism provide longer stimulation of the immune system. Despite this limitation, there have been a number of effective killed microbe vaccines
Inactivated polio vaccine (Salk)
Influenza (Classic)

16. Whole agent vaccines -- Attenuated
attenuated - a process that lessens the virulence of a microbe
Attenuation is usually achieved by modfying the growth conditions or manipulating microbial genes in a way that eliminates virulence factors.
Attenuation methods include long-term cultivation, selection of mutant strains that grow at lower (or higher) temperatures, passage of the microbe through unnatural hosts or tissue culture
TB vaccine was obtained after 13 years of subculturing an agent of bovine TB
oral polio vaccine (Sabin),
MMR (measles, mumps, rubella)
Influenza -- Flumist TM

17. Vaccines stimulate immune memory
Killed virus vaccine requires multiple doses (booster shots) to adequately stimulate a protective immune response
Live virus vaccines replicate in the host.
No requirement for boosters.

18. Attenuation of viruses by passage through non-human cells
Pathogenic virus isolated from patient, grown in human cells
Infect monkey cells with cultured virus
Virus acquires many mutations that allow it to grow well in monkey cells
Mutations make the virus unable to grow well in human cells
 Vaccine candidate 1 2 3 4

19. Advantages for live vaccines
multiply like natural organism
require fewer doses and boosters
long-lasting
Disadvantages for live vaccines
special storage
back mutation
side effects
side effects - both live and dead whole cell vaccines

20. Live attenuated Sabin oral poliovirus vaccine

21. Construction of recombinant attenuated virus
Isolate virus
Clone genome
Isolate virulence gene
Mutate or delete virulence gene
Resulting virus is
Viable
Immunogenic
Not virulent
Can be used as a vaccine

22. Subunit vaccines Single antigen or mixture of antigens
Safer (cannot reproduce)
However, often less effective than whole agent vaccines
Can be costly
Always require boosters
Provide an alternative to whole microbes vaccines in cases where the Whole microbes are toxic. Subunit vaccines have two drawbacks.
COST: it is much more expensive to extract and purify isolated antigens than to use intact microbes.
BOOSTERS: must be administered more than once to mimic the repeated stimulation of the immune system by a living organism.
Their safety has made them very popular.

23. Overcoming Subunit vaccine problems
Multiple doses - booster shots
Use adjuvants
prolongs stimulation of immune response
works by trapping the antigens in a chemical complex and releases them slowly
DTp - p was killed bacteria for whooping cough (Bordetella pertussis)
aP - acellular pertussis is now a toxoid - as effective as killed whole cells
Usually require a series of injections (boosters) b/c cannot replicate - THIS IS A PROBLEM!!

24. Vaccine delivery systems and adjuvants
ISCOMS as peptide delivery systems
Fig. 19.9

25. Recombinant vaccines Genetic engineering approach Hepatitis B
Vaccina or adenovirus alteration
Hep BA second vaccine, produced by recombinant DNA technology, has since become available. Previously, vaccine administration was restricted to individuals who were at high risk of exposure to hepatitis B, namely: infants of hepatitis B carrier mothers, health care workers, homosexual men and intravenous drug abusers. However, hepatitis B has been targetted for eradication , and since 1995 the vaccine has been included in the universal childhood immunization schedule. Three doses are given; at 6, 10, and 14 weeks of age. As with any killed viral vaccines, a booster will be required at some interval (not yet determined, but about 5 years) to provide protection in later life from hepatitis B infection as a venereal disease. Another strategy to make a bacterial vaccine is to use part of the sugar coating (or polysaccharide) of the bacteria. Protection against infection by certain bacteria is based on immunity to this sugar coating. However, because young children don't make a very good immune response to the sugar coating alone, the coating is linked to a harmless protein (this is called a "conjugated polysaccharide" vaccine). The haemophilus influenzae B (or Hib) and pneumococcal vaccines are made this way.

26. Create a recombinant plasmid containing a gene encoding a specific antigen.
Engineer in sequences
Enabling it to be expressed in humans
Passaged through bacteria
Introduce it into humans
Let the human cells produce the antigen
Present it to T-cells
Provoke immune response
DNA vaccines

27. Representative results of DNA vaccine trials