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Vaccines

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... Cowpox/Swinepox 1800 s Compulsory childhood vaccination 1930 s Last natural UK case 1940 s last natural US case 1958 WHO program October 1977: ... – PowerPoint PPT presentation

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Title: Vaccines


1
Vaccines
  • Successes of the Past
  • Possibilities for the Future

2
Vaccines
  • Immunity to viral infections usually depends on
    the development of an immune response to
  • Antigens on the virus surface
  • Antigens on the virus-infected cell
  • In most cases response to internal proteins has
    little effect on humoral immunity to infection
  • Humoral antibodies can be important
    diagnostically (HIV)

3
Vaccines
  • Minor role for internal proteins can be seen in
    influenza pandemics
  • New flu viral strain contains a novel
    glycoprotein
  • Pandemic virus contains internal proteins to
    which the population has already been exposed
  • Nevertheless the CTL response to internal
    proteins is important

Surface glycoprotein protective immunogen which
must be identified for a logical vaccine
4
Vaccines
  • Some viruses have more than one surface protein
  • Influenza (Orthomyxovirus)
  • Hemagglutinin - attaches virus to cell receptor
  • Neuraminidase - involved in release of virus
    from cell
  • Hemagglutinin is major target stimulates
    neutralizing antibody

5
Vaccines
  • Neutralization may result from
  • Binding of antibody to site on virus surface -
    block interaction with receptor
  • Aggregation of virus by polyvalent antibody
  • Complement-mediated lysis

6
Vaccines
Addition points to note Site in body at which
virus replicates Three major sites for viral
replication
7
Three major sites for viral replication
  • Mucosal surfaces of respiratory tract and GI
    tract. Rhino myxo corona parainfluenza
    respiratory syncytial rota
  • Infection at mucosal surfaces followed by spread
    systemically via blood and/or neurones to target
    organs picorna measles mumps HSV varicella
    hepatitis A and B
  • Direct infection of blood stream via needle or
    bites and then spread to target organs hepatitis
    B alpha flavi bunya rhabdo
  • Local immunity via IgA very important in 1 and 2.

8
There is little point in having a good
neutralizing humoral antibody in the circulation
when the virus replicates, for example, in the
upper respiratory tract. Clearly, here secreted
antibodies are important. Although in the case of
influenza serum antibodies may be important
9
Vaccines - Problems
  • Different viruses may cause similar
    disease--e.g. common cold
  • Antigenic drift and shift -- especially true of
    RNA viruses and those with segmented genomes
  • Shift reassortment of segmented genomes (flu
    A but not rota or flu B)
  • Drift rapid mutation - retroviruses
  • Large animal reservoirs - Reinfection may occur

10
Vaccines - Problems
  • Integration of viral DNA. Vaccines will not work
    on latent virions unless they express antigens on
    cell surface. In addition, if vaccine virus
    integrates it may cause problems
  • Transmission from cell to cell via syncytia
  • Recombination of the virulent strain or of the
    vaccine virus

11
Smallpox
12
Smallpox
13
Smallpox
14
Smallpox
15
Polio Vaccine
16
100
Inactivated (Salk) vaccine
Cases per 100,000 population United States
10
Oral vaccine
1
Reported cases per 100000 population
0.1
0.01
0.001
1950
1960
1990
1970
1980
17
Total casesSweden and Finland
10000
Killed (Salk) vaccine
1000
Reported cases
100
10
1
0
1950
1955
1960
1965
1970
1975
18
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19
Sabin Polio Vaccine
  • Attenuation by passage in foreign host
  • More suited to foreign environment and less
    suited to original host
  • Grows less well in original host
  • Polio
  • Monkey kidney cells
  • Grows in epithelial cells
  • Does not grow in nerves
  • No paralysis
  • Local gut immunity (IgA)
  • Pasteur rabies vaccine also attenuated

20
Salk Polio Vaccine
  • Formaldehyde-fixed
  • No reversion

21
Polio Vaccine
  • Why use the Sabin vaccine?
  • Local immunity Vaccine virus just like natural
    infection
  • Stopping replication in G.I. Tract stops viral
    replication TOTALLY
  • Dead Salk vaccine virus has no effect on gut
    replication
  • No problem with selective inactivation
  • Greater cross reaction as vaccine virus also has
    antigenic drift
  • Life-long immunity

22
Polio Vaccine
  • New CDC Guidelines
  • Last US natural (non-vaccine associated) case was
    15 years ago
  • 2 does injectable (Salk) vaccine
  • 2 doses oral
  • Vaccine cases 1 in 3 million does
  • New strategy will prevent about 5 of the 10
    vaccine-associated cases (the five found in
    vaccinees)
  • Cost 20 million
  • Savings from eradication 230 million

23
New Recommendations
To eliminate the risk for Vaccine-Associated
Paralytic Poliomyelitis, the ACIP recommended an
all-inactivated poliovirus vaccine (IPV) schedule
for routine childhood polio vaccination in the
United States. As of January 1, 2000, all
children should receive four doses of IPV at ages
2 months, 4 months, 6-18 months, and 4-6 years.
24
Vaccines
Advantages of Attenuated Vaccines I
  • Activates all phases of immune system. Can get
    humoral IgG and local IgA
  • Raises immune response to all protective
    antigens. Inactivation may alter antigenicity.
  • More durable immunity more cross-reactive

25
Vaccines
Advantages of Attenuated Vaccines II
  • Low cost
  • Quick immunity in majority of vaccinees
  • In case of polio and adeno vaccines, easy
    administration
  • Easy transport in field
  • Can lead to elimination of wild type virus from
    the community

26
Vaccines
  • Disadvantages of Live Attenuated Vaccine
  • Mutation reversion to virulence (often
    frequent)
  • Spread to contacts of vaccinee who have not
    consented to be vaccinated (could also be an
    advantage in communities where vaccination is not
    100)
  • Spread vaccine not standardized--may be
    back-mutated
  • Poor "take" in tropics
  • Problem in immunodeficiency disease (may spread
    to these patients)

27
Vaccines
  • Advantages of inactivated vaccines
  • Gives sufficient humoral immunity if boosters
    given
  • No mutation or reversion
  • Can be used with immuno-deficient patients
  • Sometimes better in tropics
  • Disadvantages of inactivated vaccines
  • Many vaccinees do not raise immunity
  • Boosters needed
  • No local immunity (important)
  • Higher cost
  • Shortage of monkeys (polio)
  • Failure in inactivation and immunization with
    virulent virus

28
New Methods
  • Selection of attenuated virus strain
  • Varicella
  • Hepatitis A
  • Use monoclonal antibodies to select for virus
    with altered surface receptor
  • Rabies
  • Reo
  • Use mutagen and grow virus at 32 degrees. Selects
    for temperature-sensitive virus. Grows in upper
    respiratory tract but not lower
  • flu (new vaccine)
  • respiratory syncytial virus

29
New Methods
Recent flu vaccine from Aviron Passage
progressively at cold temperatures TS mutant in
internal proteins Can be re-assorted to so that
coat is the strain that is this years flu strain
30
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31
New Methods
  • Deletion mutants
  • Suppression unlikely (but caution in HIV)
  • Viable but growth restrictions
  • Problems
  • Oncogenicity in some cases (adeno, retro)

32
New Methods
33
Single gene (subunit) - problems
  • Surface glycoprotein poorly soluble - deletion?
  • Poorly immunogenic
  • Post-translational modifications
  • Poor CTL response

34
Single gene (subunit) in expression vector
  • Vaccinate with live virus
  • Canary Pox
  • Infects human cells but does not replicate
  • Better presentation
  • CTL response
  • Vaccinia
  • Attenuated Polio
  • Being developed for anti-HIV vaccine

35
New Methods
  • Chemically synthesized peptide
  • malaria
  • poorly immunogenic

36
New methods
Anti-idiotype vaccine
Virus
epitope
Antibody with epitope binding site
37
Anti-idiotype vaccine cont
Make antibody against antibody idiotype
Anti-idiotype antibody mimics the epitope
38
Anti-idiotype antibody cont 2
Use anti-idiotype antibody as injectable vaccine
Use as vaccine
Binds and neutralizes virus
Antibody to anti-idiotype antibody
39
New Methods
  • New Jennerian Vaccines
  • Live vaccines derived from animal strains of
    similar viruses
  • Naturally attenuated for humans
  • Rotavirus Monkey Rota
  • 80 effective in some human populations
  • Ineffective in others
  • Due to differences in circulating viral serotypes

40
New Methods
  • New Jennerian Vaccines
  • Bovine parainfluenza Type 3
  • Bovine virus is
  • Infectious to humans
  • Immunogenic (61 of children get good response)
  • Poorly transmissable
  • Phenotypicaly stable

41
New Methods
42
Vaccines
  • 1796 Jenner wild type animal-adapted virus
  • 1800s Pasteur Attenuated virus
  • 1996 DNA vaccines
  • The third vaccine revolution

43
DNA Vaccines
Gene for antigen
Muscle cell
plasmid
Muscle cell expresses protein - antibody made CTL
response
44
DNA Vaccines
  • Plasmids are easily manufactured in large
    amounts
  • DNA is very stable
  • DNA resists temperature extremes so storage and
    transport are straight forward
  • DNA sequence can be changed easily in the
    laboratory. This means that we can respond to
    changes in the infectious agent
  • By using the plasmid in the vaccinee to code for
    antigen synthesis, the antigenic protein(s) that
    are produced are processed (post-translationally
    modified) in the same way as the proteins of the
    virus against which protection is to be produced.
    This makes a far better antigen than purifying
    that protein and using it as an immunogen.

45
DNA Vaccines
  • Mixtures of plasmids could be used that encode
    many protein fragments from a virus/viruses so
    that a broad spectrum vaccine could be produced
  • The plasmid does not replicate and encodes only
    the proteins of interest
  • No protein component so there will be no immune
    response against the vector itself
  • Because of the way the antigen is presented,
    there is a CTL response that may be directed
    against any antigen in the pathogen. A CTL
    response also offers protection against diseases
    caused by certain obligate intracellular
    pathogens (e.g. Mycobacterium tuberculosis)

46
DNA Vaccines
  • Possible Problems
  • Potential integration of plasmid into host
    genome leading to insertional mutagenesis
  • Induction of autoimmune responses (e.g.
    pathogenic anti-DNA antibodies)
  • Induction of immunologic tolerance (e.g. where
    the expression of the antigen in the host may
    lead to specific non-responsiveness to that
    antigen)

47
DNA Vaccines
  • DNA vaccines produce a situation that reproduces
    a virally-infected cell
  • Gives
  • Broad based immune response
  • Long lasting CTL response
  • Advantage of new DNA vaccine for flu
  • CTL response can be against internal protein
  • In mice a nucleoprotein DNA vaccine is effective
    against a range of viruses with different
    hemagglutinins

48
Towards an anti-HIV Vaccine
  • Questions
  • For a vaccine what are the measures of
    protection?
  • Can we overcome polymorphism?
  • What are the key antigens?
  • Attenuated or killed or neither?
  • Mucosal immunity critical?
  • Prevent infection or prevent disease?
  • Animal models
  • How does HIV kill cells anyway?

49
Towards an anti-HIV Vaccine
50
Towards an anti-HIV Vaccine
51
Towards an anti-HIV Vaccine
  • Chimp studies designed for success
  • Animals challenged with small doses of virus at
    moment that antibody levels high (virus --not
    infected cells!)
  • Challenge virus same strain as that used to
    induce antibody
  • No vaccine made from one virus strain has
    protected chimps from another virus strain
  • Protection in man may not result from
    neutralizing antibodies at all
  • Ability to raise neutralizing antibodies in
    monkeys does not correlate with protection
  • Cell-mediated immunity is the key
  • This is also key in humans
  • HIV-exposed but not infected people shows signs
    of a cell-mediated response

52
Towards an anti-HIV Vaccine
Since 1986 gt 15 SUBUNIT VACCINES Based on
gp160/gp120 All safe None effective Low levels
of strain-specific antibodies that quickly
disappear Only ephemeral effects of
cell-mediated immunity All done with gp160/gp120
of syncytium-inducing virus None tested on large
groups of high risk people
53
Towards an anti-HIV Vaccine
  • A Classical Approach?
  • December 1992 Live attenuated SIV vaccine
    protected all monkeys for 2 years against massive
    dose of virus
  • All controls died
  • cell mediated immunity was key

54
Towards an anti-HIV Vaccine
Humans NEF deletion mutant
55
Towards an anti-HIV Vaccine
  • Live attenuated
  • Pro
  • SIV with NEF deletion protects after ONE
    immunization
  • Long lived cell-mediated and humoral immunity
  • Possible herd immunity
  • Con
  • Safety in immunodeficient people
  • LTR
  • Reversion
  • Need multiple strains polymorphism

56
Towards an anti-HIV Vaccine
  • Inactivated
  • Pro Simple
  • Mimics natural infection
  • Protects against systemic and rectal challenge
  • No reversion
  • Con
  • Polymorphism
  • LTR
  • Inactivation failure

57
Towards an anti-HIV Vaccine
  • Subunit vaccine
  • Pro
  • Safety
  • Con
  • Ephemeral humoral response
  • Little cell mediated response

58
Towards an anti-HIV Vaccine
  • Subunit in vector
  • Pro
  • Potent cell-mediated immunity

59
Towards an anti-HIV Vaccine
  • Problems for all vaccines
  • Enhancing antibody
  • Vaccine may be immunosuppressive (anti-MHC)

60
Towards an anti-HIV Vaccine
  • Summary of problems
  • Virus can hide in cells
  • Cell-cell transmission
  • Ethical problems
  • Lack of animal models
  • Immuno-silent sugars
  • Polymorphism/hypervariability DRIFT
  • Activation of same cells that virus infects
  • Useless if T4 cells are depleted
  • Blood brain barrier
  • Oncogenicity
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