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VACCINES

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VACCINES Outline Why do we need vaccines? Concept of vaccination - how vaccines work Types of vaccines Success and failure of vaccines Vaccine development Why do we ... – PowerPoint PPT presentation

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Title: VACCINES


1
VACCINES
2
Outline
  • Why do we need vaccines?
  • Concept of vaccination - how vaccines work
  • Types of vaccines
  • Success and failure of vaccines
  • Vaccine development

3
Why do we need vaccines?
  • Infectious Disease
  • 1969 U.S. Surgeon General time to close the book
    on infectious disease
  • 1996 Director General WHO We stand on the brink
    of a global health crisis in infectious diseases

4
Challenges
  • Increase in nosocomial infections
  • Drug resistance pathogens
  • Immunosuppressed patients
  • Aging population
  • New emerging diseases
  • Globalization (increased movement and trade)
  • Bioterrorism

5
Control of Infectious Disease
  • Antimicrobials
  • Vaccines
  • Immune modulators

6
History of vaccination
  • Jenner observation that milkmaids did not develop
    smallpox disease
  • Introduced the concept of vaccination using live
    vaccinia virus
  • 100 years later Pasteur introduced a new approach
    in vaccination by killing the organism and
    introducing the agent as a non-replicating
    vaccine
  • Today genetic engineering and biotechnology
    generated recombinant subunit vaccines HBsAg, HPV

7
Concept of vaccination - how vaccines work
  • Individual
  • - Stimulation of immune responses (humoral and
    cellular)
  • - Induction of neutralizing antibody
  • - Training the adaptive immune response to
    generate immune memory
  • Community
  • - Herd immunity reducing transmission of the
    pathogen

8
Ideal situation
  • Epidemiologist would suggest that the ideal
    situation would be that everyone in the world is
    vaccinated except you. In this situation you
    derive most of the benefit and none of the risk.
  • This situation breaks down if you know that you
    will be exposed to the pathogen

9
Infection and disease
  • The selection of immune memory cells by
    vaccination allows the animal to control the
    infection before it gets out of control

10
Correlates of disease protection
  • It is likely impossible to develop an effective
    vaccine to a disease where there is no correlate
    of disease protection (If an infection is always
    fatal)

11
Importance of the proper immune response
  • It is critical for a vaccine to generate the
    appropriate immune response necessary for
    protection
  • A vaccine must stimulate the appropriate immune
    response

12
Vaccine Classes
  • Prophylactic/acute disease
  • Therapeutic/chronic
  • Physiological alteration
  • - Contraceptive
  • - Production alteration
  • Food safety vaccines

13
Types of Vaccines
  • 1 Conventional
  • Live
  • Inactivated
  • 2 Genetically Engineered
  • Live
  • Replication defective
  • Subunit
  • DNA vaccines

14
Live vaccines
  • Pros
  • - Induce broad immunity (both cellular and
    humoral)
  • - Induce stronger immune memory then killed
    vaccines
  • - Can induce mucosal immunity if administered at
    mucosal surfaces
  • - Can shed from vaccinated individuals to
    vaccinate unvaccinatated individuals
  • - Do not require adjuvants
  • Cons
  • Safety issues
  • Can cause disease
  • Reversion to virulence
  • Can be shed from vaccinated population

15
Inactivated killed vaccines
  • Pros
  • - Safe since they are killed
  • - Multiple antigens for more broad immunity
  • Cons
  • - Require adjuvants
  • - Difficult to generate cell mediated immunity
  • - Difficult to generate mucosal immunity

16
Genetically engineered vaccines live replication
defective
  • Pros
  • - Generation of both cellular and humoral
    immunity
  • - Natural antigen expression
  • - Good induction of immune responses
  • Cons
  • - Immunity generated to the vector
  • - Regulatory hurdles

17
Subunit vaccines
  • Pros
  • - Safety
  • - More expensive
  • Cons
  • - Require adjuvants
  • - Antigen is not processed effectively on class
    I MHC therefore CTLs are not effectively
    generated
  • - Only a few vaccines are recombinant (HBsAg)
  • - Usually only a single antigen

18
Conjugated vaccines
  • Conjugation to add help Haemophilus influenzae
    type B vaccine
  • Bacterial polysaccacharides T cell independent
    antigens

19
DNA Vaccines Work by Transfection of Host Cells
20
Production of DNA vaccines
  • Pros
  • - Single simple platform
  • - Ease of manipulating DNA to create vaccine
  • - Ease of mixing different antigen-encoding
    plasmids together
  • - Ease in manufacturing
  • - Low cost
  • - Rapid production
  • Cons
  • - Current capacity to produce Kg quantities of
    plasmid is very limited
  • - Current production processes need to be
    streamlined and become more efficient

21
Distribution of DNA vaccines
  • Pros
  • - Do not require refrigeration
  • Cons
  • - Currently there are no commercial DNA vaccines
    for any human disease

22
Safety of DNA vaccines
  • Pros
  • - Non-infectious (no reversion to virulence)
  • - Low toxicity
  • - Low immunogenicity compared to conventional
    vectors
  • - No harsh adjuvants (plasmid backbone has
    adjuvant properties)
  • Cons
  • - Regulatory issues
  • - Very small risks of integration
  • - Risk adverse society that may not accept the
    extremely rare theoretical risks with DNA
    vaccines.

23
Immunity generated by DNA vaccines
  • Pros
  • - Antigen is produced in natural form
  • - No specific immunity is generated to plasmid
    vector
  • - Antigen presentation on both MHC I and MHC II
  • - Generate both humoral and cellular immunity
  • - Protective immunity demonstrated for several
    infectious agents
  • - Potential for improved memory responses
  • Cons
  • - Poor translation of results from mice to host
    species
  • - Some pathogens may require many antigens to
    induce protective immunity
  • - Require some molecular knowledge of pathogen
  • - Limited studies evaluating immune memory

24
Adjuvants
  • An agent that without antigen does not stimulate
    the adaptive immune response but when combined
    with antigen enhances the adaptive immune
    response.
  • How do adjuvants work?
  • - Stimulation of innate immune responses such as
    inflammation
  • - Improved antigen uptake and processing

25
Adjuvants
  • Licensed adjuvants
  • - Alum
  • - QS21 MF59
  • Safety issues with adjuvants
  • - Alum can cause sarcomas at the injection site
    in cats following vaccination

26
Immunization with cocktail of HIV-derived
peptides in montanide ISA-51 is immunogenic, but
causes sterile abscesses and unacceptable
reactogenicity.
Graham BS, et al. PLoS One. 2010 5e11995.
27
Success and failure of vaccines
  • Vaccination is one of the most cost-effective
    approaches for the management of infectious
    disease

28
Vaccines/Disease Eradication
  • Small pox -1980
  • Polio WHO target 2005
  • Measles WHO target 2010

29
Failure of vaccines
  • There are still many infectious diseases where
    there is no effective vaccine
  • Diseases which cell mediated immunity is
    essential are very difficult to generate vaccines
    to
  • Viruses that are latent are difficult to generate
    vaccines for
  • Viruses that mutate frequently require new
    vaccines each year

30
RSV vaccine failure
  • Vaccine increased pathogenesis of RSV in infants
    following exposure to RSV
  • Mechanism hypothesised
  • - formalin inactivated RSV induced biased Th2
    responses that lead to increased disease caused
    by RSV

31
Influenza A vaccines
  • Require a new vaccine to be generated every year
  • There is no universal vaccine available for
    influenza

32
Common cold virus vaccine
  • Failure to generate a vaccine for the common cold
  • Reason
  • - there are several different viruses and
    serotypes that cause colds
  • To generate a vaccine for the common cold it
    would require antigens from all of the different
    cold viruses

33
Herpes simplex virus vaccines
  • No licensed vaccine
  • Reason
  • - Latent nature of HSV means the vaccine must
    provide sterile immunity since once infected the
    virus will go latent

34
HIV vaccine failure
  • Neutralizing antibodies can be evaded by mutation
    of HIV envelop glycoproteins
  • Latent HIV can hide from the immune system
  • Resistance of exposed individuals to HIV is
    questionable
  • Mechanism of protection is not well understood or
    may not exist

35
Vaccines for parasites
  • Complicated lifecycle
  • Many different antigens in the parasite make
    antigen selection difficult

36
Summary of success and failure of vaccines
  • Clearly there have been successful application of
    vaccines against infectious disease
  • However there is still challenges in developing
    vaccines to many different pathogens

37
Immune memory
  • 500 B.C. Thucydides noted that those whose
    survived the plague were protected from the
    plague the same man was never attacked twice
  • Definition An immune response that is more rapid
    and vigorous in amplitude
  • Greater number of antigen specific cells and
    cells that can respond to antigen faster than
    naïve cells.

38
How is immune memory measured
  • Antigen recall responses
  • Antibody responses in serum
  • Cellular immune responses ELISPOT, CTL, and FACs
    analysis
  • Challenge experiments

39
Immune memory
40
Memory cells
  • There is a time lag for memory cells to become
    effector cells
  • This is illustrated best with Montezumas Revenge
  • - locals have immunity, however when the leave
    for a period of time and come back they get sick
  • Reason
  • - their effector cells have waned and there is a
    lag time for memory cells to become effector cells

41
Rabies Vaccine
  • Can give the vaccine following exposure
  • Reason
  • - Virus is slow growing and effector cells can
    be generated by vaccination in time to protect
    from disease

42
Can immune memory last a lifetime
  • It has been illustrated that B cell memory can
    last at least 50 years after Smallpox vaccination
  • However, memory wanes with time
  • Other vaccines do not induce long lasting immune
    memory
  • Require repeated administration of vaccines

43
Ideal vaccine
  • Safe
  • Single administration (ideally needle-free)
  • Long lasting immunity
  • Protect against many diseases (combination
    vaccine)
  • Induce sterile immunity
  • No current vaccine has all the traits of an ideal
    vaccine

44
Future Directions
  • Improved delivery of vaccines
  • Mucosal protection
  • Improved vaccine production (influenza vaccine)
  • Combination vaccines
  • Universal vaccines
  • Single dose vaccines
  • Improved adjuvants
  • Improved efficacy of DNA vaccines

45
Improved delivery of vaccines
  • Why?
  • - Improved compliance
  • - Ease of delivery (No need for trained medical
    personnel)
  • - Prevent disease caused by needle-sticks
  • - Prevent disease caused by the reuse of needles
  • How
  • - Needle-free delivery
  • - Oral
  • - Nasal
  • - Topical

46
Mucosal immunity
  • Why
  • - The vast majority of pathogens enter via
    mucosal surfaces
  • - Especially important for respiratory
    infections
  • - Can reduce shedding at mucosal surface
  • Challenge
  • - Development of vaccines the stimulate mucosal
    immunity
  • - Oral and nasal delivery of vaccines

47
Topical delivery of vaccines
  • Principle
  • - Topical application of vaccines has been
    demonstrated to induce immunity
  • Challenges
  • - Inefficient antigen penetration through the
    skin
  • Possible solutions
  • - Delivery using liposomes
  • - Delivery using physical methods to penetrate
    the skin

48
Improved vaccine production
  • Why
  • - Lack of vaccine production capacity
  • - Illustrated by influenza virus vaccines
  • - If there was an influenza virus pandemic there
    would not be enough vaccine to vaccinate the
    entire population
  • Challenges
  • - Develop improved vaccine production methods
    using cell culture in addition to current egg
    production methods

49
Combination vaccines
  • Why
  • - Improve compliance
  • - Reduce the number of vaccine administrations
  • Challenges
  • - Regulatory issues
  • - Need to demonstrate safety and efficacy with
    the new vaccine combination

50
Single dose vaccines
  • Why
  • - Generate rapid immunity
  • - Reduce the number of vaccine administrations
  • Challenge
  • - It is difficult to generate strong primary
    immune responses to vaccines other then live
    vaccines

51
Universal vaccines
  • Why
  • - Eliminate the need for new vaccines to be
    developed each year for changing pathogens
  • Challenge
  • - It is more difficult to generate vaccines
    eliciting cell mediated immunity required for
    universal vaccines then antibody mediated
    vaccines

52
Improved adjuvants
  • Why
  • - Limited number of licensed adjuvants
  • - Alum Th2 skewing
  • - Adjuvants not potent enough
  • - Allow antigen sparring
  • - Faster induction of immune responses
  • Current work
  • - Stimulation of Toll-like receptors using their
    ligands, CpG

53
Immunostimulatory effects of CpG DNA
CpG
Proliferate TH1, CTL
T Cell
IL-12 TNF-a IFN-a
Class II MHC B7-1, B7-2
Monocyte Macrophage Dendritic Cell
NK Cell
B Cell
IFN-g
Secrete IL-6 IL-8 Cytokines
IL-6, IL-10 Immunoglobulin
proliferate express class II MHC, B7-1,
B7-2 become apoptosis resistant
54
New development in adjuvants
  • Controversy
  • - Myd88/Trif Lps2/Lps2 mice immunized with
    different adjuvants (Freund's complete and
    incomplete adjuvant) still responded to the
    adjuvant
  • - Results indicate that TLRs are not essential
    for adjuvants to work
  • Explanation
  • - Redundancy of the immune system in knock-out
    mice

55
Improved efficacy of DNA vaccines
  • Methods for increasing DNA vaccine efficacy
  • DNA Prime followed by a recombinant vector boost
  • Electroporation

56
Veterinary applications
  • Differentiating infected from vaccinated animals
    (DIVA)
  • Using a vaccine that does not elicit antibodies
    that occur following natural infection
  • Examples 3ABC from foot and mouth disease

57
Process development
  • Identification of suitable antigens, adjuvants
    and delivery systems
  • Regulatory
  • Technical and production issues
  • Timeline for development 7-9 years

58
Vaccine development
  • Antigen selection
  • Vaccine type and formulation
  • Animal challenge model
  • Efficacy testing

59
Antigen selection
  • How do you determine what antigen(s) to use in a
    vaccine?
  • Selection of antigens by screening convalescent
    sera
  • Understanding receptors responsible for pathogen
    binding/uptake

60
Vaccine type and formulation
  • How do you determine what type and formulation to
    use?

61
Animal challenge model
  • How do you develop an animal challenge model?
  • Problems with animal models
  • Models sometimes do not generate the same results
    as the host species
  • Mice seem to always generate positive vaccine
    study results

62
Efficacy testing
  • Following animal trials the vaccine must be
    evaluated in the target species
  • Vaccines must have a high level of efficacy 90
    or greater

63
Development of an attenuated influenza virus
vaccine for swine
  • Identify an approach to attenuate influenza virus
  • Modify the HA that requires trypsin to activate
    it to require elastase
  • Demonstrate that the virus is attenuated and does
    not cause disease in swine (Reverse
    genetics-generated elastase-dependent swine
    influenza viruses are attenuated in pigs. Masic
    A, Babiuk LA, Zhou Y. J Gen Virol. 2009
    90375-85.)

64
Development of an attenuated influenza virus
vaccine for swine
  • Demonstrate protection in swine against
    homologous and heterologous influenza virus
    challenge (Elastase-dependent live attuenuated
    swine influenza A viruses are immunogenic and
    confer protection against swine influenza A virus
    infection in pigs. Masic A, Booth JS, Mutwiri GK,
    Babiuk LA, Zhou Y. J Virol. 2009 8310198-210.)

65
Antibody responses following vaccination
Masic et al. J Virol. 2009 8310198-210.
66
Gross pathology following influenza challenge
Masic et al. J Virol. 2009 8310198-210.
67
Influenza virus titers following challenge
Masic et al. J Virol. 2009 8310198-210.
68
Development of an attenuated influenza virus
vaccine for swine
  • Demonstrate protection in swine against H1N1 2009
    influenza

69
Influenza titers in lungs following pandemic H1N1
challenge
70
Influenza viral RNA copies in lungs following
pandemic H1N1 challenge
71
Shedding following pandemic H1N1
72
Development of an attenuated influenza virus
vaccine for swine
  • Evaluate if a single dose would be effective as a
    vaccine
  • Conduct field trials for true evaluation of
    efficacy
  • Deal with regulatory issues and manufacturing
    issues
  • Marketing of the vaccine

73
Summary
  • Clearly there are many areas in vaccine research
    that can be improved

74
Group discussion
  • Putting knowledge learned today into practice

75
Group discussion
  • What part of the immune response would and ideal
    adjuvant influence?

76
Group discussion
  • Is it possible to develop a vaccine to protect
    against a novel pandemic influenza virus before
    the pandemic started?
  • Is so what type of vaccine would this be?

77
Group discussion
  • Why do live vaccines generate improved immunity
    compared to killed vaccines?

78
Group discussion
  • Are there ways of mimicking a live virus
    infection for vaccination?
  • Are these methods currently as good as live virus
    infections?

79
Group discussion
  • How would you go about developing an HIV vaccine?

80
Group discussion
  • It is possible to develop a vaccine to help drug
    addicts?
  • How would you make this type of vaccine?
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