chapter 18 vaccination chun-keung yu, dvm, phd department of microbiology and immunology college of...
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Chapter 18 Vaccination
Chun-Keung Yu, DVM, PhDDepartment of Microbiology and Immunology
College of Medicine
National Cheng Kung University
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• Vaccination is the best known and most successful application of immunological principles to human health.
• Edward Jenner (1749-1823): used vaccinia (the cowpox) to prevent smallpox
• Louis Pasteur (1822-1895): altered preparations of microbes to generate enhanced immunity against fully virulent organism (dried rabies-infected rabbit spinal cords; heated anthrax bacilli 炭疽 )
• Clonal selection theory
• Discovery of T and B lymphocytes
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(佐劑 )
(immunity of the population – protect non-immune individual)
• Two ways to induce immune response Infection and vaccination
• Vaccination = active immunization Prime and boost
• Passive immunization = ?
(primary response)
(secondary response)
1
2
3
4
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Vaccine
• Antigen of microbes (contain multiple epitopes)
• Whole cell (organism) or part of it (protein, sugar, genome)
– the more antigens of the microbe retained in vaccine, the better
• Living (natural or attenuated 減毒 ) or non-living (inactivated 去活化 )
– living tend to be more effective than killed
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© 2005 Elsevier
The only one. Use as vector for other microbe antigens
白喉
斑疹傷寒
百日咳 傷寒 霍亂 鼠疫
水痘 - 帶狀皰疹
卡介苗
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© 2005 Elsevier
Highly successful: reduce virulence and retain immunogenicity (virus > bacteria)
(Sabin)
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Attenuation • Virulence: the ability to replicate efficiently and disseminate within the
body with pathological consequences
• Attenuated microbes are less able to cause disease in natural hosts
• Adaption (in vitro or in vivo) in adverse conditions of growth: induce random set of mutations– Type I polio vaccine: 57 mutations, never reverted to wild type– Types 2 and 3 polio vaccine: 2 mutations, frequent reversion to wild type,
lead to paralytic poliomyelitis– Yellow fever virus: 17D strain, passage in mice and chick embryo– BCG: M. Bovis → BCG (13 years of culture in vitro)
• Attenuated viruses often do not make good vaccine: do not induce inflammation and thus no adjuvant effect.
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Very effective
Moderately effective
Why?
Poor
(Salk)
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破傷風
白喉
Most successful bacterial vaccines
霍亂
No vaccines against staphylococcal and streptococcal exotoxins, or against endotoxins (i.e., LPS).
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Antigens purified from bacteria or produced by recombinant DNA technology
Carrier proteins: tetanus toxoid or diphtheria toxoid
More Expensive!
Poor immunogenic
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Antigens with no or low antigenicity
Anti-antigen antibody (protein in nature)
Make monoclonal antibody against its V region
Screening
As an antibody it can be massively produced and good in antigenicity
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Adjuvant• Certain substances, i.e., aluminum salts, added to or
emulsified with an antigen, greatly enhance antibody production
• Effect of adjuvant– Concentrate antigen at site of immune response– Induce cytokines
• Many bacterial carbohydrates and glyolipids are good adjuvant (TLR activation)– Complete Freund’s adjuvant– Experimental use; killed mycobacteria suspended in oil
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(concentrate antigen)
(effective adjuvant when coupled directly to antigen)
氫氫化鈹
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Vaccine delivery• Injection: mostly use; have safety concerns (transmit
diseases, i.e., HIV, HBV, HCV…)• Mucosal immunization
– Oral immunization: live polio vaccine (Sabin) work, most killed vaccines do not work
• Antigens may be broken down in GI tract. Intestinal immune system is designed to generate tolerance rather than immune response
• Intestinal adjuvant (toxins from pathogenic intestinal microbes) may overcome this problem
– Nasal immunization
• Transdermal route
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Vaccine efficacy
• Sufficient immunogenicity: live vaccine > killed vaccines (need boost with adjuvant)
• Stable on storage: live vaccines, ‘cold chain’ from manufacturer to clinic
• Induce the right sort of immunity:
– Antibody for toxins and extracellular microbes
– Cell-mediated immunity for intracellular microbes
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Properties of antigen determine the type of immunity induced
• Live vaccines: prolonged antigenic stimulation with greater number of microbial antigens; work in the right site (live polio)
• Killed vaccines: short antigenic stimulation
• Subunit vaccines: – Poor immunogenic – (Hypothetically) smaller the antigen, more MHC
restriction– Polysaccharides are thymus independent, do not bind to
MHC, do not immunize T cells; need carrier proteins
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© 2005 Elsevier
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Vaccine safety has become an overriding consideration
• 國光的 H1N1疫苗安全嗎?• 打完翻白眼 !國光疫苗逾 10童暈眩• 疫苗含汞• 劉小弟疑打疫苗致死案• 疫苗緩打潮、疫苗信心危機
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Minor local pain, swelling at injection site, mild fever
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2010.2.5
The MMR vaccine controversy resulted in measles epidemics
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22
Giving five immunogens simultaneously?‘Too much’ for the delicate immune system of infants?
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Already 5-in-1Hib
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Vaccines in general use have variable success rates (eradication of disease)
• Smallpox: global eradication
• Poliovirus: almost succeed – Live (Saban) poliovirus vaccine: types 2 and 3
reversion to virulence; use Salk vaccine
• Other vaccines: unlikely to succeed– Carrier state: hepatitis B– Suboptimal effectiveness: BCG– Side effect: reduce willingness– Free-living forms and animal hosts
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Designing an effective vaccine is difficult when the ideal type of immune response is not clear (lack of understanding of how to induce effective immunity)
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Toxin
Toxin
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Rheumatoid arthritis
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Vaccines for non-infectious conditions
• Tumors
• Human chorionic gonadotropin (hCG): birth control
• Drugs: treatment of drug dependency
• Lipid-binding proteins: lowering cholesterol
• Amyloid plaque: prevent Alzheimer’s disease
Possible problem: breakdown tolerance of self molecules
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Future vaccines will use genes and vectors to deliver antigens
• Vaccina is a convenient vector
• Attenuated bacteria: BCG and salmonellae
• Transgenic plants expressing vaccine antigens
• ‘Naked’ DNA
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