Chapter 18 Vaccination

Chun-Keung Yu, DVM, PhDDepartment of Microbiology and Immunology

College of Medicine

National Cheng Kung University

• 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

(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

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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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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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.

Very effective

Moderately effective

Why?

Poor

(Salk)

破傷風

白喉

Most successful bacterial vaccines

霍亂

No vaccines against staphylococcal and streptococcal exotoxins, or against endotoxins (i.e., LPS).

Antigens purified from bacteria or produced by recombinant DNA technology

Carrier proteins: tetanus toxoid or diphtheria toxoid

More Expensive!

Poor immunogenic

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

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

(concentrate antigen)

(effective adjuvant when coupled directly to antigen)

氫氫化鈹

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

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

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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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

Minor local pain, swelling at injection site, mild fever

2010.2.5

The MMR vaccine controversy resulted in measles epidemics

22

Giving five immunogens simultaneously?‘Too much’ for the delicate immune system of infants?

Already 5-in-1Hib

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

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)

Toxin

Toxin

Rheumatoid arthritis

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

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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