1 IMMUNIZATION

2 Immunization is a means of providing specific protection against many common and damaging pathogens by stimulating an organism's immune system.

3 Milestones in immunization u1500BC uTurks introduce variolation u 3000BC u Evidence of sniffing powdered small pox crust in Egypt u 2000BC u Sniffing of small pox crust in China u 1700AD u Introduction of variolation in England and later in the US

4 1920s Diphtheria and Tetanus 1934 Pertussis 1955 Salk polio Modern era of the vaccine 1885 Rabies vaccine (Pasteur)

5 1960s Mumps measles and rubella virus Sabin polio 1990s Hepatitis and varicella 1985 Haemophilus Modern era of the vaccine

6 Pre- & post-vaccine incidence of common preventable diseases

7 Different modes of acquiring immunity Natural Passive IgG Active Infection Immunity Acquired Passive Igs Active Vaccination

8 Natura l Artificia l Colostral transfer of IgA Placental transfer of IgG Antibodies or immunoglobulins Immune cells Passive Immunity

9 disease indication antibody source Passive Immunization human, horsediphtheria, tetanusprophylaxis, therapy vericella zoster human immunodeficiencies gas gangrene, botulism, snake bite, scorpion sting horse post-exposure rabies, human post-exposure hypogamma- globulinemia human prophylaxis

10 Advantages Disadvantages serum sickness immediate protection no long term protection graft vs. host disease (cell graft only) risk of hepatitis and Aids Advantages and Disadvantages of Passive Immunization

11 Active Immunization Natural Artificial exposure to sub- clinical infections Attenuated organisms killed organisms sub-cellular fragments toxins others

12 Types of vaccines Killed vaccines: These are preparations of the normal (wild type) infectious, pathogenic MO that has been rendered non- pathogenic, usually by chemical treatment such as with formalin that cross-links viral proteins. Attenuated vaccines: These are live MO particles that grow in the vaccine recipient but do not cause disease because the vaccine virus has been altered (mutated) to a non-pathogenic form; for example, its tropism has been altered so that it no longer grows at a site that can cause disease. Sub-unit vaccines: These are purified components of the MO, such as a surface antigen. DNA vaccines: These are usually harmless MO into which a gene for a (supposedly) protective antigen has been spliced. The protective antigen is then made in the vaccine recipient to elicit an immune response

13 Advantages of attenuated vaccines 1.They activate all phases of immune system. They elicit humoral IgG and local IgA (figure 8) 2.They raise an immune response to all protective antigens. Inactivation, such as by formaldehyde in the case of the Salk vaccine, may alter antigenicity 3.They offer more durable immunity and are more cross- reactive. Thus, they stimulate antibodies against multiple epitopes which are similar to those elicited by the wild type virus 4.They cost less to produce 5.They give quick immunity in majority of vaccinees 6.In the cases of polio and adenovirus vaccines, administration is easy 7.These vaccines are easily transported in the field 8.They can lead to elimination of wild type virus from the community

14 Disadvantages of Attenuated vaccine 1.Mutation. This may lead to reversion to virulence (this is a major disadvantage) 2.Spread to contacts of the vaccinee who have not consented to be vaccinated (This could also be an advantage in communities where vaccination is not 100%) 3.Spread of the vaccine virus that is not standardized and may be mutated 4.Sometimes there is poor "take" in tropics 5.Live viruses are a problem in immunodeficiency disease patients

15 Advantages of inactivated (Killed) vaccine 1.They give sufficient humoral immunity if boosters given 2.There is no mutation or reversion (This is a big advantage) 3.They can be used with immuno-deficient patients 4.Sometimes they perform better in tropical areas

16 Disadvantages of inactivated (Killed) vaccines 1.Some vaccinees do not raise immunity 2.Boosters tend to be needed 3.There us little mucosal / local immunity (IgA). This is important (figure 8) 4.Higher cost 5.In the case of polio, there is a shortage of monkeys 6.In the case of smallpox, there have been failures in inactivation leading to immunization with virulent virus.

17 tuberculosis Polio (Oral) Sabin not used in std. schedule measles, mumps & rubella yellow fever Military and travelers Varicella zoster children with no history of chicken pox hepatitis A not required in SC Live Attenuated Vaccines

18 Polio Salk IM influenza elderly and at risk typhoid, cholera, plague epidemics and travelers rabies post exposure pertussis replaced by the acellular vaccine Killed Whole-Organism Vaccines Q fever population at risk

19 Microbial Fragment Vaccines Bordetella. Pertussis virulence factor protein Haemophilus influenzae B protein conjugated polysaccharide Streptococcus pneumoniae Polysaccharide mixture Neisseria meningitidis polysaccharide

20 Microbial Fragment Vaccines Clostridium tetani (tetanus) inactivated toxin (toxoid) Corynebacterium diphtheriae inactivated toxin (toxoid) Vibrio cholerae toxin subunits Hepatitis B virus cloned in yeast

21 Modification of Toxin to Toxoid toxin moiety antigenic determinants chemical modification ToxinToxoid

22 Future Vaccines

23 NEW METHODS OF VACCINE PRODUCTION 1.Selection for mis-sense 2.Synthetic peptides 3.Anti-idiotype vaccines 4.Recombinant DNA techniques

24 Selection for mis-sense Conditional lethal mutants. Temperature-sensitive mutants in influenza A and RSV have been made by mutation with 5-fluorouracil and then selected for temperature sensitivity. In the case of influenza, the temperature-sensitive gene can be reassorted in the laboratory to yield a virus strain with the coat of the strains circulating in the population and the inner proteins of the attenuated strain. Cold adapted mutants can also be produced in this way. It has been possible to obtain mis-sense mutations in all six genes for non-surface proteins.

25 Synthetic peptides Injected peptides which are much smaller than the original virus protein raise an IgG response but there is a problem with poor antigenicity. This is because the epitope may depend on the conformation of the virus as a whole. A non-viral example that has achieved some limited success is a prototype anti-malarial vaccine.

26 Anti-idiotype vaccines An antigen binding site in an antibody is a reflection of the three-dimensional structure of part of the antigen, that is of a particular epitope. This unique amino acid structure in the antibody is known as the idiotype which can be thought of as a mirror of the epitope in the antigen. Antibodies (anti-ids) can be raised against the idiotype by injecting the antibody into another animal. This gives us an anti-idiotype antibody and this, therefore, mimics part of the three dimensional structure of the antigen, that is, the epitope. This can be used as a vaccine. When the anti- idiotype antibody is injected into a vaccinee, antibodies (anti-anti-idiotype antiobodies) are formed that recognize a structure similar to part of the virus and might potentially neutralize the virus. This happens: Anti-ids raised against antibodies to hepatitis B S antigen elicit anti-viral antibodies.

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28 Recombinant DNA techniques 1.Attenuation of virus 2.Single gene approach (Yeast) 3.Cloning of a gene into another virus

29 DNA VACCINES These vaccines are based on the deliberate introduction of a DNA plasmid into the vaccinee. The plasmid carries a protein-coding gene that transfects cells in vivo at very low efficiency and expresses an antigen that causes an immune response.

30 Advantages of DNA vaccines 1.Plasmids are easily manufactured in large amounts 2.DNA is very stable 3.DNA resists temperature extremes and so storage and transport are straight forward 4.A DNA sequence can be changed easily in the laboratory. This means that we can respond to changes in the infectious agent 5.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, for example, using a recombinant plasmid to produce an antigen in yeast (e.g. the HBV vaccine), purifying that protein and using it as an immunogen. 6.Mixtures of plasmids could be used that encode many protein fragments from a virus or viruses so that a broad spectrum vaccine could be produced 7.The plasmid does not replicate and encodes only the proteins of interest 8.There is no protein component and so there will be no immune response against the vector itself 9.Because of the way the antigen is presented, there is a cell-mediated response that may be directed against any antigen in the pathogen. This also offers protection against diseases caused by certain obligate intracellular pathogens (e.g. Mycobacterium tuberculosis)

31 Possible Problems of DNA vaccines 1.Potential integration of plasmid into host genome leading to insertional mutagenesis 2.Induction of autoimmune responses (e.g. pathogenic anti-DNA antibodies) 3.Induction of immunologic tolerance (e.g. where the expression of the antigen in the host may lead to specific non- responsiveness to that antigen)

32 Problems in vaccine development Different types of virus may cause similar diseases -- e.g. the common cold. As a result, a single vaccine will not be possible against such a disease Antigenic drift and shift -- This is especially true of RNA viruses and those with segmented genomes Large animal reservoirs. If these occur, re-infection after elimination from the human population may occur Integration of viral DNA. Vaccines will not work on latent virions unless they express antigens on cell surface. In addition, if the vaccine virus integrates into host cell chromosomes, it may cause problems (This is, for example, a problem with the possible use of anti-HIV vaccines based on attenuated virus strains) Transmission from cell to cell via syncytia - This is a problem for potential AIDS vaccines since the virus may spread from cell to cell without the virus entering the circulation. Recombination and mutation of the vaccine virus in an attenuated vaccine.

33 The eradication of smallpox There is no animal reservoir for variola, only humans are infected by this virus Once a person has been infected by the virus, there is lifelong immunity, although this may not be the case with people immunized using the vaccine strain Subclinical cases rare and so an infected person can be identified and isolated Infectivity does not precede overt symptoms, that is there is no prodromal phaseprodromal There is only one Variola serotype and so the vaccine is effective against all virus strains The vaccine is very effective There has been a major commitment by the World Health Organization and governments

34 Vaccination checklist Here's a checklist of the vaccines that are routinely offered to everyone in the UK for free on the NHS, and the age at which you should ideally have them. 2 months: Diphtheria, tetanus, pertussis (whooping cough), polio and Haemophilus influenzae type b (Hib, a bacterial infection that can cause severe pneumonia or meningitis in young children) given as a 5-in-1 single jab known as DTaP/IPV/Hib Pneumococcal infection

35 Vaccination checklist Basic Vaccination Schedule جدول التطعيمات الأساسية Visit Vaccine اللقاحالزيارة At Birth BCG الدرن الولادة HepB الإلتهاب الكبدي ( ب ) 2 months IPV شلل الأطفال المعطل شهرين ( DTP, HepB )( الثلاثي البكتيري ؛ الإلتهاب الكبدي ( ب ) ؛ المستدمية النزلية ) 4 months OPV شلل الأطفال الفموي 4 شهور (DRP, HepB, Hib)( الثلاثي البكتيري ؛ الإلتهاب الكبدي ( ب ) ؛ المستدمية النزلية ) 6 months OPV شلل الأطفال الفموي 6 شهور (DRP, HepB, Hib)( الثلاثي البكتيري ؛ الإلتهاب الكبدي ( ب ) ؛ المستدمية النزلية ) 9 months Measles (mono) الحصبة المفرد 9 شهور 12 months OPV شلل الأطفال الفموي 12 شهر MMR الثلاثي الفيروسي Varicella الجديري المائي 18 months OPV شلل الأطفال الفموي 18 شهر ( DTP m Hib H influenzae type B ) ( الثلاثي البكتيري ؛ المستدمية النزلية ) Hepatitis ( A ) الإلتهاب الكبدي ( أ ) 24 months Hepatitis ( A ) الإلتهاب الكبدي ( أ ) 24 شهر 4-6 years OPV شلل الأطفال الفموي 4-6 سنوات DTP الثلاثي البكتيري MMR, Varicella الثلاثي الفيروسي + الجديري المائي

36 Adverse Events Occurring Within 48 Hours DTP of Vaccination Event local redness, swelling, pain systemic: Mild/moderate fever, drowsiness, fretfulness vomiting anorexia systemic: more serious persistent crying, fever collapse, convulsions acute encephalopathy permanent neurological deficit