1 Milestones in immunization u 1500BC u Turks introduce variolation u 1885AD u Pasteur discovers rabies attenuated vaccine 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 u 1780AD u Edward Jenner discovers small pox vaccine

2 The wife of the British Ambassador in Turkey, in March 1717 wrote, following the variolation of her son, to a friend in England: “The small pox, so fatal, so general amongst us, is entirely harmless here by the invention of ingrafting….I am patriot enough to bring this invention into fashion in England. The wife of the British Ambassador in Turkey, in March 1717 wrote, following the variolation of her son, to a friend in England: “The small pox, so fatal, so general amongst us, is entirely harmless here by the invention of ingrafting….I am patriot enough to bring this invention into fashion in England. Introduction of variolation

3 Edward Jenner Discovery of small pox vaccine

4 Edward Jenner Among patients awaiting small pox vaccination

5 1920s Diphtheria and Tetanus 1934 Pertussis 1955 Salk polio 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 resistance Artificial Natural Passive Artificial Natural Active Immunity Acquired

8 NaturalArtificial 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 tuberculosis used at birth polio* 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 our country Live Attenuated Vaccines

13 polio 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

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

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

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

17 anti-Idiotype Vaccine Immuno-dominant peptide Future Vaccines DNA

18 Recommended Childhood Immunization Schedule (2003)

19 ATTRIBUTES OF A GOOD VACCINE n Appropriate immune response n Long-term protection n Safe n Stable n Affordable

20 RESPONSE TO IMMUNIZATION Depends on Viability of antigen Total dose especially killed vaccine Route and site of administration Age of recipient Patient’s condition and immune state Genetic factors

21 TYPES OF ANTIGENS 1.Live attenuated (oral polio, BCG, VZV) 2. Killed vaccine (influenza, IPV, Hepatitis A, pertussis) 3. Toxoid (tetanus, diphtheria) 4. Purified (subunit) antigen (Meningococcal vaccine, Haemophilus influenzae vaccine) 5. Recombinant antigen (hepatitis B) 6. DNA vaccines (in investigational phase) 7. Synthetic peptides (in investigational phase)

22 LIVE ATTENUATED VACCINES n Live organisms – reproduce natural infection, without conferring disease n Virulence much reduced n In vitro culture n Select strains that replicate poorly in target organ - minimize damage

23 LIVE ATTENUATED VACCINES n Undergoes potency testing, neuro-virulence testing, test for wild-type strains and other infectious agent n E.g. measles, mumps, rubella, VZV, OPV (Sabin), BCG è what adverse events are likely to be associated with live vaccines? è what potential safety problems would you expect?

24 KILLED/INACTIVATED VACCINES n Live microorganisms inactivated by heat or chemical means (e.g. formalin) n Final concentrate tested for sterility, microorganism inactivation, potency, endotoxin, residuals concentration, pH, etc. n E.g. Salk polio vaccine, rabies vaccine, hepatitis A vaccine, pertussis vaccine

25 PURIFIED (SUBUNIT) ANTIGEN n Only parts of pathogen necessary to elicit the immune response are used n Potential toxins are avoided n Need to be conjugated to evoke an adequate T-cell response

26 POLYSACCHARIDE CONJUGATE VACCINES n Polysaccharide/oligosaccharide of antigen is linked (conjugated) to a protein carrier – increases antibody response and increases of production of memory cells – immunologic response at earlier age – booster effect on subsequent exposure to antigen (via infection /immunization exposure) n E.g. meningococcal vaccine, Haemophilus influenzae type B (Hib) vaccine

27 RECOMBINANT ANTIGEN VACCINES n Bulk production of antigenic protein using recombinant technique n Recombinant technique - insert DNA from pathogen into expression vehicle (i.e. E. coli, Chinese Hamster ovary cells, yeast, etc) n Antigenic protein produced, harvested and purified before use n Example – recombinant hepatitis B vaccine

28 METHODS USED TO ENHANCE IMMUNITY n Conjugation e.g. Hib vaccine n Adjuvants - aluminium salts è why are adjuvants used? è what adverse reactions are associated with their use?

29 COMPONENTS OF THE VACCINE FORMULATION n Suspending agents e.g. water, saline n Preservatives e.g. thiomerosal n Stabilisers e.g. sorbitol and hydrolyzed gelatin - MMR n Adjuvants e.g. aluminium Salts Other substances which may be present n Residuals in the growth medium n Antibiotics, e.g. neomycin, streptomycin - IPV, varicella vaccine  consider these components as well when assessing causality!

30 COMBINATION VACCINES n Diphtheria-tetanus-pertussis (DPT) – pertussis component has adjuvant effect for diphtheria and tetanus toxoids n Different viruses in one vaccination e.g. OPV-type 1, 2, 3 polioviruses

31 ROUTE OF ADMINISTRATION n Should elicit immune response with minimal risk n Deep IM preferable for vaccines with adjuvants (depot effect and less granuloma formation) n SC/intradermal - better for live vaccines to lessen risk of neurovascular injury but still immunogenic (e.g. BCG)

32 Vaccines Safety n Checking vials, ampules when applicable, and labels. n Storing vaccine n Checking vaccine and diluent vials/ampules n Checking the vaccine vial monitors

33 Checking Vials (Ampules) and Labels 1. Label 2. Age of the vaccine (expiration) 3. Signs of contamination 4. Exposure to freezing 5. Exposure to excessive heat

34 Assessing Contamination n If leaks or cracks are present, discard it n Change in appearance or floating particles are seen, discard it n If submerged in water, discard it n If pierced with used needle, discard it n If vaccine was reconstituted more than 6 hours before, discard it n Vial opened for more than 4 weeks, discard it (WHO)

35 Assessing Exposure to Freezing n DPT, DT, Td, TT, hepatitis B, diluents and Hib should be discarded if you highly suspect or are certain that they are/were frozen n “Shake taste” DPT, DT, Td and TT (contain aluminum hydroxide adjuvant) when refrigerator log shows subfreezing temperatures. If failed, discard.

36 Assessing Exposure to Freezing n Hepatitis B and Hib vials should be discarded if frozen or suspected of freezing. The “shake test” doesn’t work for them. n Frozen diluent vials may crack, allowing contamination of the diluent, discard it

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38 Freeze Watch

39 Freeze-tag Shelf life is 5 years.

40 Assessing Exposure to Heat n Vaccine Vial Monitor (VVM) Present: – If VVM inner square is the same color or darker than the outside circle, discard the vial n Vaccine Vial Monitor (VVM) Not Present: – Check temperature log and cold-chain monitoring cards. If exposed to temperatures above 8º C, discard it.

41 Checking Vaccine Vial Monitors n VVM is a label made of heat-sensitive material, placed on the vial to show cumulative heat exposure over time n VVM reduces waste of vaccine, ensuring that only good vaccine is used

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44 Storage n Fill syringe only when patient is ready to receive an injection n Do not combine partially opened vials n Keep opened vials in the refrigerator in a special box marked “returned”, but remember to discard reconstituted vaccines after 6 hours of reconstitution

45 Storage Thermostat Ice Packs in freezing compartment “Returned box Oral Polio, Measles BCG, DPT, TT, diluent Ice packs

46 Checking the Vaccine and Diluent Vials n Before use, check the following: – Is the label still attached to the vial? – Is the right vaccine and right diluent? – Expiration date? – Contamination (discard reconstituted vaccine 6 hours after reconstituted) – Cold sensitive vaccines show no signs of freezing – No signs of heat exposure