1. BACTERIAL VACCINES DR. BIMAL KUMAR DAS, M.D. DEPARETMENT OF MICROBIOLOGY ALL INDIA INSTITUTE OF MEDICAL SCIENCES NEW DELHI

2. BACTERIAL VACCINES

3. History and Achievements of Vaccines During the 15th century, an early form of smallpox vaccination was practiced in China and other parts of the world. Healthy people were intentionally infected with substances from the pustules of people suffering from smallpox, a technique called variolation. A mild form of smallpox usually resulted from this practice. An English doctor, Edward Jenner, improved the variolation technique to create the first vaccine in 1796. Dr. Jenner had heard that dairymaids who had been infected with cowpox, a disease related to but milder than smallpox, were not susceptible to smallpox, and decided to test the idea. He performed the first vaccination on a boy with material taken from lesions of cowpox. In fact, the word vaccination comes from the Latin word for cow, vacca.

4. Benefits of Vaccines Smallpox eradicated –In 1900 - >20,000 cases and 1,000 deaths Polio eliminated Control or near elimination of –Measles –Mumps –Rubella –Tetanus –Diphtheria –Pertussis –Haemophilus influenzae type b (Hib)

5. Vaccine Preventable Bacterial Diseases Diphtheria Diphtheria Pneumococcal disease Hib disease Meningococcal meningitis Pertussis (Whooping Cough) Tetanus (Lockjaw) Pertussis (Whooping Cough) Tetanus (Lockjaw) Typhoid Cholera Anthrax Plague

6. Terms Vaccination & Vaccine –Derive from the term vaccinia, the virus once used as smallpox vaccine. Originally, the term vaccine only meant protection from smallpox. Immunization –The process of inducing or providing immunity artificially by administering an immunobiologic. May be passive or active

7. Immunization Vocabulary Terms Immunobiologic –Antigenic substances (vaccines and toxoids) or antibody-containing preparations (globulins and antitoxins) from human or animal donors. Used for active or passive immunization. Examples include: Vaccine Toxoid Immune globulin (IG) Intravenous immune globulin (IGIV) Specific immune globulin Antitoxin

8. How Vaccines Work 1.Active Immunization 2. Passive Immunization 3. Community immunity or “herd immunity” is an important part of protecting the community against disease

10. Immunity Active Immunization –Production of antibody (humoral immune response) through the administration of a vaccine or toxoid. Passive Immunization –Provision of temporary immunity by the administration of preformed antibodies Pooled human IG or IGIV Specific immune globulin preparations antitoxins

11. Active Immunity from person's own immune system. Generally long- lasting, even a lifetime Protection after disease--immunologic memory. Memory B-cells circulate in blood and reside in bone marrow Vaccine Factors that influence immune response to vaccination ·Presence of maternal antibody. ·Nature and dose of antigen. ·Route of administration ·Presence of adjuvants (aluminum containing materials to improve immunogenicity, also gold).

12. Properties of an ideal vaccine 1. 100% safe 2. Do not cause disease in others 3. No residual pathogenicity 4. Will prevent disease 5. Effective against all strains 6. Only one dose required 7. Compatibility with other vaccines 8. Deliverable without hypodermic syringe 9. Indefinite room temperature storage 10. Cheap to manufacture 11. Capable of inducing effective herd immunity

13. There are two general categories of vaccines whole-cell vaccines subunit vaccines

14. Whole-cell vaccines Whole-cell vaccines consist of entire organisms that have been modified in some manner so that they are unable (or drastically less able) to cause disease. Whole-agent vaccines consist of two general categories: inactivatedinactivated (whole killed) genetically attenuatedgenetically attenuated (live-attenuated) Subunit vaccines VaccinesVaccines made from well defined components of microorganisms are called a subunit vaccine Recombinant vaccines A subunit vaccine that is produced using recombinant techniques is called a recombinant vaccine.

15. Newer vaccines – Still Experimental DNA vaccine Peptide vaccine Anti-idiotype vaccine

16. Advantages of DNA vaccines 1)Plasmids are easily manufactured in large amounts 2) DNA is very stable 3) DNA resists temperature extremes so storage and transport are straight forward 4) DNA sequence can be changed easily in the laboratory. 5) By using the plasmid in the vaccinee to code for antigen synthesis, 6) Mixtures of plasmids could be used that encode many protein fragments from a virus/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) there is a CTL response

17. Possible Problems 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)

18. Immunogiologic components Suspending fluids –Sterile water, saline, or fluids containing proteins Preservatives, stabilizers, antibiotics –Inhibit or prevent bacterial growth in viral cultures, or to stabilize the antigens or antibodies Allergic reactions can occur if the recipient is sensitive to one of these additives –Thimerosal, phenol, albumin, glycine, neomycin Adjuvants –Components used to enhance the immunogenicity of the immunogiologic Aluminum phosphate, aluminum hydroxide

19. ConditionLiveInactivated Allergy to Component CC Encephalopathy --C Pregnancy CV Immunosuppression CV Moderate/severe illness PP Recent Blood Product PV

20. DTP Diphtheria, Tetanus, & Pertussis Prevents –Diphtheria caused by Corynebacterium diphtheriae ( Vaccine Protective efficacy 95%) –Tetanus caused by Clostridium tetani (Vaccine Protective efficacy 100%) –Pertusis (whooping cough) caused by Bordetella pertussis (Vaccine Protective efficacy 71%) Not given to children over 7 years

21. Hib Haemophilus influenzae B Prevents meningitis caused by H. influenzae B Products available PRP-D (ProHIBIT) (Used only in infants over 18 months) HbOC (HibTITER) PRP-T (ActHIB & OmniHIB) PRP-OMP (PedVaxHIB) Storage –Refrigerate Administration –IM Side effects –Pain, redness, swelling at site Vaccine Protective Efficacy 95%

24. PCV7 Pneumococcal conjugate Prevents pneumococcal disease, including bacterial meningitis & otitis media Vaccine effectiveness lasts 3 years –Most pneumococcal disease occurs in 1 st 2 years Recommended as of 7/21/2000 for routine use in infants under 23 months, and high-risk infants between 24-59 months Vaccine Protective Efficacy 90%

25. PCV7 Given at 2,4,6, and 12-15 months Administration –IM Side effects –Pain & redness at site, fever Alternative vaccine –PPV23 (Pneumococcal Polysaccharide)

26. Meningococcal Vaccine Prevents bacterial meningitis caused by Neisseria meningitidis –Groups A, C, Y, W- 135 Risk factors –Intimate & household contact –Dormitory living –Travelers –Military Storage –Refrigerate Administration –SQ Side effects –Pain & redness at site –Headache, malaise, fever Protective Efficacy 85%

27. Typhoid vaccine Two typhoid vaccines are currently available for use (Killed TAB vaccine is replaced by the newer vaccine) 1. an oral, live-attenuated vaccine (Vivotif Berna(tm) vaccine, manufactured from the Ty21a strain of S. typhi by the Swiss Serum and Vaccine Institute) Oral Ty21a (Gal E mutant) Primary vaccination with oral Ty21a vaccine consists of a total of four capsules, one taken every other day. Repeat the series every five years if needed for continued coverage. 2. a capsular polysaccharide vaccine for injection (Typhim Vi(tm), manufactured by Pasteur Merieux). Typhim Vi Primary vaccination with Typhim Vi consists of one injection given intramuscularly. Repeat this every two years if needed for continued coverage. Protective efficcacy 50%-80% of recipients.

28. Bacillus of Calmette and Guérin (BCG) vaccine Reduce mortality and morbidity in Children< 5years old Two meta-analyses of the published results of BCG vaccine clinical trials and case-control studies confirmed that the protective efficacy of BCG for preventing serious forms of TB in children is high ( >80%). These analyses, however, did not clarify the protective efficacy of BCG for preventing pulmonary TB in adolescents and adults; this protective efficacy is variable and equivocal.

29. Cholera vaccine Whole cell killed vaccine Whole cell killed vaccine + B subunit vaccine (WC/rBS) Live attenuated vaccine CVDHg103R Two recently developed vaccines for cholera are licensed and available are - Dukoral®, Biotec AB - Mutacol®, Berna. Both vaccines appear to provide a somewhat better immunity and fewer side-effects than the previously available vaccine. Vaccine Protective Efficacy in the first six months Vaccine Protective Efficacy 50-60% in three years ( Also effective against ETEC) Not effective against O139

30. Lyme disease Prevents Lyme disease caused by Borrelia burgdorferi transmitted by ticks –Used in persons over 15 years –Vaccine not 100% effective; Tick bite protection recommended Series of 3 vaccines should be completed before tick season (before April) Storage –Refrigerate Administration - IM

31. Vaccine against Anthrax Vaccine for humans: ( avirulent and nonencapsulated) sublethal amounts of the toxin produced Licensed in the U.S. is a preparation of the protective antigen (PA) Dose: A. 3 doses subcutaneously at the interval of 2 wks B. Followed by three additional doses at 6,12 and 18 months C. Annual booster dose Professionals ( Veternarians, butcher, Zoo keeper, Wild life workers, Forest guards, Military personnels ) Vaccine against Plague Available since 1896 Efficacy not determined in proper studies Two vaccines : Killed vaccine : 2 dose at 7-14 days interval, booster at 6 months Live vaccine : Y. pestis ( Otten’s Tjiwidej, EV 76 strain) – No longer used

32. Other Infant Vaccines Combination Vaccines –Hep-B and Hib (Comvax) Not used in infants under 6 weeks Not used if mother HBsAg+ –DTaP and Hib (TriHIBit) Used for 4 th dose only

33. Special Issues for Infant Vaccination Pre-term birth –Pre-term infants should be vaccinated at the same chronological age and according to schedule as full-term infants and children. –Birthweight and size are not factors to postpone vaccination. –Divided or reduced doses are not recommended. Breastfeeding –Breastfed infants are vaccinated with the same schedule. –Breastfeeding is not a contraindication for vaccination.

34. Special Considerations Health Care Workers –Hep-B –Influenza –MMR –Varicella Immunosuppressed Adults –Do NOT administer MMR International Travelers –Determine recommended vaccines by checking CDC Travelers’ Destination web page

35. Vaccine Development During the 20 th century, several infectious diseases have been eliminated or reduced dramatically through the introduction of vaccines. Current bacterial vaccine development –Tuberculosis –Foodborne bacterial infections –Anthrax –On-going work to improve current vaccines –Needle-free technology

36. Adverse Events Adverse Event –Any event following a vaccine May be a true adverse reaction, or only coincidental May be local, systemic, or allergic Adverse Reaction –Unintended effect caused by the vaccine –May be contraindication for future doses Side Effect –Common event to be expected in percentage of recipients –Usually not serious –Not contraindication for future doses

37. VACCINE DEVELOPOMENT Vaccine licensure is a lengthy process that may last up to 10 years. 1. Laboratory studies : Safety and Immunogenicity Studies Clinical trials 2. Phase I trial : Phase One trials are small, involving only 20-100 volunteers. To continue to gather information on efficacy and safety of each vaccine, 3. Phase II trial : Phase Two trials are larger (with several hundred volunteers), and last anywhere from a few months to a few years. 4. Phase III trial : Phase Three trials have several hundred to several thousand participants and typically last many years. 5. Phase IV trial: Vaccine is licensed and marketed. Data regarding side effects are collected

38. Inherent Weaknesses Of current vaccine Vaccines prevent disease, not infection Vaccination against a disease which does not induce natural immunity, even given exposure to the wild pathogen, is difficult Vaccines against toxins for various reasons must be boosted from time to time Because vaccines are biological materials, they suffer from the inherent lability of such materials and therefore are difficult to deliver intact to geographically remote locals

39. Edward Jenner

41. Advantages: Very close to infectious agent Immune response similar to natural infection Disadvantages: Severe or fatal reactions possible Reversion to pathogenic (wild) form Interference from circulating antibody Stability Currently available live attenuated vaccines: Viral: measles, mumps, rubella, yellow fever, vaccinia, varicella Bacterial: BCG Recombinant Typhoid vaccine

43. Advantages: Nonreplicating Noninfectious Minimal interference from circulating antibody Disadvantages: Immune response mostly humoral Antibody titer falls over time Principal antigen may not be well defined Require multiple doses. The first primes the immune system. The protective response after occurs after the second or third dose. Boosters are often necessary. Currently available inactivated vaccines: Viral: influenza, polio, rabies, hepatitis A Bacterial: typhoid, cholera, plague Fractional vaccines: hepatitis B, influenza, acellular pertussis Toxoids: diphtheria, tetanus, botulism, acellular pertussis Pure polysaccharides: pneumococcal, meningococcal Polysaccharide conjugates: Haemophilus influenzae type b, pneumococcal