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BACTERIAL VACCINES
DR. BIMAL KUMAR DAS, M.D.DEPARETMENT OF MICROBIOLOGY
ALL INDIA INSTITUTE OF MEDICAL SCIENCESNEW DELHI
BACTERIAL VACCINES
History and Achievementsof 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 vaccinationon a boy with material taken from lesions of cowpox. In fact, the word vaccination comes from the Latin word for cow, vacca.
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)
Vaccine Preventable Bacterial Diseases
DiphtheriaPneumococcal disease
Hib diseaseMeningococcal meningitis
Pertussis (Whooping Cough)Tetanus (Lockjaw)
TyphoidCholeraAnthraxPlague
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
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
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
Principles of Vaccination
General RuleThe more similar a vaccine is to
the natural disease, the better the immune response to the vaccine.
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
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).
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
There are two general categories of vaccines
whole-cell vaccines subunit vaccines
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:
inactivated (whole killed) genetically attenuated (live-attenuated)
Subunit vaccines Vaccines 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.
Newer vaccines – Still Experimental
•DNA vaccine
•Peptide vaccine
•Anti-idiotype vaccine
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
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)
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
Contraindications and Precautions
Condition Live Inactivated Allergy to Component C C Encephalopathy -- C Pregnancy C V Immunosuppression C V Moderate/severe illness P P
Recent Blood Product P V
C=contraindication P=precaution V=vaccinate if indicated
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
HibHaemophilus 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%
Haemophilus influenzae type b Vaccine
Routine Schedule
Vaccine 2 mo 4 mo 6 mo 12-18 mo
HbOC x x x x
PRP-T x x x x
PRP-OMP x x x
PRP-D >15 mo
Pneumococcal Vaccines
1977 14-valent polysaccharide vaccine licensed
1983 23-valent polysaccharidevaccine licensed
2000 7-valent polysaccharideconjugate vaccine licensed
PCV7
Pneumococcal conjugate
• Prevents pneumococcal disease, including bacterial meningitis & otitis media
• Vaccine effectiveness lasts 3 years – Most pneumococcal disease occurs in 1st 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%
PCV7
• Given at 2,4,6, and 12-15 months
• Administration – IM
• Side effects – Pain & redness at site, fever
• Alternative vaccine – PPV23 (Pneumococcal Polysaccharide)
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%
Typhoid vaccineTwo 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.
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.
Cholera vaccine
Whole cell killed vaccineWhole 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 monthsVaccine Protective Efficacy 50-60% in three years ( Also effective against ETEC)
Not effective against O139
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
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 wksB. Followed by three additional doses at 6,12 and 18 monthsC. Annual booster dose
Professionals ( Veternarians, butcher, Zoo keeper, Wild life workers, Forest guards, Military personnels )
Vaccine against Plague
Available since 1896Efficacy not determined in proper studiesTwo vaccines :
Killed vaccine : 2 dose at 7-14 days interval, booster at 6 monthsLive vaccine : Y. pestis ( Otten’s Tjiwidej, EV 76 strain) – No longer used
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 4th dose only •
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.
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
Vaccine Development
• During the 20th 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
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
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 hundredvolunteers), 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
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
Edward Jenner
Live Attenuated Vaccines
Attenuated (weakened) form of the "wild" virus or bacteria
Must replicate to be effective
Immune response similar to natural infection
Usually effective with one dose
Advantages:
Very close to infectious agentImmune response similar to natural infection
Disadvantages:
Severe or fatal reactions possibleReversion to pathogenic (wild) formInterference from circulating antibodyStability
Currently available live attenuated vaccines:Viral: measles, mumps, rubella, yellow fever, vaccinia, varicellaBacterial: BCGRecombinant Typhoid vaccine
Inactivated VaccinesGenerally require 3-5 doses
Immune response mostly humoral
Antibody titer falls over time
Principal antigen may not be defined
Advantages:NonreplicatingNoninfectiousMinimal interference from circulating antibody
Disadvantages:Immune response mostly humoralAntibody titer falls over timePrincipal antigen may not be well definedRequire 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 ABacterial: typhoid, cholera, plagueFractional vaccines: hepatitis B, influenza, acellular pertussisToxoids: diphtheria, tetanus, botulism, acellular pertussisPure polysaccharides: pneumococcal, meningococcalPolysaccharide conjugates: Haemophilus influenzae type b, pneumococcal
Combination Vaccines
Whole cell DTP - Hib - Tetramune- ActHIB/DTP
DTaP - Hib (for 4th dose)- TriHIBit
Hepatitis B - Hib- COMVAX