BACTERIAL VACCINES

DR. BIMAL KUMAR DAS, M.D.

DEPARETMENT OF MICROBIOLOGY
ALL INDIA INSTITUTE OF MEDICAL SCIENCES
NEW DELHI

BACTERIAL VACCINES

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.

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
Diphtheria
Pneumococcal disease
Hib disease
Meningococcal meningitis
Pertussis (Whooping Cough)
Tetanus (Lockjaw)
Typhoid
Cholera
Anthrax
Plague

Terms
Derive from the term vaccinia, the virus once used as
smallpox vaccine. Originally, the term vaccine only meant
Vaccination
& Vaccine
protection
from smallpox.
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-co

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 Rule
The 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 longlasting, 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 nonresponsiveness 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
Allergy to Component
C
Encephalopathy
-Pregnancy
C
Immunosuppression
C
Moderate/severe illness P
Recent Blood Product

Inactivated
C
C
V
V
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

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%

Haemophilus influenzae type b

Vaccine
Routine Schedule
Vaccine

2 mo

4 mo

6 mo

12-18 mo

HbOC

PRP-T

PRP-OMP

PRP-D

x
>15 mo

Pneumococcal Vaccines
1977 14-valent polysaccharide
vaccine licensed
1983 23-valent polysaccharide
vaccine licensed
2000 7-valent polysaccharide
conjugate 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, W135

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 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.

Bacillus of Calmette and Gurin (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 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

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 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 ( Ottens 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 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

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 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

Inactivated Vaccines
Generally require 3-5 doses
Immune response mostly humoral
Antibody titer falls over time
Principal antigen may not be
defined

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

Combination Vaccines
Whole cell DTP - Hib
- Tetramune
- ActHIB/DTP
DTaP - Hib (for 4th dose)
- TriHIBit
Hepatitis B - Hib
- COMVAX