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VACCINES
A vaccine can be defined as a preparation of bacterial, viral or other pathogenic agents or of their isolated
antigens which is administered with the objective of stimulating a recipients protective immunity. After
primary exposure of antigen to immunocompetent lymphocytes, there occurs an immune
response called primary immune response. Primary immune response peaks on approximately
the 14th day of antigen exposure. There are two main outcomes of primary response: first,
specific immunocompetent cells (B and T cells) are activated; and second memory cells are
formed. Subsequent exposure to the same antigen stimulates these memory cells which results
in a rapid and more heightened immune response
Thus, a vaccine is basically an antigen or its component that can induce secondary or adaptive immunity in the host. It aims to prevent severe complications of infections by reinforcing or
broadening the defenses by introducing immunological memory.
There are several types of vaccines that are currently and conventionally used. These include
natural live ,live attenuated vaccine, inactivated vaccine, toxoid vaccine, polysaccharide vaccine,
recombinant antigen vaccine live vector vaccine and DNA vaccine.
1. NATURAL LIVE VACCINE:
These preparations include natural non-pathogenic organisms, but which still induce specific
immunity. Currently, live natural vaccines are rarely used. Apart from the cowpox virus
vaccine, no other natural organism is usually used, though live simian and bovine rotaviruses
have been used in vaccination against infant diarrhoea with moderate success.
The problems of these vaccines reside in their ability (albeit hidden) to mutate and convert
into forms that could be pathogenic to human hosts.
2. LIVE ATTENUATED VACCINE:
Attenuation (Latin: attenuare—to weaken) refers to the weakening of the pathogenic bacteria or
virus by making it less virulent without altering its immunogenicity. Microorganisms are
attenuated or weakened so that they do not cause any disease. Attenuation can be achieved by
growing pathogenic microorganisms (bacteria or virus) for a long period of time in a foreign
host such as embryonated eggs or tissue culture cells.
The process of attenuation involves growing microbes (bacteria or viruses) under abnormal
in vitro conditions, be it high bile concentration or passage through foreign cell/tissue such as
embryonated eggs. These abnormal environmental conditions select those mutant cells that are
able to survive and multiply under these conditions. These microbes are then harvested and
used as vaccine. In a normal host, these "pathogenic" microorganisms either fail to multiply or
multiply very slowly because these microbes are now "used to be grown" under abnormal
conditions.
ADVANTAGES OF ATTENUATED VACCINES
Because of the slow growth of attenuated viruses under normal body conditions, attenuated
vaccines provide for prolonged exposure of viral antigen to the immune system resulting in the
production of a large number of B and T cells and, more importantly, memory cells. As a
consequence, most of these vaccines are administered once in a lifetime and do not require
repeated boosters.
The attenuated vaccines that are given orally to children (e.g. Sabin polio vaccine type I) is
given orally on sugar cubes or drops. The attenuated virus enters the gastrointestinal tract and
induces the production of secretory IgA as well as humoral IgG. These antibodies serve as an
important defense against naturally occurring poliovirus.
DISADVANTAGES OF ATTENUATED VACCINES
A major disadvantage of using live attenuated vaccine is the possibility of their reversion to
the virulent form. Type 2 and type 3 Sabin polio vaccine have been shown to revert frequently to
their wild type form.
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Another disadvantage of live attenuated vaccines is that they cannot be given to persons
having immunodeficiency diseases as the immune system of these patients is severely
compromised and these pathogens, even though attenuated or weakened, can induce some
damage.
Sometimes attenuated viruses shed from a recently vaccinated individual via faeces revert to
virulence and cause disease in other individuals.
3.INACTIVATED VACCINES
Another commonly used method for vaccine production is to inactivate the whole pathogen and
then use it for vaccination. The inactivation could be achieved by modifying the antigen
(pathogen) chemically by formaldehyde treatment or physically by heat treatment.
The killed bacteria or viruses are then used in vaccines. Heat inactivation of microbes has
one potential problem. Heat inactivation of microbes causes the denaturation of surface
proteins, that is, its antigenic determinants, and so their antigenic structure is altered. The
antibody/immune response induced by vaccinating these altered antigens may not be effective
against natural pathogen.
Chemical inactivation gives better results. The bacteria or viruses are treated with
formaldehyde, phenol or propionolactone or other amino acid modifying agents for a suitable
period of time. This treatment usually results in the killing of the bacteria or virus with almost
no change in the antigenic structure.
However, chemically inactivated pathogens in vaccines are associated with some risks. The
chemical agent sometimes does not kill all the pathogens present and, as a result, if these
preparations (that contain chemically inactivated pathogen plus some live pathogen that has
somehow escaped inactivation) are administered, it might result in the disease in the vaccinee
(person receiving vaccination).
One of the greatest advantages of using inactivated/killed pathogen in a vaccine is that there
is no danger of mutation or reversion to the pathogenic form. Killed/inactivated vaccines
induce sufficient humoral immunity (if boosters are given). However, they are less effective in
inducing cell-mediated immunity or eliciting mucosal immunity. Since, these are killed
pathogen inactivated vaccine can safely be used in immunodeficient patients.
The disadvantages include the need for repeated boosters, higher cost, and sometimes, as
mentioned previously, a failure in inactivation of virus or bacteria resulting in immunization
with virulent virus.
Advantages
1.No mutation or reversion to wild type
forms since pathogenic organism is dead.
Disadvantages
Weak cell-mediated responses.
2.Provides sufficient humoral immunity.
Requires booster stimulation since organism
cannot replicate inside host.
3. Heat-stable.
Higher cost.
4. Can be used in immunodeficient patients
Inadequate killing of virulent organism can
result in occurrence of the disease.
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Theoretically, live vaccines (natural or attenuated), are generally more effective than
killed ones. Live vaccines provide a large and continual antigenic challenge (slow-growing
pathogen) that replicates to give a large antigenic dose which lasts for days or weeks. Hence
there is no need for giving repeated booster doses. Moreover, antigens of live vaccine are
presented by both class I and class IIMHC molecules inducing balanced response that
includes Tcyt cell as well as TH cell and antibody responses.
Killed whole organism vaccine microbes are presented mainly by the class 11 pathway and
hence establish good humoral immunity. Dead microbe vaccines do not induce good Tcyt-cell
responses; the immunity is short lasting (requires booster) and often not detectable against all
of the viral antigens.
4. TOXOID VACCINES:
The virulence of some pathogenic bacteria depends primarily on the production of exotoxin.
If exotoxins can be neutralized by the body the disease will not occur. These exotoxins are
isolated and chemically modified (usually with formaldehyde) so that their toxicity (but not
immunogenicity) is lost. These non-toxic yet immunogenic derivatives of exotoxin, or toxoids,
are commonly used in vaccines.
Vaccination with a toxoid induces antitoxoid antibodies which are capable of binding the
toxin and neutralizing it. Diphtheria and tetanus vaccines are among the most successful of
all bacterial vaccines produced from toxoids. The toxoids are generally mixed with aluminum
hydroxide which acts as an adjuvant resulting in an increased production of specific
antibodies, encouraging its removal by phagocytic cells and hence stimulating T-cell
response.
There are two major drawbacks.
a. Not all pathogenic organisms produce exotoxin.
b. Those who do produce them secrete them in minuscule quantities so it is difficult to purify
them.
5.POLYSACCHARIDE VACCINES:
The surface of bacteria is the first thing that is exposed to the immune system. Therefore, the
surface antigens can serve as an excellent vaccine. Moreover, some bacteria have resistance to
phagocytic invasion because these cells have capsular polysaccharides that resist
phagocytosis (for example, the polysaccharide capsules of S. pneumoniae, Haemophilus
influenzae and Klebsiella pneumoniae). The coating of these capsular polysaccharides with
antibodies and/or complement components marks them for destruction by phagocytosis.
These observations have paved the way for synthesizing vaccines against bacterial-purified
polysaccharides.
The current vaccine against the bacteria Neisseria meningitidis which causes meningococcal
meningitis, contains purified capsular polysaccharide from types A and C. Another vaccine
against Haemophilus meningitis which is caused by bacteria Haemophilus influenzae type b
consists of purified capsular polysaccharide from H. influenzae type b (Hib). The vaccine for
pneumococcal pneumonia, (which is caused by about 80 different types of strains of
Streptococcus pneumoniae) consists of 23 antigenic ally different types of capsular
polysaccharides.
One major drawbacks of polysaccharide vaccines is their inability to TH cells
or induce adequate memory response. Polysaccharide antigens can be made to stimulate TH
cells by conjugating them to some sort of a protein carrier. The polysaccharide-protein
conjugate activates TH cells which in turn enables the formation of memory B cells. Even
though memory T cells are not formed for some unknown reasons and very few memory B
cells are formed, these polysaccharide vaccines can often provide long-lasting immunity.
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6. RECOMBINANT ANTIGEN VACCINES
With the advent of recombinant DNA technology, virtually any gene-encoding immunogenic
protein can be introduced and expressed in yeast, bacterial or even mammalian cells, using
recombinant DNA technology. These cells are then cultured in the laboratory and the protein
produced endogenously is harvested. The genes that are selected for making recombinant
antigen vaccine are usually surface antigens (mostly glycoproteins). A number of genes
coding for various surface antigens have been successfully cloned in bacterial, yeast and
mammalian cells cultures. Yeasts have emerged as a better choice for making these surface
antigens as they add and process carbohydrate molecules on the protein in their. One such
vaccine approved for human use is hepatitis B vaccine. A single gene for the major surface
antigen of hepatitis B virus (HbsAg) is cloned in yeast cells.
Recombinant antigen vaccines have both advantages and disadvantages. The advantages
include i)the inexpensive production of a large amount of antigens ;
ii) genetic manipulation of antigens. As a foreign gene is introduced from outside into the
yeast cell, and usually the gene sequence of this gene is known, genetic manipulation of the
gene is possible.
iii) Exotoxins of tetanus and diphtheria, can be genetically inactivated. Similarly, antigens can
be made more immunogenic.
The main limitation of this technique is the same as of inactivated vaccine.
i) The recombinant antigens evoke humoral response, stimulating B cells and TH cells (since
antigen is processed by class II MHC pathway) but do not generate potent Tcyt-cell response.
ii) Another limitation which is inherent to the technique itself is that recombinant DNA
technology cannot be used to synthesize carbohydrate antigen. Therefore, this technique is
ineffective in producing antigen if it is a carbohydrate.
7. L I V E V E C T O R V A C C I N E S
In live vector vaccines, the desired gene coding for target antigens of the virulent pathogen is
put into a vector (attenuated bacteria or virus) and then this vector is infected (or
administered orally) to the vaccinee. This vector slowly replicates inside the inoculated
individual and it serves as a source of the antigen, delivering a large amount of antigen into
the system and provoking a strong immune response. A number of organisms have been
used as vectors. The most commonly used viral vectors are the vaccinia virus (the smallpox
vaccine virus), adenovirus and canary pox virus (that infects cells but does not replicate in
humans). The bacterial vectors include attenuated Salmonella typhi (Ty2la), BCG strain o f
Mycobacterium bovis.. In fact, all of the attenuated viral/bacterial vaccines have been suggested
as possible vectors for their use in live vector vaccines.
The greatest advantage of using live vector vaccine is that there is complete immune
response, that is, both humoral and cell-mediated protection systems are activated.
a)VIRAL VECTOR VACCINE
The most commonly used viral vector is the vaccine virus, though genetically engineered
recombinant viral vectors such as pox viruses or adenovirus are also deliberated upon.
Genes that have the potential to induce protective immunity (such as coat antigens) are inserted into attenuated live virus. Vaccinia, a commonly used virus has a large, doublestranded genome (about 187,000 kb and approximately 200 genes).
The advantages of viral vector vaccine include induction of both cell-mediated and hum. r
immunity against the foreign antigen expressed by the vaccinia virus.
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Advantages
Disadvantages
Strong humoral and cell-mediated immune
responses.
Several segments of DNA encoding
antigens from different pathogens can be
inserted in a single virus vector.
Can be targeted to specific tissues due to
viral tropism.
Danger of reversion to virulence is always
there.
No interference in protection produced
Immune response to virus infected cells
may cause damage to vaccine
by other types of vaccine.
Some
viruses
have
transforming
capabilities
making
infected
cells
cancerous.
Inexpensive and easy to transport.
b) Bacterial Vector Vaccine:
Like the live viral vectors, some attenuated bacterial strains have been engineered to carry
genes of virulent pathogens. The DNA encoding the antigenic determinants is inserted into the
attenuated bacterial genome. The bacteria then express the antigen along with its own protein
.The production and expression of antigen by the bacterial vector inside the host body stimulates the immune system.
The advantage of this type of vaccine includes the fact that attenuated strains of S.
typhimurium, V. cholera and BCG are easily available and their genomes can easily be
manipulated. The use of such bacterial vaccine will produce immune response both against the
vector as well as the inserted antigen (an inserted gene product).
The use of some bacteria such as Salmonella has an additional advantage: the bacteria not only
induces cell-mediated and humoral immunity but also mucosal immunity (IgA production)
since these bacteria survive in the GI tract. Immunity against the pathogens of gonorrhoea and
cholera are best provided by mucosal IgA.
The disadvantages of bacterial vector vaccine include reversion and emergence of the
pathogenic form of bacteria, rejection and elimination of bacterial vector before it can express
the recombinant protein (as most of the population is already vaccinated against the bacteria
being used as vector). Moreover, antigens formed inside the bacteria may be proteolysed by
endogenous bacterial enzymes.
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Advantages
Strong humoral and cell-mediated immune
responses.
Several segments of DNA encoding
antigens from different pathogens can be
inserted in a single virus vector.
Can be targeted to specific tissues due to
viral tropism.
No interference in protection produced
Disadvantages
Danger of reversion to virulence is always
there.
Some viruses have transforming capabilities
making infected cells cancerous.
Immune response to virus infected cells
may cause damage to vaccine.
by other types of vaccine.
I n expensive and easy to transport.
8. DNA VACCINE:
The term “DNA vaccine” is misnomer. It wrongly implies that the DNA is used as an antigen
and antibodies are formed against DNA. This is not the case. The DNA vaccine (or more
properly DNA-based vaccine) represents a new class of vaccines in which there is a deliberate
introduction of a DNA plasmid usually into the muscle cell of the recipient. The plasmid
contains a protein-coding gene (of antigen) that gets expressed in the cell leading to both
humoral and cell-mediated immune responses. The plasmid DNA can be introduced into the
muscle cell either by infection or by bombarding the skin with DNA-coated gold particles
with a fine air gun (gene- gun) Currently, attempts are also underway to introduce DNA into
nasal tissue via nasal drops. Once inside the cells of the recipient, the plasmid does not
replicate, but only expresses itself, that is, protein is produced. Usually bacterial plasmid is
used.
The DNA vaccines have several advantages.
i)
They are heat-stable as the DNA is a stable molecule-and so the storage and transport of
these vaccine are easy.
ii) The chimeric plasmids can be easily made in a laboratory in large amounts and, if the need
slight modifications in the DNA sequence (and hence the antigens' amino acid sequence)
can b e introduced.
iii) The DNA vaccines stimulate both cell-mediated and humoral responses.
The major drawbacks of the DNA vaccine is :
i)
The concern over potential integration plasmids into the DNA of cells. Such an integration
could lead to insertional mutagenesis and cause the cell to become cancerous.
ii) Danger of induction of anti-DNA antibodies causing pathological autoimmune reactions.
iii) DNA vaccine can only be formed against protein antigens.
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Advantages
Disadvantages
Insertion of foreign DNA into host genome
may cause cell to become cancerous.
Danger of autoimmune response due to
formation anti DNA antibodies.
Easy to manufacture in large amounts.
Stable and easy to transport
DNA sequence and hence antigen can easily
be changed.
Mixture of plasmids could be used to form
broad-spectrum vaccine.
May induce immunologic tolerance by
antigen(s) expressed inside host body.
Cannot be formed against polysaccharide
antigens.
Absence of protein components ensures
there is no strong immune response against
vaccine
NEW VACCINE STRATEGIES
Vaccine Strategy
Synthetic Vaccine
Micro encapsulation
delivery system
SMAA
Liposomes and Micelles
ISCOMS
Anti-idiotype Vaccine
Antigen Cochelate
Disease(s) against which it is currently directed or
explored
Currently been experimented against diseases
such as AIDS, malaria, schistosomiasis,
hepatitis(B). Use of multiple antigenic
peptides increases immune response
Influenza (inactivated virus), tetanus (toxoid)
Clinical trials ongoing for several infectious
diseases
Hepatitis A
Measles
Hepatitis B
Currently been explored for number of
infectious diseases
AN IDEAL VACCINE
i) Vaccine should be able to generate immunological memory. Both memory B cells and T cells
should be formed.
ii) A vaccine should provide lifelong immunity with a single dose.
iii) It should be preferably introduced into the recipient by non-invasive methods such as oral
administration or nasal spray.
iv) It should not e any side effects.
v) Vaccines should stimulate both arms of the immune system—humoral and -mediated
immunity.
vi) Vaccines should be inexpensive, easily manufactured and stable in extremes of temperature or
humidity
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Factors impacting vaccine effectiveness
Host factors
Age.
Comorbidity- including frailty/function
Prior exposure.
Time since vaccination.- Annual Revaccination:
Vaccine characteristics.
Mode of delivery.
Live vs inactivated.
Vaccine composition- addition of adjuvant.
Human Factors
Incorrect handling or storage of the vaccine:
Insufficient time between vaccination and exposure:
Environmental Factors
Ref: The Elements of Immunology by Fahim Halim Khan
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