Immunoprophylaxis and

Immunotherapy of Infectious
Diseases

Immunization
- is one of the greatest public health
achievements;
- is one of the few cost-saving
interventions to prevent infectious
diseases;
- is the principal factor contributing to the
reduction of morbidity and mortality
around the world.

Benefits of vaccines
Individual

Public health (Social)

Economic

Impact of immunization
The epidemiologically appropriate use of vaccines has resulted in
the global eradication of smallpox and the cessation of smallpox
vaccination.
Immunization has eliminated naturally transmitted poliomyelitis
from the Western Hemisphere, Europe, and the Western Pacific.
Measles, which had a nearly 100% infectivity rate in the
prevaccination period, has been effectively eliminated from most
of the Western Hemisphere and Europe by widespread
immunization.

Vaccination and immunization

Vaccination = immunization?
Vaccination denotes only the
administration of a vaccine.
Immunization describes the process of
inducing or providing immunity by any
means, whether active or passive.
Vaccination does not guarantee
immunization.

Active and passive

immunization
Active immunization refers to the induction of
immune defenses by the administration of antigens
in appropriate forms.

Passive immunization involves the provision of

temporary protection by the administration of
exogenously produced immune substances.

Definitions of Immunizing Agents I

Vaccine a substance that stimulates an
immune response that can either prevent an
infection or create resistance to an infection.
No vaccine is 100% effective (most are 7095%), no vaccine is 100% safe.

Definitions of Immunizing Agents II

Toxoid - a modified bacterial toxin that
has been made nontoxic but retains the
capacity to stimulate the formation of
antitoxin.

Definitions of Immunizing Agents III

Immune globulin - an antibody-containing
protein fraction derived from human plasma
and used primarily for maintenance of the
immunity of persons with immunodeficiency
disorders or for passive immunization when
there is no opportunity for active immunization.
Antitoxin - an antibody derived from the serum
of animals after stimulation with specific
antigens and used to provide passive immunity
to the toxin protein to which it is directed.

Approaches to active immunization

The two standard approaches to active immunization
are:
(1) the use of live, generally attenuated, infectious agents
(e.g., rubella vaccine);
(2) the use of inactivated agents or their constituents or
products obtained by genetic recombination (e.g., acellular
pertussis vaccines).

For many diseases (e.g., poliomyelitis), both

approaches have been employed.

The generations of vaccines

The first generation of vaccines:
included whole killed bacteria,
partially purified microbial products that induced protective
antibodies (e.g., diphtheria toxoid),
live attenuated microorganisms.

The second generation of vaccines has taken advantage of

molecular genetics and protein chemistry:
purified proteins or subunits of organisms have been isolated and
manipulated,
genetically engineered and attenuated live native organisms have
been generated, as have cloned antigens expressed by harmless
vector organisms.

The third generation of vaccines:

in which nucleic acids are used to induce immunity.

The types of vaccines

Live
Attenuated
vaccines

Killed
Inactivated
vaccines

Toxoids

Cellular fraction
vaccines
(Subunit vaccines)

Recombinant
vaccines

BCG
Measles
Mumps
Rubella
Varicella
Intranasal
Influenza
Typhoid oral
Yellow fever
Oral polio

Intramuscular
influenza
Polio
Pertussis
Rabies
TBE
Japanise
encephalitis
Typhoid
Cholera
Hepatitis A

Diphtheria
Tetanus

Meningococcal
Hepatitis B
polysaccharide
vaccine
vaccine
(N.meningitidis A, C,
Y, W-135)
Pneumococcal
polysaccharide
vaccine
(S.pneumoniae 23
valent adult,
S.pneumoniae 7, 13
valent pediatric)
Acellular B. pertussis

Live attenuated vaccines

- consisting of selected or genetically altered organisms that are avirulent

or attenuated, but remain immunogenic, generally produce long-lasting
immunity (e.g. measles, mumps).

These agents are expected to cause a subclinical illness and immunologic

response mimicking natural infection.

They offer the advantage of replication in vivo, which increases the

antigenic load presented to the hosts immune system.

They may confer lifelong protection with one dose.

They present all expressed antigens, thus overcoming immunogenetic

restrictions in some hosts.

They may reach the local sites most relevant to the induction of protective
immunity.

Live attenuated vaccines

Despite their advantages, live vaccines are not always
preferable.
For example, live oral vaccines are contraindicated for
use in children and adults with immune deficiency
diseases.

Live attenuated viral vaccines

Polio (oral vaccine)

Measles, mumps, rubella
Yellow fever
Varicella

Inactivated vaccines
- typically require multiple doses and periodic boosters
thereafter for the maintenance of immunity.
Nonviable vaccines administered parenterally fail to
elicit mucosal IgA-mediated immunity, as they lack a
delivery system that can effectively transport them to
local antigen processing cells.
However, killed vaccines can be extremely successful
(the nonviable HepA vaccine appears to be close to
100% effective in inducing protective immunity).

Inactivated vaccines
Currently available nonviable vaccines consist
of:
inactivated whole organisms (e.g., pertusis vaccine);
detoxified protein exotoxins (e.g., tetanus toxoid);
recombinant protein antigens by use of genetic
engineering (e.g., HepB vaccine);
carbohydrate antigens present as soluble purified
capsular material (e.g., Streptococcus pneumoniae
polysaccharides)
conjugated to a protein carrier (e.g., pneumo
conjugated vaccine ).

Inactivated vaccines
Subunit vaccines use only those antigenic
fragments of a microorganism that best stimulate an
immune response.
Recombinant vaccines are subunit vaccines
that are produced by genetic modification techniques,
meaning that other microbes are programmed to
produce the desired antigenic fraction.
the vaccine against the hepatitis B virus consists of a
portion of the viral protein coat that is produced by a
genetically modified yeast.

Advantages of DNA Vaccines

Safe; cannot cause infection;
Stable and heat resistant;
No need to express or purify antigens in vitro; no
need for adjuvants; can be genetically engineered;
Normal processing of gene product closely
resembling native conformation;
Persistence for prolonged periods; induction of
durable immune response;
Induction of both humoral and cell mediated
immunity, including cytotoxic T cells;
Likely to be safe in immunosuppressed patients.

Disadvantages of DNA Vaccines

Potential risk of integration of viral genes from the vector;
Tumor promotion from integration near proto-oncogenes or
tumor suppressor genes;
Possible induction of tolerance or autoimmunity by vaccine
persistence;
Possible influence of strong promoters on expression of host
genes, with adverse consequences.

Route of administration

Vaccines can be administered

orally,
intranasally,
intradermally,
subcutaneously,
intramuscularly.

The route of administration in part determines the rapidity and nature

of the immune responses to vaccines.

Parenterally administered vaccine may not induce mucosal secretory

IgA, and mucosal immunization may not induce good systemic
responses.

Route of administration

Vaccines must be administered by the licensed route to ensure

immunogenicity and safety.
administration of vaccine into the gluteal rather than the deltoid muscle
often fails to induce an adequate immune response,
subcutaneous rather than intramuscular administration of vaccine
increases the risk of reactions.

Adjuvants

Adjuvants enhance the protection provided by vaccines.

The immune response to some antigens is potentiated by the addition of

adjuvants such as aluminum salts or, in the case of polysaccharides
(e.g., of Hib), by conjugation to a carrier protein.

Adjuvantsnonspecific boosters of immune responsesare used with

inactivated products such as diphtheria and tetanus toxoids, acellular
pertussis vaccine, and HepB vaccine.

The mechanism for adjuvant enhancement of immunogenicity is not well

defined but relates in part to:

immunostimulatory adjuvants work by targeting receptors that recognise pathogens,

such as Toll-like receptors or NOD (nucleotide-binding oligomerisation domain) proteins,
which induce the production of inflammatory cytokines;

the rendering of soluble antigens into a particulate form;

the mobilization of phagocytes to the site of antigen deposition;

the slowing down of the release of antigens, which prolongs stimulation of the immune
response;

immunostimulatory adjuvants can generate antibodies with increased binding affinity and
neutralisation capacity.

Adjuvants
Antigen + adjuvant

Primary
immune
response
Antigen

Time
Adjuvanted vaccines can provide an improved
magnitude, duration and cross-protection response
compared to unadjuvanted vaccines.
Adapted from Corradin G, Del Giudice G. Curr Med Chem. 2005;4:185-191.

Description of immunity

Postinfection

Postvaccine

Active

Passive

Humoral

Cellular

Antibacterial
Antitoxins
Specific
Group specific, species specific

Antiviruses
Antifungal
Nonspecific
Type-specific

The immune response

While many constituents of infectious
microorganisms and their products, such as
exotoxins, are or can be made to be
immunogenic, only a limited number
stimulate a protective immune response.
The immune system is complex, and antigen
composition and presentation are critical for
stimulation of the desired immune
responses.

The primary immune response

In the primary response to a vaccine antigen, an
apparent latent period of several days precedes
the detection of humoral and cell-mediated
immunity.
Although the immune response begins with
initial recognition of the antigen by the immune
system, measurable circulating antibodies do
not appear for 7 to 10 days.

The primary immune response

The immunoglobulin class of the response also changes over time.
The primary response is characterized by early-appearing IgM
antibodies.
IgM antibodies generally exhibit only low affinity for the antigen,
whereas later appearing IgG antibodies display high affinity.
Some individuals do not respond, even when presented repeatedly
with a vaccine antigen, often because they lack the major
histocompatibility complex determinants required to recognize the
antigen (primary vaccine failure).

Primary immune response after

vaccination

The secondary immune response

Heightened humoral or cell-mediated responses are elicited by a
second exposure to the same antigen and occur rapidly, usually
within 4 or 5 days.
The secondary response depends on immunologic memory after
the first exposure and is characterized by a marked proliferation
of IgG antibodyproducing B lymphocytes and/or effector T cells.
Whereas polysaccharide vaccines, such as that for S.
pneumoniae, evoke immune responses that are independent of T
cells and are not enhanced by repeated administration,
conjugation to proteins converts the polysaccharides to T cell
dependent antigens that induce immunologic memory and
secondary responses to revaccination.

The secondary immune response

Although levels of vaccine-induced antibodies may decline over time
(secondary vaccine failure), revaccination or exposure to the
organism generally elicits a rapid protective secondary response
consisting of IgG antibodies with little or no detectable IgM.
This anamnestic response indicates that immunity has persisted.
Lack of measurable antibody does not necessarily mean that the
individual is unprotected.
The mere presence of detectable antibodies after the administration
of some vaccines and toxoids does not ensure clinical protection.
A minimal circulating level of antibody is known to be required for
protection from some diseases (e.g., 0.01 IU/mL for tetanus
antitoxin).

Mucosal immunity

Some pathogens are confined to and replicate only at mucosal

surfaces (e.g., Vibrio cholerae), while others are able to penetrate the
mucosa and replicate (e.g., rubella virus, and influenza virus).

At the mucosal site, these organisms induce secretory IgA.

The induction of secretory IgA by vaccines may be an efficient way to

block the essential first steps in pathogenesis, whether the organism
is restricted to mucosal surfaces or invades the host across mucosal
surfaces.

Measurement of the immune response

Immune responses to vaccines are often measured
by the concentration of specific antibody in serum.
While seroconversion serves as a dependable
indicator of an immune response, it measures only
one immunologic parameter and does not
necessarily indicate protection.
The development of circulating antibodies after
immunization often correlates directly with clinical
protection (e.g., against rubella).

Herd immunity
Vaccination provides direct protection against infection of
individuals, thereby decreasing the percentage of susceptible
persons within a population.
At a definable prevalence of immunity in the population (herd
immunity), an organism can no longer circulate freely among the
susceptible.
This indirect protection of unvaccinated (nonimmune) persons is
called the herd immunity effect.

Herd immunity

The level of vaccination coverage needed to elicit a herd immunity effect

is dependent on the mixing patterns of the population and the biology of
the specific infectious agents. (e.g., measles viruses have high
transmission rates and therefore require a higher level of vaccine
coverage to elicit herd immunity than do organisms with lower
transmission rates, such as S. pneumoniae.)

Herd immunity may wane if immunization programs are interrupted (as

was the case for diphtheria in the former Soviet Union) or if a sufficient
percentage of individuals refuse to be immunized (as occurred for
pertussis in the UK because concern about infrequentalbeit severe
vaccine reactions came to exceed the fear of the disease itself).

Loss of herd immunity led to renewed circulation of the organism and

subsequent large outbreaks.

Target populations and timing of

immunization
Different age groups have different disease attack rates, and
the effectiveness of vaccines depends on a variety of factors,
including the individuals responsiveness to vaccines, the
demographic features of the populations at risk, and the
duration and character of the immunologic response.
In vaccination programs schedules for immunization are based
on careful consideration of the variables affecting agedependent responses and population interactions (e.g., school
entry, college enrollment) as well as the feasibility of
implementation.

Target populations and timing of

immunization
For common and highly communicable childhood diseases like
measles, the target population is the universe of susceptible
individuals, and the time to immunize is as early in life as is
feasible.
Epidemiologic differences in measles transmission in different
settings dictate different strategies for immunization:
In the industrialized world, immunization with live-virus vaccine at 12
to 15 months of age has been the norm because the vaccine protects
95% of those immunized at this age and there is little measles
morbidity or mortality among very young infants.
In the developing world, measles is a significant cause of death in
young infants, and it is desirable to immunize children earlier to
narrow the window of vulnerability between the rapid decline of
maternal antibody after 4 to 6 months and the development of
vaccine-induced active immunity.

Target populations and timing of

immunization

Rubella is primarily a threat to the fetus; young infants and children

are not at risk of serious illness.

An ideal strategy would be to immunize all women of reproductive age

before pregnancy.

Because it is difficult to systematically vaccinate adolescent and

young adult females and to assure the protection of as many women
as possible, rubella is included in a combination vaccine (MMR
vaccine) that is administered during infancy.

Target populations and timing of

immunization
Some vaccines were originally formulated primarily
for adults, e.g., influenza virus and polyvalent
pneumococcal polysaccharide vaccines are used to
prevent pneumonia, hospitalizations, and deaths
among the elderly.
Infants can also be targeted to receive these adapted
for this age group vaccines.

Vaccine research
Long, expensive, complicated process
On average,
It has taken 10-15 years to develop a vaccine
Costliness

Many experimental vaccines fail along the

way

Ideal vaccine should be

Safe
Efficacious
Available
Affordable
Stable

Strategy for vaccine development

Vaccine development depends on the systematic application of
a four-phase strategy:
1- studies in animals to identify protective antigens,
2- determination of how to present this antigen effectively to the
immune system,
3- assessment of the safety and immunogenicity of the preparation
in small and then in large human populations at various ages,
4- evaluation of safety and efficacy in the target population.

Each of these steps is simple in concept but difficult in

execution; failure at any level stops the process.

Strategy of vaccine development

The goal of vaccine development is not only to select the
correct antigens but also to ensure that the vaccines will result
in the type of immune response needed for protection, whether
T cellmediated activation of macrophages or the generation of
cytotoxic T cells, B cellmediated secretory IgA, or a particular
IgG subtype response to a specific polysaccharide epitope.
To create a deliverable vaccine, constituents other than
antigens are also required.
These constituents can affect the immunogenicity, efficacy, and
safety of a vaccine and can render one formulation superior to
another.

Constituents of vaccines
Preservatives, stabilizers, antibiotics:
these components are used to prevent deterioration of the vaccine
before use, to inhibit or prevent bacterial growth, or to stabilize the
vaccine;
any of these additions can cause allergic responses.

Adjuvants:
this type of additive (e.g., aluminum salts) is intended to enhance
the immune response (e.g., to toxoids).

Suspending fluid:
the suspending fluid can be sterile water, saline, buffer, or more
complex fluids derived from the growth medium or biologic system
in which the agent is produced (e.g., egg antigens, cell culture
ingredients, serum proteins).

Production of vaccines
As products to be given to healthy individuals to prevent disease,
vaccines must not only be efficacious but also cause no harm.
Quality assurance is the responsibility of vaccine manufacturers.
Proof of the safety, efficacy, sterility, and purity of products is
required before licensure, and sterility and purity are continually
monitored for all lots of vaccine after licensure.
Postmarketing studies of safety are part of routine regulatory
control.

Administration of vaccines
Different vaccines should not be mixed in the same syringe unless
such a practice is specifically endorsed by licensure.
The development and use of combinations of vaccines allows to
administer multiple injections at a single clinic visit.
Without systematic attention to the completion of multiple-dose
vaccine schedules, coverage rates for second, third, and booster
doses may drop off significantly.

Adverse events
An adverse reaction or vaccine side effect is an untoward effect
caused by a vaccine that is extraneous to its primary purpose (to
produce immunity).
An adverse event can be either a true vaccine reaction or a
coincidental event.
Modern vaccines, while safe and effective, are associated with
adverse events that range from infrequent and mild to rare and lifethreatening.
The decision to recommend the use of a vaccine involves an
assessment of the risks of disease and the benefits and risks of
vaccination.

Adverse events
Vaccine components, including protective antigens, animal proteins
introduced during vaccine production, and antibiotics or other
preservatives or stabilizers, can certainly cause allergic reactions in
some recipients.
Allergic reactions may be local or systemic and include urticaria and
serious anaphylaxis.
The most common extraneous allergen is egg protein introduced when
vaccines such as those for measles, mumps, influenza, and yellow
fever are prepared in embryonated eggs.
Gelatin, which is used as a heat stabilizer, has been implicated in rare
but severe allergic reactions.

Contraindications
Among the valid contraindications applicable to all vaccines are a
history of anaphylaxis or other serious allergic reactions to a vaccine
or vaccine component and the presence of a moderate or severe
illness, with or without fever.
Because of theoretical risks to the fetus, pregnant women should not
receive live vaccines.
Live vaccines are contraindicated in immunocompromised persons.
Diarrhea, minor respiratory illness (without fever), mild to moderate
local reactions to a previous dose of vaccine, the concurrent or recent
use of antimicrobial agents, mild to moderate malnutrition, and the
convalescent phase of an acute illness are not valid contraindications
to routine immunization.
Failure to vaccinate because of these conditions is viewed as a
missed opportunity for immunization.

Simultaneous Administration of Multiple Vaccines

There are no contraindications to the simultaneous administration of
several vaccines.
The use of combination vaccines can potentially reduce the required
number of injections from 9 to 3 during a childs first 6 months of life
and from 21 to 13 during the first 2 years.
Simultaneous administration of the most widely used live and
inactivated vaccines has not resulted in impaired antibody responses
or in increased rates of adverse reactions.
Simultaneous administration is useful in any age group when the
potential exists for exposure to multiple infectious diseases during
travel to endemic countries.
When live-virus vaccines are not given together on the same day, an
interval of at least 30 days should be allowed.

Handling of vaccines
Vaccines must be handled and stored with
care.
Vaccines should be kept at 2 to 8C and, with
the exception of varicella vaccine, should not
be frozen.
Measles vaccine must be protected from
light, which inactivates the virus.

IMMUNOTHERAPY
Treatment of the disease by Inducing, Enhancing or
Suppressing the Immune System.

Active Immunotherapy: -

Passive Immunotherapy: -

It stimulates the bodys own

immune system to fight the
disease.

It does not rely on the body to

attack the disease, instead
they use the immune system
components ( such as
antibodies) created outside the
body.

Passive immunity
Passive immunity doesnt last as long as
active immunity (only weeks or months).
No lymphocytes are stimulated to clone
themselves.
No memory cells have been made.
This type of immunity can only last as long
as the antibodies/antitoxins last in the
blood.

Antibody (IgG, IgM) concentration (titer)

Passive
immunotherapy
Injection

Boosters

Initial
inoculation

Time

Active
immunization

Passive immunization
- is generally used to provide temporary immunity in
an unimmunized subject exposed to an infectious
disease when active immunization either is unavailable
or has not been implemented before exposure (e.g., for
rabies).
Passive immunization (immunotherapy) is used in the
treatment of certain disorders associated with toxins
(e.g., diphtheria, tetanus, botulism), in certain bites
(those of snakes and spiders), and as a specific or
nonspecific immunosuppressant [Rho(D) immune
globulin and antilymphocyte globulin, respectively].

Classification the serum

preparations
Homogeneous serum: serum obtained
from blood donor volunteers, have been
immunized.
Heterogeneous serum: serum obtained
from blood of animals hyperimmunized.

Passive immunization
Three types of preparations are used in
passive immunization:
standard human immune serum globulin for
general use (e.g., globulin), administered
intramuscularly or intravenously;
special immune serum globulins with a known
content of antibody to specific agents [e.g.,
hepatitis B virus (HBV) or varicella-zoster immune
globulin];
animal sera and antitoxins.

Postexposure immunization
For certain infections, active or passive
immunization soon after exposure prevents
or attenuates disease expression.
Recommended postexposure immunization
regimens against tetanus, rabies.