5.14 immunoprophylaxis immunotherapy
TRANSCRIPT
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Immunization
• - is one of the greatest public healthachievements;
• - is one of the few cost-saving
interventions to prevent infectiousdiseases;
• - is the principal factor contributing to thereduction of morbidity and mortalityaround the world.
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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.
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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.
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Definitions of Immunizing Agents I
• Vaccine – a substance that stimulates an
immune response that can either prevent aninfection or create resistance to an infection.
• No vaccine is 100% effective (most are 70-95%), no vaccine is 100% safe.
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Definitions of Immunizing Agents II
• Toxoid - a modified bacterial toxin thathas been made nontoxic but retains thecapacity to stimulate the formation of
antitoxin.
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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 whenthere 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.
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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 harmlessvector organisms.
• The third generation of vaccines:
– in which nucleic acids are used to induce immunity.
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The types of vaccinesLive
Attenuatedvaccines
Killed
Inactivatedvaccines
Toxoids Cellular fractionvaccines
(Subunit vaccines)
Recombinantvaccines
•BCG•Measles
•Mumps
•Rubella
•Varicella•Intranasal
Influenza
•Typhoid oral
•Yellow fever•Oral polio
•Intra-muscular
influenza
•Polio
•Pertussis
•Rabies
•TBE
•Japaniseencephalitis
•Typhoid
•Cholera
•Hepatitis A
•Diphtheria•Tetanus
•Meningococcalpolysaccharide
vaccine(N.meningitidis A, C,Y, W-135)
•Pneumococcalpolysaccharidevaccine(S.pneumoniae 23valent adult,S.pneumoniae 7, 13valent pediatric)
•Acellular B. pertussis
•Hepatitis Bvaccine
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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 host’s 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.
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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.
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Live attenuated viral vaccines• Polio (oral vaccine)
• Measles, mumps, rubella
• Yellow fever
• Varicella
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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).
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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 ).
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• Subunit vaccines use only those antigenicfragments of a microorganism that best stimulate animmune response.
• Recombinant vaccines are subunit vaccinesthat are produced by genetic modification techniques,meaning that other microbes are programmed toproduce the desired antigenic fraction.
– the vaccine against the hepatitis B virus consists of aportion of the viral protein coat that is produced by agenetically modified yeast.
Inactivated vaccines
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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.
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Route of administration
• Vaccines must be administered by the licensed route to ensureimmunogenicity 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.
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Adjuvants
Adapted from Corradin G, Del Giudice G. Curr Med Chem. 2005;4:185-191.
Antigen
ime
Antigen + adjuvant
Primary
immune
response
Adjuvanted vaccines can provide an improvedmagnitude, duration and cross-protection response
compared to unadjuvanted vaccines.
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Description of immunity
Postinfection Postvaccine
Active Passive
Humoral Cellular
Antibacterial Antiviruses
Antitoxins Antifungal
Specific Nonspecific
Group specific, species specific Type-specific
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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 forstimulation of the desired immune
responses.
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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 withinitial recognition of the antigen by the immune
system, measurable circulating antibodies do
not appear for 7 to 10 days.
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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) .
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Primary immune response aftervaccination
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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 responseconsisting 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 administrationof 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 tetanusantitoxin).
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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.
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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 notnecessarily indicate protection.
• The development of circulating antibodies after
immunization often correlates directly with clinical
protection (e.g., against rubella).
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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 thesusceptible.
• This indirect protection of unvaccinated (nonimmune) persons is
called the herd immunity effect .
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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 infrequent—albeit 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.
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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 individual’s 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 age-
dependent responses and population interactions (e.g., school
entry, college enrollment) as well as the feasibility of
implementation.
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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 isfeasible.
• 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 ofvaccine-induced active immunity.
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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 andyoung 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.
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Target populations and timing of
immunization
• Some vaccines were originally formulated primarily
for adults, e.g., influenza virus and polyvalentpneumococcal 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.
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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
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Ideal vaccine should be
• Safe• Efficacious
• Available
• Affordable
• Stable
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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 preparationin 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.
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• 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 cell–mediated activation of macrophages or the generation of
cytotoxic T cells, B cell–mediated 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.
Strategy of vaccine development
Constituents of vaccines
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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 systemin which the agent is produced (e.g., egg antigens, cell culture
ingredients, serum proteins).
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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.
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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-dosevaccine schedules, coverage rates for second, third, and booster
doses may drop off significantly.
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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 withadverse events that range from infrequent and mild to rare and life-
threatening.
• The decision to recommend the use of a vaccine involves anassessment of the risks of disease and the benefits and risks of
vaccination.
Ad t
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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 whenvaccines 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
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• Among the valid contraindications applicable to all vaccines are ahistory 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 contraindicationsto routine immunization.
• Failure to vaccinate because of these conditions is viewed as a
missed opportunity for immunization.
Simultaneous Administration of Multiple Vaccines
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Simultaneous Administration of Multiple Vaccines
• There are no contraindications to the simultaneous administration ofseveral vaccines.
• The use of combination vaccines can potentially reduce the required
number of injections from 9 to 3 during a child’s 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
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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.
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IMMUNOTHERAPYTreatment of the disease by Inducing, Enhancing or
Suppressing the Immune System.
Active Immunotherapy: -
It stimulates the body’s own
immune system to fight the
disease.
Passive Immunotherapy: -
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.
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Passive immunity
• Passive immunity doesn’t 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 theblood.
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Passive
immunotherapy
Injection
BoostersActiveimmunization
Time
Initialinoculation
A n t i b o d y ( I g G ,
I g M ) c o n c e n t r a t i o n ( t i t e r )
P i i i i
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Passive immunization
• - is generally used to provide temporary immunity in
an unimmunized subject exposed to an infectious
disease when active immunization either is unavailableor 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
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Classification the serum
preparations
• Homogeneous serum: serum obtainedfrom blood donor volunteers, have beenimmunized.
• Heterogeneous serum: serum obtainedfrom blood of animals hyperimmunized.
P i i i ti
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Passive immunization
• Three types of preparations are used inpassive immunization:
– standard human immune serum globulin forgeneral use (e.g., globulin), administeredintramuscularly or intravenously;
– special immune serum globulins with a knowncontent of antibody to specific agents [e.g.,hepatitis B virus (HBV) or varicella-zoster immuneglobulin];
– animal sera and antitoxins.
P t i i ti
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Postexposure immunization
• For certain infections, active or passive
immunization soon after exposure preventsor attenuates disease expression.
• Recommended postexposure immunization
regimens against tetanus, rabies.