self study assignment vacc inati on immunization types · self study assignment vacc inati on ......

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September 13, 2001 of 16

SELF STUDY ASSIGNMENTVacc inati on

As a supplement to the textbook reading assignment, you are responsible for the followingkey learning objectives. This material was taken from the 2nd Edition of “MedicalMicrobiology”, Mims et al and from the 4th Edition of “Immunology, A Short Course”,Benjamini et al.

Immunization TypesI. Active immunization

A. Administration of a vaccine that elicits a protective immune responseB. Natural infection can elicit an active response

II. Passive immunizationA. Transfer of maternal antibody to infant via placenta or colostrumB. Therapeutic administration of antibodies that afford protection to the host

III. Post-exposure immunizationA. Passive + active immunization may be usedB. Used for diseases with potentially acute onset and fatal outcomes

1. Toxoid and antitoxin given for diphtheria exposure2. Immune globulin and vaccine for rabies exposure

Mechanisms of ProtectionI. Induction of secondary response

Rapidity of the anamnestic response is important for the prevention of diseases with shortincubation periods. For example, multiple injections of tetanus toxoid are given to children aspart of DPT to boost production of protective levels of circulating antibody.

II. Role of innate responseA. Acquired immunity may function independent of innate defenses

For example, an antibody to a toxoid directly neutralizes a toxinB. Acquired immunity may function in concert with innate defenses

For example, a protective antibody may opsonizes an infectious particle or interact withcomplement to induce lysis of an infecting agent.

III. Age of immunizationMaternal immunoglobulin protects fetus and newborn. A newborn has the capacity to mount aresponse to parenterally administered toxoids and polio vaccine (inactivated or attenuated).Circulating maternal antibody can interfere with immunization against measles, so thatvaccine is delayed until the child is 1 year old.

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Vaccine Requirements“Vaccination aims to prime the adaptive immune system to the antigens of a particular pathogenso that a first infection induces a secondary response.” Mims Medical Microbiology, 1998

I. A vaccine must induce the right type of immune response.A. Tuberculosis requires a vaccine that elicits a cell-mediated response.B. Streptococcal pneumonia requires a vaccine that elicits anti-capsular antibodyC. High levels of serum antibody are unlikely to protect from poliovirus mucosal infection.

II. An effective vaccine must induce memory to protect against future infections.A. “Natural boosting” occurs during periodic outbreaks in the community.B. Paradox of vaccination:

The less disease that there is in the community increases the importance of vaccination.III. Vaccines must be stable and relatively inexpensive.

Success rates of various anti-viral vaccines

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Types of Vaccines: Live Attenuated

I. Methods of preparationA. Repeated passage in culture: Pathogen is repeatedly passed in culture until its virulence is

reduced. This method has been used for the development of viral vaccines. BCG is the bestexample of a bacterial vaccine strain developed using this method.

B. Cold adaptation of virus may be used, forcing it to grow less well in the human body.

Preparation Methods for Live Attenuated VaccinesPathogen Method of Attenuation

Viruses / StandardPoliovirus (Sabin) Passage in monkey kidney cellsMeasles Passage in human kidney cellsRubella Passage in rabbit kidney cellsMumps Passage in chick fibroblastsYellow fever virus Passage in monkey cells

Viruses / ExperimentalInfluenza Cold adaptationRespiratory Syncytial Cold adaptationRotavirus Cold adaptationHerpesvirus Passage in human fibroblast

Bacteria / StandardMycobacterium tuberculosis (BCG) 10 yr. passage in culture mediaSalmonella typhi Chemical mutagenesis

Bacteria / ExperimentalShigella spp. Chemical mutagenesisVibrio cholerae Toxin deletion

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II. Risks associated with attenuated vaccinesA. Insufficient attenuation or reversion to wild type. Mutations induced in the vaccine strain

during attenuation are entirely at random and not predictable. It is possible to use geneticengineering to construct vaccine strains with defined mutations. Examples are poliovirusstrains with a single base change or Salmonella strains with mutations in the aroA or galEgenes.

B. Persistent infection induced by living virusC. Risks to the immunocompromised or a fetus

Types of Vaccines: Killed Organisms

Killed vaccines may be used if attenuation of the pathogen has not been achieved or if the risk ofreversion to the wild type form is too high. Killed vaccines are safer but the trade-off is theirreduced immunogenicity and the need for multiple doses. The poliovirus vaccine exists in bothinactivated (Salk) and attenuated (Sabin) forms.

Methods Used to Prepare InactivatedVaccines

Pathogen Method of InactivationViruses

Rabies _-propiolactoneInfluenza _-propiolactonePolio (Salk) Formaldehyde

BacteriaSalmonella typhi Heat plus phenolBordetella pertussis Heat or formaldehydeYersinia pestis Formaldehyde

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Types of Vaccines: Subcellular

Subcellular vaccines are useful when protective immunity may be induced against somecomponent of the pathogen. Capsular polysaccharides and inactivated toxins (toxoids) havebeen used as subcellular vaccines. Due to the poor immunogenicity of some subcellularfractions, conjugate vaccines may be used. These consist of a toxoid conjugated to thecapsular material of a bacterial pathogen. One example of a conjugate vaccine is theHaemophilus influenzae b (Hib) capsular polysaccharide conjugated to tetanus toxoid.

Types of Vaccines: Recombinant Vectors

With the advent of recombinant DNA technology, it is possible to engineer bacterial orviral strains expressing a variety of antigens. Candidate vectors are vaccinia virus, anattenuated strain of Salmonella typhi, and BCG. Because S. typhi is an enteric pathogen, itcould be used as a vector for the antigens of pathogens such as Vibrio cholerae. BCG has theadvantage of eliciting a T cell-mediated response and could be used as a vaccine for persistentintracellular pathogens such as Toxoplasma and Listeria.

Subcellular VaccinesPathogen Vaccine component

BacteriaHaemophilus influenzae b Capsular polysaccharidePneumococcus Capsular polysaccharideMeningococcus Capsular polysaccharideCorynebacterium diphtheriae Diphtheria toxoidCorynebacterium tetani Tetanus toxoid

VirusesHepatitis B Recombinant surface antigensInfluenzae Surface coat antigens

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Advantages and Disadvantages of Vaccines

There are advantages and disadvantages associated with living (attenuated) and non-livingvaccines. Attenuated vaccines best prevent those childhood diseases that induce effectivelong-term immunity following recovery from infection. Attenuated vaccines localize to thenatural site of infection and replicate there. Shedding of the vaccine into the community mayinduce immunity in unvaccinated individuals, a concept referred to as “herd immunity.”Another advantage is that T cells process the peptide antigens of attenuated vaccines andassociated them with MHC class I molecules using the native route. However, a keydisadvantage of attenuated vaccines is the risk of reversion to virulence and restricted use inimmunocompromised individuals. Some diseases such as influenza do not lend themselves toa live vaccine due to the antigenic diversity of the pathogen. Therefore, a subcellular vaccinecontaining the antigens required for viral attachment or entry would be more effective. Poliois the only disease for which live and killed vaccines have comparable effectiveness.

COMPARISON OF LIVING AND NON-LIVING VACCINESLiving Non-Living

Preparation Attenuation InactivationAdministration route May be natural (e.g. oral) InjectionDosage Single dose possible Multiple requiredAdjuvant Not required Usually requiredRisks Reversion possible Allergic reactionStability (Tropical use) Cold storage required Relatively stableCost Low HighDuration of protection May be years Boosting requiredImmune response IgG, IgA, cell-mediated IgG, little cell-mediated

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Vaccine-Associated Complications

I. Polysaccharide antigens that fail to stimulate T cells induce only a primary response,regardless of dosage. These antigens are particularly ineffective in children under two years ofage. Therefore, polysaccharide antigens are typically conjugated with a protein to induce asecondary response. One example is the PRP vaccine for Haemophilus influenzae b, which isconjugated to diphtheria toxoid or an outer membrane protein of Neisseria.

II. Living vaccines pose a particular problem for immunocompromised individuals, especiallyvaccinia and BCG in patients with severe T cell deficiency. However, it is recommended thatHIV-infected persons without severe immunosuppression receive the measles, mumps, andrubella (MMR) vaccine. The risk of death from natural infection in these individuals outweighspotential complications from vaccination.

III. Pathologic consequences of vaccination may be due to contaminated preparations or to anunintended immune response. Because monkey cell lines are used to propagate attenuatedviruses, there is the potential for contamination of a preparation with a lethal monkey virus.Hypersensitivity to egg proteins that contaminate viral vaccines grown in chick embryo cells isanother potential complication. Children with a history of sensitivity to eggs may requiremultiple low dose immunizations with some vaccines. High titers of non-neutralizing antibodyinduced by the older killed measles vaccine lead to the formation of immune complexes and asevere type III hypersensitivity reaction during a measles infection. Therefore, this vaccine wasreplaced with an attenuated strain of measles that induces a neutralizing immune response to thefusion protein of the virus. Finally, the development of any new vaccine must take intoconsideration the potential complication an autoimmune reaction induced by an antigen thatcross-reacts with a host protein.

PATHOLOGIC COMPLICATIONS OF SOME VACCINESVaccine ComplicationLive measles, mumps Hypersensitivity to egg antigensKilled measles, RSV Hypersensitivity to viral antigensPertussis, measles Convulsions, encephalitisa

Mumps Meningitisa

Rubella Arthritisa Occurrence rate = 1 per million doses

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Vaccine Practice

This section describes vaccines that are in current use in the U.S. and other countries.

I. Diphtheria, Tetanus, Pertussis (DTP) vaccineA. The diphtheria component of the DTP vaccine is an inactivated form of diphtheria toxin

(toxoid). Although this vaccine is targeted to the toxin, it decreases Corynebacteriumdiphtheriae colonization rates. This suggests that diphtheria toxin plays a role incolonization of the upper respiratory tract by C. diphtheriae.

B. Tetanus toxoid is universally used and highly effective. Boosters are recommendedevery 10 years. Antitoxin plus the toxoid are administered in cases of suspected exposure,e.g. a dirty wound.

C. Concerns regarding reported side effects caused by the killed, whole cell pertussisvaccine led to the development of an acellular vaccine, which is in use today. Becausepertussis is a multifactorial disease, it was necessary to combine several Bordetellapertussis virulence factors into the acellular vaccine. Controversy surrounding thepotential side effects of the pertussis vaccine led to a brief period of diminished use andthe 1978-1979 epidemic in the U.K.

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II. Measles, Mumps Rubella (MMR)A. Measles, mumps and rubella are all live, attenuated vaccines. The age of

administration for these vaccines depends on the incidence rates. Administration of theMMR vaccine is given at 1 yr. of age in developed countries due to the relatively lowoccurrence of the diseases. However, in developing countries where the diseases are stillwidespread, vaccination is given at 6 mos. and at 1 yr.

B. There is some debate regarding the administration of the rubella vaccine to boys.Because rubella is a relatively mild disease, there is the argument that it should only begiven to adolescent girls to prevent transmission to the fetus. However, the vaccineprogram in the U.S. is tailored toward the eradication of disease, so boys and girls receivethe rubella vaccine.

C. The rubella vaccine illustrates the paradox of immunization. As disease rates declinedue to an effective vaccine program, so does the natural immunization process that occursduring outbreaks. Therefore, cases of rubella may occur at a later age when the protectionprovided by childhood immunization has waned. This would increase the incidence ofcongenital rubella.

III. Polio vaccineA. There are 2 types of polio vaccine, the inactivated polio vaccine (IPV) and the

attenuated oral polio vaccine (OPV). Salk developed the IPV in 1954 and Sabindeveloped the OPV in 1957.

B. OPV induces secretory immunity to intercept virus at portal of entry.

C. IPV induces immunity to viremic stage

D. Although the inactivated and attenuated polio vaccines are equally effective, there areadvantages and disadvantages of each.

COMPARISON OF POLIO VACCINESIPV (Salk) OPV (Sabin)

Advantages 1. Cannot revert to virulence2. Used in

immunocompromised

1. Oral administration2. Inexpensive3. Natural infection route4. Induces herd immunity

Disadvantages 1. Parenteral administration2. Expensive3. No gut immunity

1. Reversion to virulence2. Cannot be used in

immunocompromised3. Requires refrigeration

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IV. Attenuated tubercle bacillus (BCG)A. Calmette and Guérin’s attenuated tubercle bacillus (BCG) has been in use for

protection against Mycobacterium tuberculosis for 70 yr.B. The primary disadvantage of the vaccine is that it destroys the diagnostic value of the

tuberculin skin test. There is some debate regarding its effectiveness and it is onlyadministered at birth to high-risk populations in the U.S.

C. Due to its effectiveness as an adjuvant, BCG has been proposed as a vector forrecombinant genes from other pathogens.

V. Hepatitis BA. Recombinant hepatitis B surface antigen (HBsAg) is now routinely administered to

infants in the U.S. beginning at 2 mos. Infants born to HBsAg-positive mothers aresimultaneously immunized at birth with HBsAg and hepatitis B immune globulin.

B. HBsAg immunization is also recommended for the following high-risk adults:1. Medical staff in high-risk situations2. Family contacts of known carriers3. Male homosexuals4. Intravenous drug addicts5. Immunocompromised6. Patients receiving repeated blood transfusions

VI. Haemophilus influenzae b (Hib)Due to the poor immunogenicity of the polyribitol phosphate capsule of H. influenzae b, it isconjugated to diphtheria toxoid or the outer membrane protein of meningococcus.

VII. Varicella zoster vaccine (VZV)A. The occasional severe complications associated with varicella (chickenpox) have

warranted the inclusion of this attenuated vaccine in the immunization schedule.B. There is some controversy regarding its use due to the potential risk associated with

latency (zoster).

VIII. InfluenzaA. The influenza vaccine is only partially effective due to antigenic shift and drift. The

vaccine is prepared by chemical inactivation of the virus containing the hemagglutinin andneuraminidase types anticipated in the population.

B. Vaccination is recommended for high-risk individuals such as the elderly andindividuals with chronic respiratory illness.

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IX. Pneumococcal vaccineA. There are 84 serotypes of Streptococcus pneumoniae in the population, but

immunization against a subset of 23 offers protection – Pneumovax .B. As with Hib, the pneumococcal vaccine is composed of the polysaccharide capsule. This

capsular vaccine is poorly immunogenic and is not useful for children under two.Conjugation to a protein carrier increases immunogenicity. However, conjugation of all 23serotypes would be a monumental task.

C. Indications for immunization are for the same high risks groups receiving the influenzavaccine.

D. New childhood vaccine composed of 7 serotypes – Prevnar .

X. Meningococcal vaccineA. The meningococcal vaccine is composed of capsular polysaccharide serotypes A and C.

A vaccine to serotype B is not available. The immune response to this vaccine is poor,especially in children. Conjugation to a meningococcal protein improves immunogenicity.

B. Immunization is recommended for individuals traveling to endemic areas (parts of Africaand India) and military recruits.

AVAILABLE VACCINESVaccine Preparation method Immunization schedulea

Diphtheria, Pertussis, Tetanus(DPT)

Pertussis – AcellularDiphtheria, Tetanus - Toxoid

2, 4, 6, 15 mos. & 5 yr.

Polio Attenuated (Sabin)Killed (Salk)

2, 4, 6 mos. & 5 yr.

Measles, Mumps, Rubella(MMR)

Attenuated 1 & 5 yr.

Hepatitis B Recombinant surface antigen 1, 2, 6 mos.H. influenzae b (Hib) Capsular polysaccharide 2, 4, 6 mos.Varicella Attenuated 1 yr.Tuberculosis (BCG) Attenuated High risk in U.S.Hepatitis A Killed High riskPneumococcus 23 Capsular polysaccharides High riskInfluenza Prevailing H and N types High riskMeningococcus Polysaccharide A+C High riskYellow fever, Typhoid Attenuated High riskCholera Killed High riska. Based on the childhood immunization schedule published by the Centers for Disease Control.The minimum age of immunization is given for each vaccine.

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Diseases With No Available Vaccine

There are a variety of reasons why there are no effective vaccines for some pathogens.Serotypic diversity of adenovirus, rhinovirus, and Neisseria gonorrhoeae hampers thedevelopment of effective vaccines. The risk of latency has restricted development of a liveherpes virus vaccine. A lack of convincing immunity to natural infection has discouragedefforts to develop a vaccine for Treponema pallidum. Extensive antigenic variation ofHIV glycoprotein 160 has slowed production of a vaccine for AIDS.

INFECTIOUS DISEASES LACKINGEFFFECTIVE VACCINES

Pathogen DiseaseViruses

HIV AIDSHerpes simplex virus Genital herpesCytomegalovirus Fetal infectionEpstein-Barr virus MononucleosisRhinovirus Common cold

BacteriaNeisseria gonorrhoeae GonorrheaMycobacterium leprae LeprosyTreponema pallidum SyphilisChlamydia trachomatis Trachoma, genital infection

ParasitesPlasmodium spp. MalariaTrypanosoma spp. Sleeping sicknessSchistosoma spp. Schistosomiasis

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VACCINE SELF STUDY ASSIGNMENTSAMPLE QUESTIONS

1. Which of the following is a DISADVANTAGE of live attenuated vaccines?A. Localization of infection to appropriate body site.B. Herd immunityC. Requirement for a cold chain.D. Replication in immunized individuals.

2. Controversy regarding the safety of that vaccine led to reduced compliance and a severeepidemic in 1978-1979?

A. PertussisB. DiphtheriaC. RubellaD. Tetanus

ANSWERS

Choice C is correct. A cold chain requirement restricts the use of a vaccine to countries withadequate storage facilities (i.e. refrigeration) that will maintain the viability of the vaccine.Choices A, B, and D are advantages of attenuated vaccines because they are native functions ofthe pathogens that facilitates the immune response.

Choice A is correct. Reports of severe reactions in children immunized with the pertussisvaccine caused reduced compliance among parents leading the way for an epidemic. Thissituation illustrated the importance of childhood immunization.

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CASE STUDY FORVACCINE SELF-STUDY ASSIGNMENT

A developing nation instituted a childhood vaccination program using the attenuated forms ofpolio, measles, mumps, and rubella viruses for immunization. The vaccines were administered tochildren at 2, 4, and 6 months of age. This country has high rates of infection with theseparticular viruses. In addition, the HIV infection rate amongst the female population in thiscountry is 40%. Unfortunately, this immunization program was a failure due to a high rate ofcomplications; nearly half of the children suffered post-immunization sequelae. In addition, theimmunized children were not protected from measles virus infection.

Questions:1. What was the most likely cause of post-immunization complications?2. Why did the measles immunization fail?

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