module general immunology

WHO/EPI/GEN/93.11ORIGINAL: ENGLISH

DISTR.: GENERAL

The Immunological Basis for Immunization Series

Module 1:

GeneralImmunology

GLOBAL PROGRAMME FOR VACCINES AND IMMUNIZATIONEXPANDED PROGRAMME ON IMMUNIZATION

World Health OrganizationGeneva

WHO/EPI/GEN/93.11ORIGINAL: ENGLISH

DISTR.: GENERAL

The Immunological Basis for Immunization Series

Module 1:

GeneralImmunology

Dr Artur M. GalazkaMedical OfficerExpanded Programme on Immunization

GLOBAL PROGRAMME FOR VACCINES AND IMMUNIZATIONEXPANDED PROGRAMME ON IMMUNIZATION

World Health OrganizationGeneva

i i

The Expanded Programme on Immunization thanks the following donors

whose support made the production of these modules possible:

United Nations Development Fund (UNDP)

The Rockefeller Foundation

The Government of Sweden

The Immunological Basis for Immunization series is available in English and

French (from the address below). It has also been translated by national health

authorities into a number of other languages for local use: Chinese, Italian,

Persian, Russian, Turkish, Ukranian and Vietnamese. The series comprises eight

independent modules:

Module 1: General Immunology

Module 2: Diphtheria

Module 3: Tetanus

Module 4: Pertussis

Module 5: Tuberculosis

Module 6: Poliomyelitis

Module 7: Measles

Module 8: Yellow fever

Produced in 1993

Reprinted (with new covers but no changes to content) in 1996

GPV Catalogue available on the Internet at:http://www.who.ch/programmes/gpv/gEnglish/avail/gpvcatalog/catlog1.htm

Copies may be requested from:

World Health OrganizationGlobal Programme for Vaccines and Immunization

Expanded Programme on ImmunizationCH-1211 Geneva 27, Switzerland

Fax: +22 791 4193/4192 E-mail: [email protected]

© World Health Organization 1993

This document is not a formal publication of the World Health Organization (WHO), and all rights arereserved by the Organization. The document may, however, be freely reviewed, abstracted, reproducedand translated, in part or in whole, but not for sale nor for use in conjunction with commercial purposes.The views expressed in documents by named authors are solely the responsibility of those authors.

WHO/EPI/GEN/93.11 Immunological Basis for Immunization / Module 1: General Immunology iii

Contents

Preface

1. Antigens Inducing Immunity

1.1 Antigens and antigenic determinants

1 .2 T-dependent and T-independent antigens

2. Vaccines Used in the EPI 2

2.1 Nature of EPI vaccines

2.2 Stability of EPI vaccines

2.3 Use of EPI vaccines 4

3. Types of Immunity

3.1 Nonspecific defense mechanisms

3.2 Specific immunity

4. Antibody-mediated Immunity

4.1 Immunoglobulins

4.1.1 Classes of immunoglobulins

4.1.2 Basic structure of immunoglobulins

4.1.3 Functions of immunoglobulins

4.1.4 Placental transfer of immunoglobulins

4.1.5 Normal development of serum immunoglobulins

4.2 Measurement of antibody activity — serological assays4.2.1 When are serological studies useful?

4.2.2 Methods to measure antiviral antibodies

4.2.3 Methods to measure antibacterial antibodies

4.3 Immune response

4.3.1 Class-specific response

4.3.2 Primary versus secondary immune response

4.3.3 Maturation of the immune response — avidity of antibodies

v

1

1

1

2

2

5

5

5

6

6

6

6

78

8

99

9

10

10

10

10

11

iv Immunological Basis for Immunization / Module 1: General Immunology

5. Cell-mediated Immunity

5.1 The nature of cell-mediated immunity

5.2 The T lymphocyte - a key cell in the immune response

5.3 Signals between cells of the immune system - lymphokines

6. Hypersensitivity

Abbreviations

WHO/EPI/GEN/93.11

11

11

11

12

12

12

References 13

WHO/EPI/GEN/93.11

Preface

Immunological Basis for Immunization / Module 1: General Immunology v

This series of modules on the immunological basis for immunizationhas grown out of the experience of persons working with the WHOExpanded Programme on Immunization (EPI). The EPI was established in1974 with the objective of expanding immunization services beyondsmallpox, with emphasis on providing these services for children indeveloping countries.

Six vaccine-preventable diseases have been included within the EPIsince its beginning: diphtheria, measles, pertussis, polio, tetanus, andtuberculosis. To protect newborns against neonatal tetanus, tetanus tox-oid is administered to the mother either during her pregnancy or prior topregnancy during the childbearing years.

Two more vaccine preventable-diseases will be addressed by the EPIduring the 1990s. The World Health Assembly has set the target ofincluding yellow fever vaccine in the EPI by 1993 in countries where thisdisease poses a risk. Hepatitis B vaccine is being added gradually, with thetarget date of 1997 for incorporation of this vaccine in the immunizationprogramme in all countries.

Titles of the nine modules in this series are listed inside the front coverof this module. They are intended to provide information on the immuno-logical basis for WHO-recommended immunization schedules. They havebeen prepared for the following main audiences:

immunization programme managers, whose questions andconcerns caused this series to be written,

consultants and advisers on immunization activities,

teachers of courses on immunization at the university leveland facilitators of workshops,

medical and nursing students as part of the basic curricu-lum,

laboratory scientists providing diagnostic or research serv-ices for vaccine-preventable diseases, and

scientists involved in basic research aimed at improving thedelivery of vaccines or providing improved vaccines.

Other modules in this series and additional materials on the EPI areavailable from the Expanded Programme on Immunization, World HealthOrganization, 1211 Geneva 27, Switzerland.

vi Immunological Basis for Immunization / Module 1: General Immunology WHO/EPI/GEN/93.11

WHO/EPI/GEN/93.11 Immunological Basis for Immunization / Module 1: General Immunology 1

General Immunology

1. Antigens InducingImmunity

1.1 Antigens and antigenicdeterminantsImmunity against infectious diseases develops

in response to antigens. Antigens are defined as mol-ecules which are recognized by the immune systemand induce an immune response. An antigen stimu-lates the production of antibodies and/or cellularimmune responses that will react specifically withthat antigen. The reaction between antigen and anti-body is similar to that between a lock and key. It isspecific and antibodies produced against one antigendo not react, or react poorly, with other antigens.

The antigen may be a soluble substance producedby a microorganism (for example, toxin or its detoxi-fied form, toxoid (Figure l), or a substance presenton a bacterium, virus, other cell surface, or in the cellwall. Most antigens are proteins, but some arepolysaccharides from bacterial capsules, or glycolipids.

The part of the antigen to which an antibodybinds is called an antigenic determinant, antigenicsite, or epitope. Antigens usually contain many deter-minants which may be different from each other ormay be repeated molecular structures.

A given microorganism contains many differentantigens. Protozoa, fungi, and bacteria contain hun-dreds to thousands of antigens. Viruses contain fromas few as three antigens (polyoma virus) to more than100 antigens (herpesviruses and poxviruses). Immuneresponses develop to many of these antigens duringinfection. Resistance to infection, however, dependsprincipally on the immune response to a smallernumber of antigens on the surface of the microorgan-ism. Relevant surface antigens have been isolated andcharacterized for some viruses. Much less is knownabout the antigens that induce resistance to bacteria,fungi, and protozoa. It is clear, however, that avail-able vaccines consisting of killed bacteria induce alarge number of irrelevant immune responses (Mims1982). Whole cell pertussis vaccine, for example,contains several components, such as lipopolysac-charide, heat labile toxin, and tracheal cytotoxin,that although antigenically active, are not importantin inducing immunity to pertussis (see Module 4).

1.2 T-dependent and T-independentantigensThere are two groups of antigens: T-dependent

and T-independent. Antigens that require the inter-vention of T lymphocytes (see section 3.2) to triggerantibody production by B lymphocytes are called

Figure 1. Detoxification of tetanus toxin into harmless tetanus toxoid without loss of antigenic properties.

Site relatedto toxicity

Detoxification by actionof formaldehyde and heat

Molecule of tetanus toxin

Legend

Antigenic determinantsrelevant to immunity

Antigenic but not toxicmolecule of tetanus toxoid

2 Immunological Basis for Immunization / Module 1: General Immunology WHO/EPI/GEN/93.11

T-dependent antigens. Most protein antigens fall intothis category. T-independent antigens are capableof stimulating B lymphocytes to produce antibodywithout the help of T lymphocytes. T-independentantigens are usually large compounds with multiplerepeating subunits such as those from the bacterialcapsular polysaccharides of Neisseria meningitidis;Haemophilus influenzae type b, or group B strepto-cocci.

T-independent antigens are weak immunogens inpersons below two years of age. The immunogenicityof T-independent antigens is increased when they aretransformed into T-dependent antigens by couplingthe antigen to a carrier protein. This phenomenon isutilized in preparing conjugated vaccines, such as avaccine against H. influenzae type b in which therelevant polysaccharide (T-independent) is coupledto diphtheria toxoid, tetanus toxoid, or another car-rier protein (T-dependent).

2. Vaccines Used in the EPI2.1 Nature of EPI vaccines

The EPI vaccines contain preparations of manydifferent kinds (Table 1).

Diphtheria and tetanus toxoids are protein toxinsthat have lost their toxicity through a detoxificationprocess with formaldehyde (Figure 1). Fluid toxoidsare relatively weak immunogens and in practice theyare used in the adsorbed form with the addition ofadjuvants (substances which increase considerablythe immunogenic power of antigens). For diphtheriatoxoid and tetanus toxoid the commonly usedadjuvant is an aluminum salt.

The available pertussis vaccines commonly con-tain the whole killed bacteria of Bordetella pertussisand usually are used as components of diphtheria-pertussis-tetanus (DPT) vaccine. The pertussis com-ponent of DPT vaccine also has an adjuvant effect forthe diphtheria and tetanus toxoids. Prospects for animproved acellular vaccine containing isolated pro-tective antigens are discussed in Module 4.

Inactivated hepatitis B (HB) vaccine contains HBsurface antigen (HBsAg) derived from the plasma ofHBsAg carriers or made by recombinant DNA tech-nology.

All killed vaccines contain a preservative, which isusually merthiolate, a mercury containing compound,in a concentration of less than 0.1 mg per ml.

Other vaccines are live, attenuated vaccines. BacilleCalmette-Guérin (BCG) vaccine contains live BCGbacteria, an attenuated form of Mycobacterium bovisorganisms (see Module 5). BCG vaccine contains nopreservatives and after reconstitution may be easilycontaminated. It should be therefore used quickly,during one immunization session.

Measles vaccine contains live measles virus of oneof a number of attenuated strains (Schwarz,Edmonston-Zagreb, Moraten, L-16, CAM-70, AIK-C). These strains were attenuated in different waysbut all of them induce similar anti-measles antibod-ies. Measles vaccine usually contains a small amountof antibiotic (neomycin, polymixin, or kanamycin,but never penicillin) as a conservative.

Trivalent oral poliovirus vaccine (OPV) representsa mixture of three distinct types of attenuatedpolioviruses (types 1, 2, and 3). A proper balancebetween different types of poliovirus is essential forensuring induction of antibodies against all threetypes (see Module 6). OPV is stabilized with magne-sium chloride or sucrose.

Yellow fever vaccine is a live attenuated vaccineproduced in chick embryos from the 17D yellowfever virus strain (see Module 8).

There are important differences between killedand live vaccines. The amount of antigen in a killedvaccine is an important parameter for its efficacy.Killed vaccines must be given in repeated doses toinduce an adequate immune response. The microor-ganisms in live vaccines, on the other hand, multiplyin the host after immunization. The antigenic mass inthe live vaccine is small but it is increased manythousand times following growth of the organism inthe body, if there are favorable conditions for suchgrowth.

Other vaccines (not shown in Table 1) are used insome countries. They include meningococcal polysac-charide vaccine and Japanese encephalitis vaccine.

2.2 Stability of EPI vaccines

In many situations, vaccines are not being prop-erly stored and transported, and queries often ariseabout what to do with stocks of vaccines that havebeen exposed to elevated temperatures for variousperiods. Unfortunately, there is no straightforwardand cheap method that can be used in the field toassess whether a vaccine that has been exposed toambient temperatures has retained at least the mini-mum required potency. This can be determined onlyin the laboratory using expensive assays, the resultsof which are often delayed by several months. Suchtests are only justified when a large number of doses(10 000 or, more) have been exposed to elevatedtemperatures. Specific instructions for when to orderpotency tests for heat-exposed vaccines and how toship vaccines for these tests are provided in an EPItraining module entitled “Manage the Cold Chain”(Document WHO/EPI/MLM/91.5).

Individual-vial thermal indicators have been de-veloped. It is anticipated that they will be introducedby manufacturers in 1993. Such indicators, placed onindividual vaccine containers, will change color when


Vaccine Nature of Potency per Amountagainst vaccine dose per dose

ToxoidDiphtheria (detoxified At least 30 IU*

10 to 20Lf**

toxin)

Toxoid At least 40 IUTetanus (detoxified in TT and 60 IU 5 to 10 Lf

toxin) in DPT

Hepatitis BHepatitis B surface antigen 2.5 to 20 mcg of HBsAg

(HBsAg)

Whole killed 10-20 xPertussis pertussis At least 4 IU 109 of

bacteria bacteria

Attenuated live At least 1000 TCID50 orMeasles

virus PFU****Freeze-dried None

Freeze-dried None

Freeze- Nonedried

Yellow feverAttenuated live At least 1000 mouse LD50 orvirus the equivalent in PFU

TuberculosisAttenuated live 50 000 to one million liveBCG bacteria particles

Attenuated liveType 1: at least 1 million;

Poliomyelitis viruses of threetype 2: at least 100 000;

typestype 3: at least 600 000TCID50

*IU = International units of potency as determined in animal test.

Fluid

** Lf = flocculation value, the amount of toxoid which when mixed with one International Unit of antitoxin produces an optimally flocculating mixture.*** In some countries deep subcutaneous injections are used.

**** TCID50 = Tissue culture infective 50%; the quantity of a virus suspension that will infect 50% of cell cultures.PFU = plaque forming unit; the smallest quantity of a virus suspension that will produce a plaque in monolayer cell cultures.

Table 1. Basic data on EPI vaccines, with vaccines listed in order of heat stability.

Form

Fluid

Adjuvant

AI(OH)3 orAIPO4

FluidAI(OH)3 orAIPO4

Fluid

Fluid

Al(OH)3

Al(OH)3 orAlPO4

None

Conservant

Usuallymerthiolate

Usuallymerthiolate

Usuallymerthiolate

Usuallymerthiolate

Smallamounts ofantibiotics

Stabilizingsubstances

None

Stabilizer:magnesiumchloride orsucrose

Mode ofadministration

Intramuscularinjection***


Intramuscularinjection


Subcutaneousinjection

Subcutaneousinjection

lntradermalinjection

Oral

Heat stability

High

High

High

Medium

High in dried form,low inreconstituted form

High in dried form,low inreconstituted form

Medium in driedform, low inreconstituted form

Low

exposed to a given temperature for a given period oftime. The change of color will show health workersthat a given vial or ampoule has been exposed topotentially harmful elevated temperature.

Information about the stability of a vaccine, andespecially about the rate at which it loses potency ata given temperature, can be useful in deciding whetherit should be used, sent for testing, or destroyed.

Data on the stability of vaccines have been re-viewed recently (Galazka 1989). Table 2 shows, insummarized form, stability data for the EPI vaccinesat various storage temperatures. The stability of theEPI vaccines varies considerably. Based on their re-sponse to storage at 37°C they can be ranked fromvaccines with relatively high stability (diphtheria tox-oid, tetanus toxoid, and hepatitis B vaccine) to thosewith relatively low stability (OPV, reconstituted BCGvaccine, reconstituted measles vaccine, and reconsti-tuted yellow fever vaccine). Work is in progress toimprove the stability of OPV. Vaccines presented in

the freeze-dried form have moderate or high stability,but after reconstitution these vaccines are unstable.Some vaccines, such as tetanus toxoid or hepatitis Bvaccine, can withstand long periods of exposure with-out significant loss of potency. This characteristiccould be important in the future for the use of thesevaccines in outreach systems to immunize children orwomen in areas where the cold chain cannot bemaintained. Studies are planned to examine the pos-sible use of hepatitis B vaccine and tetanus toxoidwithout refrigeration in special situations.

Each exposure of a vaccine to elevated tempera-ture results in some degradation, even if the residualpotency still exceeds that considered to be the mini-mum immunizing potency. Moreover, each exposureto ambient temperature has a cumulative effect onreducing vaccine potency. Present recommendationsare that all EPI vaccines should be stored routinely atthe temperatures recommended by the manufactur-ers and the national EPI.


Table 2. Stability of EPI vaccines at various temperatures (Galazka 1989).

Vaccine0°C to 8°C

Stability at different storage temperatures

22°C to 25°C 35°C to 37°C Above 37°C

Diphtheria andtetanus toxoids

3 to 7 years Several months About 6 weeks 2 weeks at 45°C; loss of potencyafter a few hours at 60°C to 65°C

18 to 24 months, although Variable; some vaccines Variable; some vaccines About 10% loss of potency per dayPertussis vaccine with continuous slow stable for 2 weeks

with a 50% loss of at 45°C; rapid loss of potency atdecrease of potency potency after one week 50°C

Freeze-dried BCG Variable; 20% to 30% loss Variable; 20% loss of Unstable; 50% loss of potency aftervaccine

1 yearof potency after 3 months potency after 3 to 14 days 30 minutes at 70°C

Reconstituted Reconstituted BCG vaccine should not be used during more than one working session. This recommendation is based on

BCG vaccine concern about the risk of contamination (since BCG vaccine contains no bacteriostatic agents) and concern about the loss ofpotency.

Freeze-driedmeasles vaccine 2 years

Reconstituted Unstable; should be used inmeasles vaccine one working session

Oral polio vaccine 6 to 12 months

Retains satisfactorypotency for 1 month

Unstable; 50% loss ofpotency after 1 hour, 70%loss after 3 hours

Unstable; 50% loss ofpotency after 20 days;some vaccines may retainsatisfactory titers for 1 to 2weeks

2.3 Use of EPI vaccines

The basic principle guiding the use of the EPIvaccines is that protection against the EPI diseasesshould be achieved prior to the time that infants areat risk from these diseases. For countries where per-tussis, poliomyelitis, and measles pose serious healthproblems in very young infants, the EPI recommendsthe immunization schedule shown in Table 3.

In countries where neonatal tetanus is an impor-tant cause of infant mortality, immunization of womenof childbearing age, and especially pregnant women,is recommended.

Reasons for a particular age for starting immuni-zation, the number of doses, and intervals betweendoses in the recommended schedule are presented inthe disease-specific modules of this series. The mod-ules also discuss alternative schedules of immuniza-tion.

Results of available studies indicate benefits fromthe simultaneous use of some vaccines (i.e. givensimultaneously at different places) or the use of com-bination vaccines (i.e. a mixture prepared in advancesuch as trivalent OPV or DPT vaccine). The adminis-tration of several vaccines simultaneously simplifiesroutine childhood immunization and reduces the

Retains satisfactorypotency for at least 1 week

Very unstable; titer may bebelow acceptable levelafter 2 to 7 hours

Very unstable; loss ofsatisfactory titer after 1 to3 days

50% loss of potency after 2 to 3days at 41°C; 80% loss of potencyafter 1 day at 54°C

Inactivation within 1 hour attemperatures above 37°C

Very unstable at 41°C, 50% loss ofpotency after one day, completeloss of potency after 1 to 3 hoursat 50°C

number of contacts. All the EPI vaccines can beadministered simultaneously (Galazka 1991) and itis common practice to give DPT vaccine and OPV atthe same visit. BCG vaccine is compatible with DPTvaccine, measles vaccine, and OPV.

Hepatitis B (HB) vaccine is compatible with theinfant vaccines and it is used in several integratedimmunization programmes simultaneously with otherEPI vaccines. Immunization schedules should be de-signed to provide the first dose of HB vaccine as earlyas possible, consistent with the epidemiology of thedisease and within the capacity of the vaccine deliv-ery system (see Module 9). Three doses are consid-ered a primary series. Where perinatal transmissionof HB virus is common, the first dose should be givenas soon after birth as possible, the second within twomonths, and the third within the first year (Table 3,Scheme A). If early transmission is not a problem, thefirst dose of HB vaccine may be given at six weeks (orlater) with the first dose of DPT vaccine and furtherHB vaccine doses may be administered simultane-ously with each dose of DPT vaccine or measlesvaccine (Table 3, Scheme B). In any case, the secondand third doses of HB vaccine should be timed tocoincide with visits required for other childhoodimmunizations.


EPI recommends that countries at risk for yellowfever should incorporate yellow fever vaccine into theroutine activities of the national immunization pro-gramme. Yellow fever vaccine can be given at 6months of age or with measles vaccine at 9 months ofage. Most African countries that have incorporatedyellow fever vaccine into their EPI give it at 9 monthsof age at the same visit as measles vaccine.

Mixing vaccines in one syringe before injection(for example using DPT vaccine as the diluent formeasles vaccine) is not recommended since the pres-ence of preservatives or stabilizers in one vaccine caninterfere with the action of the other vaccines (Galazka1991).

The first priority for routine immunization pro-grammes is to ensure that infants are completelyimmunized against the target diseases, with appropri-ate primary immunization at the youngest age possi-ble . Immunizat ion programmes consider ingimmunization schedules that include additional vac-cine doses should evaluate the epidemiological pat-tern of the target diseases in their country. Theadditional resources required and any potential nega-tive impact on sustaining high coverage in infantsshould be considered prior to implementing suchschedules.

3. Types of ImmunityThe defense mechanisms of the body are com-

plex. Despite constant microbial challenge from theenvironment, the body prevents infections by a numberof non-specific and specific mechanisms working ontheir own or together (Figure 2).

3.1 Nonspecific defense mechanismsNonspecific defense mechanisms are present in all

normal individuals. They are effective at birth andfunction without requiring prior exposure to a mi-croorganism or its antigens. They include physicalbarriers (e.g. intact skin and mucous membranes),chemical barriers (e.g. gastric acid, digestive enzymes,bacteriostatic fatty acids of the skin), phagocyticcells, and the complement system. The complementsystem contains several enzymes and consists of atleast 19 separate serum proteins. Complement playsa major role in initiating the inflammatory response,clearing immune complexes, modulating immu-noglobulin production, opsonizing microbial patho-gens (see section 4.1.2), and killing certaingram-negative bacteria.

3.2 Specific immunityIn contrast to nonspecific defense mechanisms,

specific immune defense systems are not effective

Table 3. The immunization schedule recommended by the EPI.

Age

Birth

6 weeks

10 weeks

14 weeks

9 months

Women ofchildbearingage, andespeciallypregnantwomen

VaccinesHepatitis B (HB) vaccine

Scheme A Scheme B

BCG, OPV0 * HB1

DPT1, OPV1 HB2 HB1

DPT2, OPV2 HB2

DPT3, OPV3 HB3

Measles, yellow fever ** HB3

TT1 -as soon as possible in pregnancy or as early aspossible in the childbearing years

TT2 - at least 4 weeks after TT1

TT3 - at least 6 months after TT2

TT4 and TT5 - at least one year after the previous TT dose

* OPV at birth (OPV0) is recommended in countries where poliomyelitis has not beencontrolled.** Yellow fever vaccine is recommended in countries at risk for yellow fever.

fully at birth and require time to develop after expo-sure to the infecting agent or its antigens. Specificimmunity may be acquired naturally by infection orartificially by immunization.

Specific immunity is divided into antibody-medi-ated and cell-mediated components. Reactions car-ried out by antibodies are called humoral immunereactions. The most convenient indicator of immu-nity is antibody, as antibodies are the best known ofthe many products of the immune system. Antibody-mediated immunity is related to B lymphocytes (or Bcells), and to their direct descendents, known asp l a s m a c e l l s . T h e p l a s m a c e l l s p r o d u c eimmunoglobulins (antibodies). When a B cell en-counters an antigen, recognized by the antibody ex-pressed on the antigen’s surface, the B cell is stimulatedto proliferate. This leads to expansion of the numberof lymphocytes capable of secreting antibody to thisantigen. Replication and differentiation of B cells intoplasma cells is regulated by contact with antigen andby interactions with T cells, macrophages, and com-plement.

B lymphocytes develop in fetal liver and subse-quently in bone marrow. The name “B” cell comesfrom the bursa of Fabricius, a specialized organ inbirds that acts as a site of B cell development. Mam-mals do not possess this organ. Approximately 10%of the blood lymphocytes are B cells; most B cells andalmost all plasma cells reside in peripheral lymphoidorgans, e.g. the spleen, lymph nodes, tonsils andappendix.

Cell-mediated immunity is conferred by T lympho-cytes and effected by lymphocytes and macrophages.It involves the function of T lymphocytes (T cells) of

6 Immunological Basis for Immunization / Module 1: General Immunology

Figure 2. Defense mechanisms of the body

Defense Mechanisms

Nonspecific

Barriers

Physical: Skin, mucosaChemical: gastric acid,

skin secretions,digestive enzymes

Complement

Plasma proteins

Phagocytosis

Opsonization and killingby leukocytes

Specific

Natural

Antibody-mediated

B lymphocytes; plasmacells and their products,

immunoglobulins

various types and their soluble products, lymphokines(interleukins), that act as signals for communicationbetween different types of cells involved in an im-mune response.

These two components of specific immunity areclosely related to each other. T cells interact with Bcells in the production of antibody against mostantigens. Specific antibodies and CMI are induced inall infections, but the magnitude and quality of thesetwo components varies in different infections.

4. Antibody-mediatedImmunity

4.1 Immunoglobulins

4.1.1 Classes of immunoglobulins

Antibodies are comprised of a family of globu-lar proteins termed immunoglobulins (Ig). Five differ-ent classes of immunoglobulins have been identified(IgG, IgM, IgA, IgD, and IgE), based on structuraldifferences in the composition of their heavy chains.

Some of the immunoglobulin classes contain sub-classes. For example, IgG has four subclasses: IgG1,

WHO/EPI/GEN/93.11

Artificial

Cell-mediated

T lymphocytes andmacrophages and their

soluble products, interleukins

IgG2, IgG3, and IgG4 that display differences in theirheavy chains. Each IgG subclass has distinctphysiochemical and biologic properties. For exam-ple, IgG3 has a much shorter serum half-life thanIgG1, IgG2, or IgG4. IgG1 and IgG3 activate com-plement, whereas IgG4 does not. The antibody re-sponses to most protein antigens are found primarilyin the IgG1 subclass, although significant amounts ofantiviral antibodies occur in IgG3 as well. Smallamounts of antiprotein antibodies also occur in IgG4.

There are two subclasses of IgA: IgA1 is the pre-dominant form in serum (90% of total); IgA2 is thepredominant form in secretions (60% of total).

The most abundant immunoglobulins are IgG,IgM, and IgA. IgE antibodies play a major role inallergic reactions and the role of IgD antibodies is notyet fully understood.

4.1.2 Basic structure of immunoglobulins

Each Ig class has a similar basic unit structureconsisting of two longer peptide chains, known as“heavy” or H chains, bound by disulfide bridges totwo shorter peptide chains, known as “light” or Lchains (Figure 3). Heavy chains are of five majortypes and that determine the antibodyclass. Light chains are of two major types and

IgG is a monomer with four chains. IgM is a


Figure 3. Structural models of IgG, sIgA and IgM.IgG is a monomer; sIgA is composed of two units, a J-chain and a secretory component; IgM is a pentamer composed of five basic units plusthe J-chain. Each Fab fragment has one binding site. The Fc fragment is responsible for transport of IgG across the placenta. Black circlesdenote interchain disulfide bonds.

secretorycomponent

interchaindisulphide

bonds

WHO 93022

IgM

J chain

L chain

L chain

pentamer composed of five basic units plus an addi-tional chain, the J or joining chain. Accordingly, themolecular weight of IgM is about 6 times greaterthan the weight of IgG. IgA exists in two forms, onein serum and one in the secretions. Serum IgA is amonomer, with a single basic unit. Secretory IgA(sIgA) is dimeric, composed of two units, plus J-chainand a secretory component (Figure 3).

Immunoglobulins can be split into active frag-ments by enzymatic digestion. The main fragment,F(ab’)2, is the “head” of a Y-shaped structure and iscomposed of two subfragments, Fab. The term Fab isused because it is this fragment that binds antigen.Each Fab fragment has one binding site, so there aretwo binding sites on the IgG molecule. The IgM hasten binding sites (2 x 5). The fragment Fc (the “leg”of the Y-shaped structure) has no antigen-reactivesites, but it gives the molecule certain biologic activi-ties, including the ability to activate complement andcombine with receptors on macrophages. These prop-erties are important for opsonic activity. Invadingmicroorganisms are coated by specific antibodies,opsonins, which make microorganisms more easilyattacked by macrophages. Macrophages engulf anti-body-coated microorganisms by the process of phago-cytosis. The Fc fragment is also responsible for thetransport of IgG across the placenta.

J chain

H chain

Fab

Fc

IgG

sIgA

4.1.3 Functions of immunoglobulinsThe primary function of immunoglobulins is to

serve as antibodies. This is accomplished through themolecule’s antigen binding (Fab) portion.

The size of the immunoglobulin molecule is one ofthe factors determining its tissue distribution. IgG isthe major immunoglobulin in the bloodstream andaccounts for about 80% of the total immunoglobulinpool. IgG is also present in the tissue spaces. It easilypasses through the placenta (Table 4). IgG is respon-sible for neutralization of viruses and bacterialtoxins, facilitating phagocytosis, and lysing (destroy-ing) bacteria.

IgM, the largest immunoglobulin, is confinedmainly to the bloodstream and is less able to passthrough capillary walls. IgM does not pass throughthe placenta. With its 10-valent antigen-combiningsite, IgM has a high affinity, i.e. a strong ability tobind firmly with antigen. IgM is particularly effectivein the complement-mediated lysis of microorgan-isms.

IgA is the second most abundant immunoglobulinin serum. IgA is the predominant immunoglobulin insecretions of the gastrointestinal and respiratory tractsas well as in human colostrum and milk. IgA provideslocal mucosal immunity against viruses and limitsbacteria overgrowth on mucosal surfaces. IgA also


IgM

900 000

5

100

6

90

<10

Table 4. Properties of immunoglobulins.

Property IgG

Molecular weight 150 000

Half life in days 25

Concentration in adultserum, mg/dl

1 000

% of total Igs 80

Proportion in serum (%) 50 to 60

Proportion inextracellular fluids (%)

40 to 50

Proportion insecretions (%)

0

Complement fixation ++

Opsonic activity ++++ +

Lytic activity ++

Viral neutralization +++

Transfer to offspring via placenta

* Data for secretory IgA; data for serum IgA in brackets.

0

++++

++++

++

no transfer

IgA*

385 000 (170 000)

(6)

(250)

(130)

0

0

100

0

0

0

+++

viacolostrum/milk

functions in the gastrointestinal tract and shows agreater resistance to proteolytic enzymes that otherclasses of antibodies.

4.1.4 Placental transfer of immunoglobulins

Maternal IgG (but not IgM or IgA) is trans-ported across the placenta from about 16 weeksonwards. This reflects passive transport, which in-creases progressively with gestation and is propor-tional to the maternal IgG concentration. It alsoreflects active transport, which tends to normalizeneonatal IgG concentration, suggesting that lowmaternal values stimulate and high maternal valuesinhibit transport. At full term, umbilical cord levels ofIgG can be equal to or even higher than maternallevels. Premature infants have lower IgG levels thanthose delivered at term. Passively-acquired IgG anti-bodies are responsible for the protection of newbornsand young infants against viral and bacterial diseases.

The transfer of IgG antibodies from mother tofetus across the placenta provides the newborn witha portion of the mother’s immunologic experience.This experience is different in areas where infectiousagents circulate at high levels in the population andadults are naturally immune, compared to areas wherethe circulation of infectious agents is limited andadults have low levels of immunity. In developingcountries, passive transfer occurs for diphtheria, mea-sles, polio, and rubella antibodies. Also, tetanus anti-bodies induced in the mother following immunization

with tetanus toxoid easily pass across the placentaproviding protection against tetanus in the newborn(see Module 3). In developed countries, where womenof childbearing age may have low levels of polio anddiphtheria antibodies, transfer of these antibodies ismore limited. If protective maternal antibodies arenot of the IgG type, as is usually the case for the gram-negative pathogens such as Escherichia coli and Sal-monella, the fetus does not receive antibodies fromthe mother and the neonate is not passively protectedagainst these infections.

4.1.5 Normal development of serumimmunoglobulins

Immunoglobulin synthesis starts before birth.IgM has been shown to be present at 10 weeks, IgGat 12 weeks, and IgA at 30 weeks of gestation. Mostof the antibody synthesized by the fetus is IgM.Nevertheless, the fetus grows in a sterile environmentand production of immunoglobulins by the healthyfetus is extremely limited until birth. In some fetusesimmunoglobulin synthesis may be delayed or maynot occur at all.

In the first year of life immunoglobulin levelsincrease quickly under the influence of antigenic chal-lenge from the environment (infections) and throughthe contact with vaccine antigens (Figure 4). By oneyear of age, values for the IgG, IgM, and IgA concen-trations are approximately 60%, 100%, and 30%,respectively, of those in adults.

The newborn infant is capable of responding to anumber of diverse antigens, but to fewer and at amuch reduced level compared with an adult. There islittle or no response to polysaccharide antigens. Therelative inefficiency of the fetal and newborn hu-moral immune response reflects both immaturity inthe antibody-producing B cells and plasma cells andpoor T cell — B cell cooperation.

Passively transferred antibody, especially at highlevels, may transiently suppress the response of theinfant to specific antigens. This phenomenon hasinfluenced the schedule for some immunizations.Measles immunization, for example, is postponeduntil 9 months of age when placentally transferredantibodies have fallen to low concentrations (seeModule 7). A high level of passively acquired diph-theria, tetanus, and pertussis antibodies may inhibitthe response to all components of DPT vaccine dur-ing the first weeks of life. This is the reason fordelaying the administration of the first dose of DPTvaccine until 6 weeks of age. This inhibitory effect istransient and it diminishes following subsequent dosesof DPT vaccine (see Modules 2, 3, and 4).

Infants born prematurely and infants small forgestational age respond to immunization as well asterm infants of a similar postnatal age.


Figure 4. The normal development of serum immunoglobulin levels.

BirthIgM

IgG

IgA, IgE, IgD

Maternal IgG (transplacental transfer)

Age (months)

4.2 Measurement of antibody activity serological assays

4.2.1 When are serological studies useful?

Because it is rather easy to estimate immunityby measuring circulating antibody, there is a ten-dency to identify antibody with immunity. However,the antibody level does not reflect the total immunityof the body (Ipsen 1961). The presence of serumantibody does not always mean that immunity exists,but it does indicate that the individual has had aprevious encounter with the microorganism. Further-more, for most of the EPI diseases the level of anti-body considered to be protective is defined somewhatarbitrarily or is based on artificial laboratory models(see Module 3). The level of protection depends notonly on the amount of antibody assayed, but also onthe affinity of antibodies (see section 4.3.3), theirclasses and subclasses, and their complement fixingcapacity — properties not measured in routine tests.The concentration of antibodies that exists in anindividual does not reflect the degree of priming for abooster response after subsequent exposure to themicroorganism.

Finally, currently available serological techniquescannot distinguish between antibodies induced bycontact with circulating microorganisms or their tox-ins (natural immunity) and antibodies induced byimmunization. All these factors cause serological meth-ods to have a limited value in routine monitoring ofimmunization programmes in developing countries.Other tools, such as immunization coverage surveysor different surveillance techniques for target dis-eases, may be more useful for that task.

On the other hand, serological techniques can bevery useful for providing answers to clearly defined

questions on the epidemiology of target diseases orthe efficacy of immunization programmes. They havebeen used successfully for to assess seroconversionfollowing administration of various measles vaccinesin different age groups (see Module 7), to determineantibody titers following different vaccines andimmunization schedules against poliomyelitis(Module 6) and tetanus (Module 3), to assess thediphtheria immune status in various age groups inareas where circulation of Corynebacteriumdiphtheriae is reduced (Module 2), to evaluate therate of decline of passively-acquired antibodies, andto evaluate the duration of vaccine-induced immu-nity against different target diseases.

4.2.2 Methods to measure antiviral antibodies

Antiviral antibodies can be measured by theneutralization test on tissue culture, the hemagglutina-tion inhibition (HI) test, and the enzyme-linkedimmunosorbent assay (ELISA).

The basis for the neutralization test is the propertyof viruses to propagate and to produce degenerativemorphological changes (cytopathic effect) in a sus-ceptible cell culture. If antibody is present in thesample, the virus will be neutralized and renderedinactive and will not produce a cytopathic effect.Although neutralizing antibody is the most impor-tant antibody for the resolution of infection and theestablishment of immunity, neutralization tests arenot performed routinely because they are expensiveand time-consuming.

Some viruses have hemagglutinating properties,i.e. the virus has the ability to bind to erythrocytesand form a lattice of hemagglutinated erythrocytes inthe bottom of a tube or well. Selective blocking ofhemadsorbtion by antibodies is the basis for the


commonly used hemagglutination inhibition test (seeModule 7).

In the indirect ELISA test, antibody in the testsolution is allowed to react and form a complex withthe antigen, a specific virus or viral antigen which hasbeen passively adsorbed to a surface of polystyrenemicrotiter wells or plastic beds. An enzyme-labelledantibody against bound human antibody (usuallyanti-IgG) is then attached to the antigen-antibody,complex. The uptake of label to the solid phaseshows the amount of antibody in the test sample andcan be measured by the degree of degradation of thesuitable enzyme substrate. Usually, the substrate ischosen so that the final result is a color change whichcan be assessed visually or photometrically.

4.2.3 Methods to measure antibacterial antibodies

Antibacterial antibodies are determined by twomain groups of tests: in vivo neutralization tests andin vitro techniques.

Different properties of bacterial toxins are utilizedfor in vivo neutralization tests. The dermonecroticproperty of diphtheria toxin is used to demonstratethe presence of neutralizing diphtheria antibody onthe skin of guinea pig or rabbit. An alternative is theSchick test on human skin. Tetanus toxin has nodermonecrotic effect and the proportion of mice thatsurvives after injection with a mixture of toxin andtest sample is used to measure neutralizing antibodies(see Module 3).

Neutralizing tests in vivo are sensitive and show.the functional capacity of antibodies -the neutraliza-tion of toxin — and not only a reaction between rele-vant and nonrelevant antigen-antibody systems, as isbe the case with in vitro tests. However, in vivo testsare laborious, expensive, require well trained person-nel, use a large number of costly animals, and need arelatively large amount of serum for determination oflow concentrations of antibodies.

Diphtheria neutralizing, antibodies may also betested in vitro on microcell culture (see Module 2).Neutralizing antibody to pertussis toxin can be meas-ured on microplate culture of Chinese hamster ovarycells (see Module 4).

Many other in vitro tests are used to measurebacterial antibodies. The most common are: passivehemagglutination (HA) and ELISA for diphtheria,tetanus, and pertussis antibodies; and bacterial ag-glutination for pertussis agglutinins. In general, thesetests are simple, sensitive, rapid (for example, resultsof an HA test for tetanus may be known after onehour), and inexpensive. However, in vitro tests areless specific than in vivo neutralization tests, whichare more sensitive in detecting IgM than IgG antibod-ies, particularly in the early periods of the primaryresponse to immunization or infection. Therefore,the results of in vitro techniques should be inter-

preted carefully and verified against in vivo neutrali-zation tests.

Details of particular techniques are discussed inrelevant modules for specific target diseases.

4.3 Immune response

4.3.1 Class-specific response

Immunization and natural infection induce pro-duction of antibodies of the IgG, IgM, and IgAclasses. During acute infection IgM antibody usuallyappears within the first few days after onset of symp-toms and it reaches its peak concentration by 7 to 10days. IgM gradually declines to undetectable levelsover the next several months with resolution of theinfection. Thus, the presence of IgM antibody in theserum indicates a current or recent infection, al-though there are exceptions to this rule.

In natural infection or after immunization, serumIgG antibody usually appears simultaneously withIgM, or within a day or two after. IgG rapidly in-creases in concentration thereafter (Figure 5). IgGantibody usually persists for years at low levels,which are detectable with appropriate tests of suffi-cient sensitivity. On reinfection or revaccination, abooster response occurs (section 4.3.2).

The route of immunization or infection deter-mines whether the IgA antibody response will bemainly systemic or mucosal. A systemic IgA antibodyresponse occurs with parenterally injected vaccinesor infections with microorganisms that replicate inand disseminate to inner organs and to the systemiccirculation. The serum IgA antibody response variesin onset, level, and duration, and is less predictablethan IgM and IgG antibody responses.

4.3.2 Primary versus secondary immune response

On the first introduction of an antigen into thebody, the antibody response takes up to 10 days todevelop. This period is called the lag time, or lagphase. Lymphoid cells encounter the antigen, dividerepeatedly to form a clone of cells with similar reac-tivity, differentiate, and start to synthesize antibody.The antibody levels rise steeply, reach a plateau, andthen decline.

The antibody response following the first (pri-mary) encounter with antigen differs from that fol-lowing the second (secondary) contact. The primaryresponse has a longer lag phase, reaches a lowerplateau, and declines more quickly than the second-ary response. A proportion of persons immunizedwith a killed vaccine (tetanus toxoid, for example)will be “primed” but will not show an antibodyresponse. On reexposure to antigen, there is an accel-erated response with a shorter lag period, a higherplateau and persisting levels of antibody.

A major component of the primary immune re-


sponse is IgM, whereas IgG is the main immunoglobu-lin class represented in the secondary immuneresponse. The difference between the primary and thesecondary response is most marked when the antigenstimulates both B lymphocytes and T lymphocytes(T- dependent antigens).

Subsequent doses of antigen result in a faster andmore vigorous antibody response. The capacity torespond to a booster dose of a vaccine also is pro-longed following several doses. For example, thebooster response to tetanus toxoid has been observedto last for up to 20 years following the third dose oftetanus toxoid (see Module 3).

A so-called “negative phase”, with a transientdrop in antibody levels a short time after a secondarystimulus, has been observed. Further research is neededto determine the importance and magnitude of thisphenomenon. Following a booster dose of tetanustoxoid, one study showed no change in the level oftetanus antitoxin level; however, resistance to tetanustoxin started immediately (Ipsen 1961). This may berelated to an increase in the avidity (see section 4.3.3)of the antitoxin produced.

4.3.3 Maturation of the immune response — avidityof antibodies

The immune response is characterized not onlyby the amount of antibody produced, but also by thequality of the antibody. One of the measures ofquality is the strength of the bond between a singleantigen-combining site of the antibody and anantigenic determinant of the antigen. This property istermed antibody affinity and the sum of all bindingforces is called antibody avidity. The avidity of anti-body matures during the immune response. Blymphocytes producing high-affinity antibodies aremore likely to be triggered on rechallenge, so that theaverage binding affinity of the antibody increasesfollowing subsequent exposure to the antigen. High-affinity antibody with strong binding capacity is muchmore effective in neutralizing viruses or bacterialtoxins than low-affinity antibody.

5. Cell-Mediated Immunity5.1 The nature of cell-mediated

immunityIn many infections the immunological responses

of the host include not only the synthesis of antibod-ies against various antigenic determinants, but alsothe development of cell-mediated immunity to someof components of the microorganism. The term cell-mediated immunity is a generic designation for im-mune responses that can be transferred to anonimmunized recipient by lymphoid cells, but notby antibody.

Figure 5. The temporal appearance of different classes of serum antibodiesfollowing primary immunization with live oral poliomyelitis vaccine

IgG

IgM

IgA

Weeks after immunization

Dose of OPV

5.2 The T lymphocyte — a key cell in theimmune responseCell-mediated immunity is mediated by a sub-

set of lymphocytes called T lymphocytes, or T cells.These cells circulate in the bloodstream and lym-phatic vessels and also migrate through the intracel-lular space. Immunologically-reactive T lymphocytescontrol immune responses; each immune response iscontrolled by different lymphocytes. T cells mediatethree principal functions: help, suppression, andcytotoxicity. T lymphocytes called helper cells stimu-late the immune response of other cells (i.e. T cellsstimulate B cells to produce antibodies). The helperfunctions are mediated primarily by a subset of T-cellhelpers that express CD4 surface antigen.

Other T lymphocytes, called suppressor cells, playan inhibitory role and control the level and quality ofthe immune response. Another function of T cells isrecognizing and destroying infected cells and activat-ing phagocytes to destroy pathogens they have takenup. The suppressor and cytotoxicity functions aremediated primarily by T cells expressing CD8 surfaceantigen.

5.3 Signals between cells of theimmune system — lymphokinesWhen a T lymphocyte meets a foreign antigen,

it will attach itself to the antigen or antigen-contain-ing cell. Antigen-activated T cells respond by secret-ing lymphokines, proteins that act as molecular signalsfor communication between cells of the immune


system (B cell — T cell interaction) and as systemicmediators of the host’s response to infection. Thegroup of lymphokines includes some interleukins, Bcell growth and differentiation factors, and inter-feron gamma.

Cytokine is a more general term. The cytokinesinclude lymphokines produced by T cells as well assimilar substances produced by other cell types, par-ticularly mononuclear phagocytes. Lymphokines helpB cells produce antibody and phagocytes deal moreeffectively with pathogens.

6. HypersensitivityThe term hypersensitivity is used when an im-

mune response occurs in an exaggerated or inappro-priate form causing tissue damage. Four types ofhypersensitivity reaction are known; the first threeare antibody-mediated, the fourth is mediated prima-rily by T cells and macrophages.

Type I, or immediate hypersensitivity, is charac-terized by an allergic reaction immediately followingcontact with the antigen (which is referred to as theallergen). The immediate hypersensitivity reaction isdependent on the specific triggering of IgE-sensitizedcells by antigen, resulting in the release of pharmaco-logical mediators of inflammation (for example, his-tamine). An example of immediate hypersensitivity isthe reaction to bee venom. Atopic diseases, suchasthma, eczema, hay fever, and urticaria, also belongto this category.

Type II, or antibody-dependent cytotoxic hy-persensitivity, occurs when antibody binds to antigenon cells and this leads to phagocytosis, killer cellactivity, or complement-mediated lysis. The mostclear-cut example of a type II reaction is the responseof an individual to red blood cells following anincompatible blood transfusion.

Type III, or immune complex-mediated hyper-sensitivity, develops when antibody-antigen complexesare formed in large quantities, or cannot be clearedadequately by the reticuloendothelial system, leadingto serum sickness-type reactions. Chronic immunecomplex formation, with the deposition of com-plexes in the tissues, occurs in streptococcal andstaphylococcal endocarditis, malaria infection, andhepatitis B virus infection. Neurological reactionsfollowing hyper-immunization with tetanus toxoidbelong to this category and are due to the immunecomplexes that are formed between preformed anti-body and injected toxoid. These immune complexesattract complement and leukocytes, which producelocalized vascular damage (see Module 3). Serumsickness following injection of heterologous serum isanother example of type III hypersensitivity.

Type IV, or delayed type hypersensitivity, devel-ops when antigen trapped in a macrophage cannot be

cleared. T lymphocytes are then stimulated to elabo-rate lymphokines, which mediate a range of inflam-matory responses. Delayed hypersensitivity is seenwith a variety of viral, bacterial, protozoal, fungaland helminth infections. The cutaneous delayed hy-persensitivity reaction to tuberculin is a classic exam-ple. Tuberculin is the lipoprotein obtained fromMycobacterium tuberculosis organisms. The tiny frac-tion of T cells (less than 1 in 1000) innately reactiveto tuberculin proliferates to form a clone of reactivecells after initial exposure (a clone is a group of cellsderived from a single original cell). An individualwho has been exposed to tubercle bacilli or immu-nized with BCG has T lymphocytes that are sensi-tized to tuberculin. When such an individual is injectedintradermally with tuberculin, there is a positive in-flammatory reaction at the injection site after 24 to48 hours. Further discussion on the tuberculin reac-tion can be found in Module 5.

AbbreviationsBCG

DPT

ELISA

EPI

HA

HB

IU

LD50

Lf

OPV

PFU

TCID50

TT

Bacille Calmette-Guérin, vaccine against tuber-culosis

diphtheria-tetanus-pertussis vaccine

enzyme-linked immunosorbent assay

Expanded Programme on Immunization

hemagglutination test

hepatitis B

international unit of potency

dose which kills 50% of test animals

Flocculation value, the amount of toxoid whichwhen mixed with one International Unit of anti-toxin produces an optimally flocculating mix-ture

oral polio vaccine

plaque forming unit; the smallest quantity of avirus suspension that will produce a plaque inmonolayer cell cultures

Tissue culture infective dose 50%; the quantityof a virus suspension that will infect 50% of cellcultures

tetanus toxoid

ReferencesCremer NE. Antibodies in serodiagnosis of viral

infections. In: Lennette EH, ed. Laboratory diagnosisof viral infections. New York: Marcel Dekker;l985:73-85.

Galazka A. Stability of vaccines. Document WHO/EPI/GEN/89.8. Geneva: World Health Organization, 1989.

Galazka A. Simultaneous administration of vaccines. Docu-ment EPI/RD/9l/WP.7/APR/Rev.l. Geneva: WorldHealth Organization, 1991.


Halsey NA, Klein D. Maternal immunization. PediatrInfect Dis J 1990;9:574-581.

Heinzel Fp Root RK. Antibodies. In: Mandell GL, Doug-las RG, Bennett JR, eds. Principles and practice ofinfectious diseases, 3rd ed. New York: ChurchillLivingstone;l990:41-61.

Ipsen J. Changes in immunity and antitoxin level immedi-ately after secondary stimulus with tetanus toxoid inrabbits. J Immunol 1961;86:50-54.

Mims CA. The pathogenesis of infectious disease, 2nd ed.London: Academic Press;1982.

Moxon ER, ed. A Lancet review: Modern vaccines, cur-rent practice and new approaches. London: E.Arnold;1990.

Roitt I, et al. Immunology. London: Gower Medical Pub-lishing;1989.

Smith TF. IgG subclasses. Adv Pediatr 1992;39:101-126.

Wilson CB. The cell immune system and its role in hostdefense. In: Mandell GL, Douglas RG, Bennett JR, eds.Principles and practice of infectious diseases, 3rd ed.New York: Churchill Livingstone;1990:101-138.

The Global Programme for Vaccines and Immunization, established by theWorld Health Organization in 1994, defines its goal as “a world in which allpeople at risk are protected against vaccine-preventable diseases”. The Pro-gramme comprises three units:

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The Global Programme for Vaccines and Immunization produces a range ofdocuments, audiovisual materials and software packages to disseminateinformation on its activities, programme policies, guidelines and recom-mendations. It also provides materials for group and/or individual trainingon topics ranging from repair of health centre equipment to curricula guide-lines for medical schools, nursing colleges and training of vaccine qualitycontrol personnel.

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