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Occupational Medicine 2007;57:552–556

doi:10.1093/occmed/kqm110

IN-DEPTH REVIEW
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Active and passive immunity, vaccine types,
excipients and licensing
David Baxter
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Abstract Immunity is the state of protection against infectious disease conferred either through an immune
response generated by immunization or previous infection or by other non-immunological factors.
This article reviews active and passive immunity and the differences between them: it also describes
the four different commercially available vaccine types (live attenuated, killed/inactivated, subunit
and toxoid): it also looks at how these different vaccines generate an adaptive immune response.
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Key words Active immunity; immunization; immunoglobulin preparations; passive immunity; vaccine
excipients; vaccine licensing; vaccine types.

Downloaded from http://occmed.oxfordjournals.org/ by guest on May 16, 2012
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Introduction of duration of protection are limited to ,25 years—hence,
the preceding caveat about duration of protection.
The first article of this series reviewed those host mech- Passive immunity refers to the process of providing
anisms that protect against microbial invasion. Both lim- IgG antibodies to protect against infection; it gives im-
ited effectiveness against particular pathogens together mediate, but short-lived protection—several weeks to
with pathogen evasion processes mean that certain infec- 3 or 4 months at most. Passive immunity is usually clas-
tious diseases are still a frequent occurrence; some are sified as natural or acquired. The transfer of maternal
occupationally related with the risk to health care workers tetanus antibody (mainly IgG) across the placenta pro-
being particularly well documented [1,2]. Since particu- vides natural passive immunity for the newborn baby for
lar occupationally transmitted infections can be pre- several weeks/months until such antibody is degraded
vented by immunization, this article will look at how and lost. In contrast, acquired passive immunity refers to
the different vaccine types modulate adaptive responses the process of obtaining serum from immune individuals,
to provide further protection. First, however, the terms pooling this, concentrating the immunoglobulin fraction
active and passive immunity will be considered. and then injecting it to protect a susceptible person.
The four most commonly used immunoglobulin prep-
arations are as follows.
Active and passive immunity
Active immunity refers to the process of exposing the body (i) Human Hepatitis B Immunoglobulin Ph.Eur.* Bio
to an antigen to generate an adaptive immune response: Products Laboratory: Human hepatitis B immuno-
the response takes days/weeks to develop but may be long globulin is presented as two vial sizes of 200 and 500
lasting—even lifelong. Active immunity is usually classi- IU. Each millilitre contains 10–100 mg/ml human pro-
fied as natural or acquired. Wild infection for example tein of which at least 95% are gammaglobulins (IgG).
with hepatitis A virus (HAV) and subsequent recovery This product is prepared from plasma from screened
gives rise to a natural active immune response usually donors, selected from the USA. One millilitre contains
leading to lifelong protection. In a similar manner, admin- not ,100 IU of hepatitis B antibody. Its use occupa-
istration of two doses of hepatitis A vaccine generates an tionally is for the immediate protection of non-immune
acquired active immune response leading to long-lasting health care workers exposed to hepatitis B viruses (to-
(possibly lifelong) protection. Hepatitis A vaccine has only gether with an appropriate vaccination programme).
been licensed since the late 1980s so that follow-up studies (ii) Human Rabies Immunoglobulin Ph.Eur.* Bio
Products Laboratory: Human rabies immunoglobu-
Epidemiology and Health Sciences, Stopford Building, Manchester University
lin is presented as a vial size of 500 IU. Each millilitre
Medical School, Oxford Road, Manchester, UK.
contains 40–180 mg/ml human protein of which at
Correspondence to: David N. Baxter, Epidemiology and Health Sciences,
Stopford Building, Manchester University Medical School, Oxford Road, least 95% are gammaglobulins (IgG). This product
Manchester, UK. e-mail: baxter@nhs.net is prepared from plasma from screened donors,

Ó The Author 2007. Published by Oxford University Press on behalf of the Society of Occupational Medicine.
All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

diphtheria. for example pertussis. the toxoid molecules Further detailed information about all these products is are taken up at the vaccination site by immature dendritic available at http://www. toxoid and subunit. Bind- normal bacteriological growth processes. it which are a characteristic feature of tetanus. Following deep subcutaneous/intramuscular (sc/im) administration of tetanus vaccine. ap- .100 IU of tetanus antibody. and . termed linked recog- Certain pathogens cause disease by secreting an exotoxin: nition. One millilitre contains not . It is unlikely that this more frequently than normal giving rise to muscle spasms preparation would be used for health care workers. killed inacti- Simultaneously. The toxoid is physico- the USA. the principal toxin (termed tetanospasmin) uals with a rabies prone exposure. of the vaccine antigens—live attenuated. the now activated whooping cough and polio. VACCINE TYPES. It is given as part of pear to be partly toxin mediated [3. As GABA neurons are inhibitory for motor neurons. non-functioning results in excess activity in motor neurons selected from the USA. 2012 Bio Products Laboratory: Each vial contains 250 mg ular amino acids and inducing minor molecular conforma- protein (40–180 mg/ml) of which at least 95% are tional changes. One millilitre contains not in addition. Haemophilus influenzae type b (Hib) and Neisseria T helper type 2 cells (TH2).4]. Each milli.org/ by guest on May 16. Ultrafiltration then removes unnecessary gammaglobulins (IgG). EXCIPIENTS AND LICENSING 553 selected from the USA. This product is prepared proteins left as a residual from the manufacturing process from plasma from screened donors. causing it to proliferate. selected from to produce the final product.uk. toxoid molecules not taken up by den- vated. D.emc.100 IU of chemically similar to the native toxin thus inducing Varicella-Zoster antibody. release the toxin into the supernatant and formaldehyde (iv) Human Varicella-Zoster Immunoglobulin Ph. each with their own unique meningitidis type C (Men C). MHC II:toxoid complex on its surface now comes into contact with the activated TH2 whose receptors are spe- Toxoid vaccines cific for this complex. all vaccines contain other substances ceptor that recognizes tetanus toxoid results in the (termed excipients) that are present because they im- internalization of toxoid. the metabolism of glycine which is essential for the normal litre contains 40–180 mg/ml human protein of which functioning of gama amino butyric acid (GABA) neurons. One millilitre contains not with the muscles supplied by these nerves contracting . Identifying and then binding of These different commercially available vaccines can be the MHC II:toxoid to the specific TH2 receptor then classified into one of four types depending on the nature activates the naive T cell. they may also have had measles. ing to the B cell through the specific immunoglobulin re- Additionally.org. at least 95% are gammaglobulins (IgG). individuals exposed to chickenpox. the MHC II:toxoid The majority of workers born in the UK can be expected complex then migrates to the cell surface. processing through the endoso- prove the immune response (an adjuvant). post-exposure prophylaxis to non-immune individ. It is given as part of cross-reacting antibodies but the changes induced by post-exposure prophylaxis to specified non-immune formaldehyde treatment render it non-toxigenic [5–7].oxfordjournals. the draining lymph node where they encounter naive rubella.* treatment converts the toxin to a toxoid by altering partic- Downloaded from http://occmed. BAXTER: ACTIVE AND PASSIVE IMMUNITY. migration of this toxin to the central nervous system blocks ulin is presented as a vial size of 250 IU. Depending on their age mature dendritic cell migrates along lymph channels to and gender. Subunit vaccines can be fur- dritic cells pass along lymph channels to the same draining ther subdivided into those where the antigen is produced lymph nodes where they come into contact with B cells.Eur.medicines. While this pro- to have been immunized against diphtheria. ervatives).* Bio synaptic motor nerve cells.150 IU of rabies antibody.Eur. a highly toxigenic strain of Clostridium tetani in a semi- tamination and as part of the management of all synthetic medium: bacterial growth and subsequent lysis wounds if the individual is thought to be non-immune. cess is happening within the cell. Subsequent internalization and Products Laboratory: Human tetanus immunoglob. is given both as part of the management of tetanus Tetanus toxoid vaccine is manufactured by growing prone wounds where there is heavy soil/manure con. are the vehicle for delivering vaccine (carrier) These two processes occur in the same part of the or are a residual of the manufacturing process (for exam- lymph node with the result that the B cell with the ple antibiotics or cell culture components). results in the TH2 activating the B cell to become these include tetanus. cells: within this cell. some infections. they are processed through the endosomal pathway (involving the phagolysosome) Vaccine types where they are bound to major histocompatibility com- plex type II (MHC II) molecules. their uct is prepared from plasma from screened donors. binds to specific membrane receptors located only on pre- (iii) Human Tetanus Immunoglobulin Ph. This prod. tetanus. In tetanus. using recombinant DNA technology and those based on each with their own unique B-cell receptor (BCR). mumps. The process. T-cell receptor (TCR). botulism and cholera— a plasma cell with the production initially of IgM. are necessary mal pathway and presentation on the cell surface as an for ensuring stability of the product (stabilizers and pres- MHC II:toxoid complex as happens in the dendritic cell.

they are usually stable be considered for laboratory workers working with HAV and long lasting as they are less susceptible to changes and sanitation workers in contact with sewage. not . they are safe because they cannot cause the that might be used by occupational health practitioners. each with a BCR for a separate antigenic frag- immune response is sufficiently effective to provide long. recognition with the appropriate TH2. cell culture adapted.oxfordjournals. ment.554 OCCUPATIONAL MEDICINE then there is an isotype switch to IgG. they cannot spread to un. protective efficacy is in excess of 90%. The appropriate prep. because the vaccine antigens HAV. whole cell pertussis vaccine continues to be Downloaded from http://occmed. an adjuvant is included in the vaccine. This process takes a minimum of 10–14 days but on ture dendritic cells and facilitate antigen processing in the subsequent exposure to the organism. IL4. in addition. Release by the this works by forming a depot at the injection site resulting TH2 of IL2. the most widely used killed vaccine. Polio and hepatitis A are currently the prin- Diphtheria and pertussis toxoid (in acellular pertussis cipal inactivated vaccines used in the UK—in many vaccines) are two commercially available toxoid vaccines countries. Second. It is a formalin inactivated. Ty- event of exposure to C. will be activated through with using larger doses is that tolerance can be induced to presentation by the activated mature dendritic cell. Within the draining Toxoid vaccines tend not to be highly immunogenic un. Primary immuni- usually need an adjuvant and require several doses for zation with a booster between 6 and 12 months after the the reasons discussed above. a number of TH2. such site several hours after the vaccination and resolve usually antigens are termed T-dependent vaccines since the in. an acute local inflammatory reaction. disease they prevent and there is no possibility of rever. ogous manner as described above. IL5 and IL6 induces B-cell activation. in the whereas inactivated relates to viral vaccines [3. each with a TCR for less large amounts or multiple doses are used: one problem a separate antigenic fragment. 19th century. molecules within 24–48 h. digestion within the phagolyso- fied tetanus toxoid. First. differentiation and proliferation with subsequent isotype activating cells involved in the adaptive immune response. switch (IgM to IgG) and memory cell formation. and was used among the British troops at the end of the tralizing the toxin and preventing disease development. humidity and light which can result when ally. staff working with children who are not toilet trained vaccines are used out in the community. 8 of type 2 and 32 of type 3. local reactions first should provide a minimum 25 years protection [3]. within 48–72 h. follow- aration in the UK would be Revaxis which contains not ing injection.2 IU of purified diphtheria toxoid. Vaccination should immunized individuals. lymph node. the antigen. is induced which leads to high levels of the different IgG ity clones of antibody producing B cells [9–11]. a subset at the vaccine site are more common—this may be due of B cells becomes memory cells. the whole organism is phagocytosed by . will bind antigens that drain along lymph channels: lasting immunity. II:antigenic fragment complexes. Thus. Hepatitis A is an example of an inactivated vaccine cines. they poor may also be offered vaccination.4]. Tetanus and diphtheria The adaptive immune response to a killed/inactivated vaccines (together with inactivated polio) should be of. Polysaccharide antigens in contrast activating complement by the classical pathway causing generate a somewhat different response as will be de. the separate antigens will be internalized and presented as For diphtheria. The reaction results from excess anti- volvement of T helper cells is essential for the immune body at the site complexing with toxoid molecules and response generated.20 IU of puri. 2012 against which antibodies are produced in an exactly anal. First.org/ by guest on May 16. the toxin receptor binding sites on nerve cells. The rationale for tetanus vaccination is thus based Killed/inactivated vaccines on generating antibodies against the toxoid which have an enhanced ability to bind toxin compared with The term killed generally refers to bacterial vaccines. the toxoids are adsorbed which are presented on the cell surface as separate MHC onto aluminium hydroxide as the adjuvant (see below). . against a much broader range of antigens. in sustained release of antigen over a longer period of time. tetanus and acellular pertussis vaccines. Third. an an MHC II:antigenic fragment. sponse through activation of the various memory B cells tions take place that lead to the development of high-affin. tetani. vaccine is very similar to a toxoid vaccine with the excep- fered in the occupational setting to workers who have not tion that the antibody response generated is directed completed a five-dose programme. Second. vaccination generates neutralizing antibodies and are not actively multiplying. or in residential situations where hygiene standards are Toxoid vaccines have two disadvantages. this will lead to linked aluminium salt (either the hydroxide or phosphate) is used. immature dendritic cells. to the adjuvant or a type III (Arthus) reaction—the latter The above mechanism describes the adaptive immune generally start as redness and induration at the injection response to a protein antigen-like tetanus toxoid. 40 D antigen units of inactivated polio some produces a number of different antigenic fragments type 1. In order therefore to ensure that the adaptive B cells. Addition- in temperature. scribed in the section on subunit vaccines. There are three principal advantages of toxoid vac. strain of sion to virulence. a secondary re- spleen/lymph nodes where the necessary cell–cell interac. Aluminium adjuvants are also readily taken up by imma. this large toxin:antibody phoid was one of the first killed vaccines to be produced complex is then unable to bind to the receptor so neu.

influenza is an example of a subunit vaccine a TH2 with high specificity for the carrier protein. At the injection site. IgM is highly effec- may actually down-regulate the body’s adaptive response— tive at activating complement. the TCR only recognizes protein molecules and so oid vaccines. however. EXCIPIENTS AND LICENSING 555 Killed/inactivated vaccines share the same advantages Simultaneously. leading to the production of IgM. 23 common pneumococcal serotypes which uses the cap. infection is prevented. a particular an. approaches to overcome this include the use of for TH2 involvement. it binds with high avidity to multiple recep- microbes are unable to multiply in the host and so one tors on a B cell with the appropriate specificity. There pendent response. tein conjugate and a B cell whose BCR has a high specificity tein antigens. . there is only Local reactions at the vaccine site are more common— limited isotype switching so that only small amounts of this is often due to the adjuvant. tigen (or antigens) is used such that when the antibody Following phagocytosis by immature dendritic cells. TH2 might be administered in the occupational setting is involvement leads to co-stimulation and cytokine release Pneumovax made up of the capsular polysaccharide from resulting in IgM then IgG and generation of memory cells. Because. Because the vaccine antigen consists of Killed/inactivated vaccines have a number of disadvan. Migration to the gens [3. the produced by a B cell binds to it. particularly viruses. it is significantly less able to presumably. Downloaded from http://occmed. local lymph nodes where they encounter naive TH2. Pneumovax should be offered to workers with chronic And finally. How.org/ by guest on May 16. renal and liver disease. multiple doses). particularly proteins on the surface. own unique BCR. charide complexes at the cell surface. are for the polysaccharide. non-phagocytosed polysaccharide mol- as toxoid vaccines with the additional one that all the ecules pass along lymph channels to the same draining antigens associated with infection are present and will lymph nodes where they encounter B cells. local reactions at the injection site. Subunit vaccines share the same disadvantages as tox- ever. The vaccine is toxoid vaccines with the added benefit that one can dis- administered into the deep subcutaneous tissue or intra. BAXTER: ACTIVE AND PASSIVE IMMUNITY. when Streptococcus pneu- be produced against parts of the pathogen that play no moniae crosses mucosal barriers. phagocytosed and the protein is discussed) whereas polysaccharides generate a T-inde. specific IgM antibody in role in causing disease. instead of generating antibodies T-dependent vaccines by covalently binding them (a pro- against all the antigens in the pathogen. The advantages of subunit vaccines are the same as sular polysaccharide as the vaccine antigen. killed/inactivated vaccines do not give rise to respiratory. immunosuppression or the potential for infections by intracellular pathogens. They usually require several doses because the polysaccharide. for example hepatitis B and influenza. expressed as a cell surface complex with MHC II. several doses and giving the vaccine with an adjuvant [8]. facilitating complement-mediated lysis. with two antigens (haemagglutinin and neuraminidase). Simultaneous passage of vaccine antigen along draining The adaptive immune response to a subunit vaccine lymph channels to the B-cell-rich area of draining lymph varies according to whether the vaccine antigen is a pro. Some of the antigens contained serum will bind to the pathogen’s capsular polysaccharide within the vaccine. a CSF leak: for those individuals with chronic renal dis- ease and splenic dysfunction. Using killed microbes for IgG are produced and few memory B cells formed. Subunit vaccines are a development of the killed vaccine T-independent vaccines can be converted to efficient approach: however. cess termed conjugation) to a protein molecule [9–11]. In an vaccines is inefficient because some of the antibodies will adequately immunized individual. some polysaccharide ample with hepatitis B vaccination. namely the need for an adjuvant (and often even though presented by a mature dendritic cell and dis. VACCINE TYPES. the TH2 is not involved. their presence is an evolutionary development act as a neutralizing or opsonizing antibody. where attenuation of the immune response may be expected further doses every Subunit vaccines 5 years are recommended. The polysaccharide:protein com- T-dependent vaccines like toxoid vaccines (as previously plex is internalized. Hepatitis B and Haemophilus influenzae draining lymph node will bring this activated mature den- b (Hib) are examples of subunit vaccines that use only dritic cell into the T-cell-rich area and lead to activation of one antigen. heart. 2012 that helps the pathogen overcome the body’s defences. asplenia or cytotoxic T cells which can be important for stopping hyposplenia. nodes results in binding between the polysaccharide:pro- tein or a polysaccharide—subunit vaccines based on pro. D.4]. each with their result in antibodies being produced against each of them. is then linked recognition between the activated TH2 with An example of a T-independent subunit vaccine that high specificity for the carrier protein and this B cell.oxfordjournals. together with the frequent occurrence of played on MHC II molecules. Such mul- dose does not give a strong signal to the adaptive immune tivalent binding is able to activate the B cell without the need system. only an adaptive molecules are phagocytosed by immature dendritic cells immune response to the surface antigen is possible (and macrophages). the TH2 is not activated. which subsequently migrate to the whereas with infection core and e responses occur. conjugated protein and polysaccharide molecules are pre- the key therefore to an effective subunit vaccine is to sented both as MHC II:protein and MHC II:polysac- identify that particular antigen or combination of anti. tinguish vaccinated people from infected people—for ex- muscularly. linear repeats of the same high molecular weight capsular tages.

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Inc.556 OCCUPATIONAL MEDICINE Live attenuated One disadvantage to live attenuated vaccines is the pos- sibility that they may cause the illness they are designed to Variolation. the human host and this is a particularly useful approach Downloaded from http://occmed. 11. the pep. a procedure developed in China and India protect against either because they revert to virulence or 1000 AD used a live smallpox vaccine to generate because for some individuals (for example. edn. which grows well at this lower temperature but multiplies 2. circumstances results in the appearance of a number of Varicella-Zoster and hepatitis B gammaglobulin (IgG) mutant types: those mutants with enhanced virulence for preparations are examples of passive immunity which the foreign host are then selected as potential vaccine have considerable applications to the occupational health strains since they generally show reduced virulence for situation.dh. Pober JS. 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