Informacion Suplementaria en Seguridad en Vacunas Who Part 2 2000

8/18/2019 Informacion Suplementaria en Seguridad en Vacunas Who Part 2 2000

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WHO/V&B/00.36 ORIGINAL ENGLISH

DISTR.: GENERAL

Supplementary information on

vaccine safety

Part 2: Background rates of adverseevents following immunization

World Health Organization

Geneva 2000

DEPARTM ENT OF VACCINES

AND BIOLOGICALS

World Health Organization

Geneva 20

DEPARTM ENT OF VACCINES

AND BIOLOGICALS


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Contents

G lossar y ............................................................................................................................. v

A cknow ledgement s ......................................................................................................... v i

1. Introduction..............................................................................................................1

1.1 Background ........................................................................................................ 11.2 C ommon, mild vaccine reaction rates............................................................. 21.3 Rare, mo re sever reaction rates ....................................................................... 31.4 Programme errors.............................................................................................. 5

Background rates for adverse events for specific vaccines andvitamin A supplementation

2. Adverse events following BCG vaccine...............................................................8

3. Adverse events following cholera vaccine........................................................14

4. Adverse events following diphtheria, tetanus andpertussis vaccines...................................................................................................17

5. Adverse events associated with Haemophilus influenzaetype b (Hib) vaccine...............................................................................................26

6. Adverse events following hepatitis A vaccine..................................................31

7. Adverse events associated with the hepatitis B vaccine................................34

8. Adverse events following influenza vaccine.....................................................40

9. Adverse events following Japanese encephalitis vaccine...............................45

10.Adverse events following Lyme disease vaccine..............................................48

11.Adverse events following meningococcal polysaccharide vaccine...............51

12.Adverse events following measles, mumps and rubella vaccines.................55

13.Adverse events following pneumococcal vaccine............................................69

14.Adverse events following poliomyelitis vaccine...............................................72


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15.Adverse events following rabies vaccine...........................................................79

16.Adverse events following rotavirus vaccine.....................................................84

17.Adverse events following tick-borne encephalitis virus vaccine..................87

18.Adverse events following typhoid vaccine........................................................89

19.Adverse events following varicella vaccine......................................................93

20.Adverse events following vitamin A supplementation ..................................97

21.Adverse events following yellow fever vaccine..............................................102


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E LI SA enzy me-linked immunosorbent assay

G BS G uillain–Barré sy ndrome

ID D M insulin-dependent diabetes mellitus

IO M Institute of Medicine

IP V inactivated poliovirus vaccine

LD lethal dose for mouse

O P V oral polio vaccine

PFU plaq ue forming units

P RP polyribosy lribitol phosphate

R RV-TV R hesus ro tavirus t et ravalent vaccine

RVA Rabies vaccine adsorbed

SC I D severe combined immunodeficiency

TB E tick-borne encephalitis

TM Transverse my elitis

Vi virulence (antigen)

WC /rB S w hole cell recombinant B subunit

G lossary


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Acknowledgements

V&B would like to acknowledge the technical input for this document frommany sources including: Drs Nicole G uérin (major contributor), N icole Bo uchard,Ro bert C hen, Philippe D e Wals, G eoffrey Evans, My ron M. Levine, Robert P less,Jennifer D anielson, Wikke Walop, Ro bert C hen, Bruno D e Benoist andO smand Mansoor, as well as members of the VAB t eam in WH O /G eneva.


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1.1 Background

N o b iological or pharmaceutical product has yet been developed w hich is 100% safeand 100% effective. The more modified a vaccine becomes for safety reasons,the greater the possibility that it will become less effective. Vaccine manufacturers

develop products with the highest safety and effectiveness possible, given currenttechnology. But some very rare vaccine-related adverse events will always occur.Where surveillance is not ad equate, these may no t come to the notice of immunizationstaff or the public, but they nonetheless occur.

P rogramme managers and vaccinators need to know w hat is “ normal” – what reactionrates are to be expected. There is not always a single correct answer to thisquestion as the rates for a given vaccine may be variable, depending on how they aremeasured. These rates are usually quoted in reference to a given study, but otherstudies with slightly different designs may produce rather different rates. When thereis no clear “ best study ” , rates in this document have been q uoted as a range,

e.g. “ 40–100 per million d oses administered” . Witho ut these backgr ound rates,it is impossible to know w hen they are occurring more frequently “ than expected” .Indeed rates may appear to be raised in certain situations, such as during masscampaigns (for a detailed explanation, see Supplementary inf ormation on vaccine safety; Part 1: Field i ssues WH O /V& B/ 00.24 ).

Vaccine reactions may be classified into “ common” and “ rare” . The majorityof vaccine reactions are “ common” , mild, sett le w ithout t reatment, and have nolong-term consequences. More serious reactions are very rare – usually of a fairlypredictable (albeit extremely low ) frequency. A childhood vaccine may also precipitatean event that would probably have occurred anyway (e.g. a first febrile seizure).Most important ly, vaccines are given at a time in an infant or child’s life w hen many

other events are happening: colds and coughs happen whether or not vaccines aregiven, but because a cough follows vaccination, parents may (not unreasonably)believe the two events are related.

1. Introduction


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1.2 Common, mild vaccine reaction rates

The purpose of a vaccine is to induce immunity by causing the recipient’s immunesystem to react to the vaccine. It is not surprising that vaccination results in certainmild side-effects. Local reaction, fever and systemic symptoms can result aspart o f the normal immune response. In addit ion, some of the vaccine’s components(e.g. aluminium adjuvant, antibiotics or preservatives) can lead to reactions.A successful vaccine reduces these reactions to a minimum while inducing maximumimmunity. Pain, swelling and/or redness at the injection site characterize the localreaction. Symptomatic local reactions can be expected in about 10% of vaccinerecipients (except for D TP and TT boosters w here it af fects about half). Fever occursin about 10% or less of vaccine recipients (except for D TP w here it is again abo uthalf).

BC G often causes a local reaction that starts tw o o r more w eeks after immunizationas a papule (lump), which becomes ulcerated, and heals after several months, leaving

a scar. Keloid (thickened scar tissue) from the BC G lesion is more common amongAsian and African populations.

Table 1: Summary of common minor vaccine reactions and treatment

(N ote: the rates due to the vaccine administr ation wil l be lower as these symptoms occur independent ly as part of normal chi ldhood)

a) D iarrhoea, headache, and/or muscle pains.b) Rate of local reactions likely to increase with booster doses, up to 50 to 85%.c) With w hole cell pertussis vaccine. Acellular pertussis vaccine rates are low er.

These common reactions occur within a day or two of immunization, except forfever and systemic symptoms from measles/MMR which occur from 5 to 12 daysafter immunization. Although fever and/or rash occur in 5–15% of measles/MMRvaccine recipients during this time, only around 3% are attributable to vaccine,the rest being accounted for as normal events in childhood i.e. background events.


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1.3 Rare, more severe reaction rates

Most of the rare vaccine reactions (e.g. seizures, thrombocytopaenia, hypotonichyporesponsive episodes, persistent inconsolable screaming) are self-limiting anddo not lead to long-term problems. Table 1 details rare vaccine reactions.Anaphylaxis, w hile potentially f atal, is treatable witho ut leaving any long-term effects.Although encephalopathy is included as a rare reaction t o measles or D TP vaccine,it is not certain that the vaccines, in fact, cause this.

The information in tables 1 and 2 can be used to:

Anticipate reactions fo r a specific immunizat ion programme (type and number).

Identify events that are unrelated to immunization (e.g. outside the timewindow).

C ompare reported w ith expected rates of reactions (the efficiency of reporting).

Trigger an investigat ion if the reported rat e is greater than the expected rate.


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Table 2: Summary of rare, serious vaccine reactions,onset interval and rates

a) Reactions (except anaphy laxis) do not o ccur if already imm une (~ 90% of those receiving a seconddose); children over six years unlikely t o hav e febrile seizures.

b) VAP P risk is higher for f irst do se (1 per 1.4–3.4 million d oses) compared to 1 per 5.9 million f orsubsequent doses and 1 in 6.7 million doses for contacts.

c) Seizures are mostly febrile in origin, and rate depends on past history, family history and age,w ith much low er risk in infants under the age of 4 months.

d)

Isolated cases with no denominator make it d ifficult t o assess the rate in older children and adults,but it is extremely r are (less than 1 case per 8 million doses).


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1.4 Programme errors

Most of the reactions listed as “ common, mild” and “ rare, more serious” are difficultor impossible for t he vaccinator to prevent. O ne ty pe of reaction is, how ever,very much in the hands o f the vaccinator to limit or prevent all together. This is the“ programmatic error” caused by an error or errors in the handling or administrationof a vaccine. The error is usually the fault of a person rather than the fault of thevaccine or ot her technology. It can generally be prevented t hrough proper staff trainingand an adequate supply of safe injection equipment. Every effort must be made toavoid events that can cause untold damage to individual infants, grief to parents andloss of confidence in the programme by the public. In many instances, it may alsocause the loss of employ ment of the vaccinator. There is no short cut to training andsupervision for avoiding such events.

A programme error may lead to a cluster of events, especially if one vaccinator failsto observe training. Improper immunizat ion practice may result in abscesses or o therblood-borne infections. The worst scenario is the occurrence of toxic shock fromimproper handling of vaccine vials once reconstituted. A number of infants immunizedfrom the same vial may die within a short time of injection.

Basic rules in avoiding programme errors include:

U se a sterile needle and sterile syringe for every injection.

Reconstitute using only the diluent provided with the vaccine.

D iscard reconstituted vaccine (measles, yellow fever and B C G ) after six hoursand never keep them overnight.

Follow WH O policy on re-use of mult i-dose vials (EPI 199).

Store drugs and other substances in a different fridge from vaccines.

Train and supervise workers appropriately to ensure safe injection practices.

Investigate a programme error so that the same error does not repeat itself.


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The pertussis component should be omitted and diphtheria and tetanus immunizat ioncompleted w ith D T vaccine. Vaccines cont aining th e w hole cell pertu ssiscomponent should not be given to children with an evolving neurological disease(e.g. uncontrolled epilepsy or progressive encephalopathy).

Persons with a history of anaphylactic reactions (generalized urticaria, difficulty inbreathing, swelling of the mouth and throat, hypertension, or shock) following eggingestion should not receive vaccines prepared on hen’s egg tissues (e.g. yellow fevervaccine and influenza vaccine). Vaccine viruses propagated in chicken fibroblastcells (measles or combined measles-mumps-rubella vaccines) can usually be given tosuch individuals without problems.

References

B iellik RJ , C lements C J (1997). Strat egies fo r minimiz ing no socomial measlestransmission. WH O Bul let in , 75, (4) 367-375.

C enters for D isease C ontrol and P revention (1994). G eneral recommendat ions onimmunization. R ecommendations of the Advisory C ommittee on Immunization(ACIP ). M orbi di ty and M ortality Weekly Report , 43: No RR 1.

C enters for D isease Cont rol and P revention (1996). U pdate: Vaccine side effects,adverse reactions, contraindications, and precautions. Recommendations of theAdvisory C ommittee on I mmunizat ion P ract ices. M orb id i t y and M or ta l i t y Week ly Report , 45(RR-12):1-35.

Expanded P rogramme on Immuniz ation (1988). C ontraindications for vaccines used

in EPI. Week ly Epidemiological Record , 63: 279 - 281.

Expand ed Prog ramme on Im munizat ion (1995). WH O P ol icy sta tement .The use of opened vials of vaccine in subsequent immunization sessions.WH O /EP I /L H IS/95.01.

G alazka AM, L auer B A, H enderson RH , Keja J (1984). Ind ica t ions andcontraindications for vaccines used in the Expanded Programme on Immunization.WH O Bullet in , 62: 357-66.


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Vaccine preparation

The original BC G vaccine is a live M ycobacteri um bovis strain attenuated bypassage on culture-medium that contained glycerol, potato slices and beef bile.The original strain was distributed to several laboratories in the world from which

each laboratory produced its ow n BC G and maintained it by serial passage.A stabilizer – monosodium glutamate or albumin – is added to the preparation,but no adjuvant or preservative is added. The diluent is either saline solution ordistilled w ater (Milstien & G ibson, 1990).

Four main strains account for more than 90% of the vaccines currently in useworldwide: the French Pasteur strain 1173 P2, used in 14 countries for their ownprod uction, t he D anish strain 1331, the G laxo strain 1077 derived from theD anish one and the Toky o strain 172. D espite WH O ’s attempts to standardizeproduction and vaccine characteristics, by stabilization and lyophilization,the concentration ranges from 50 000 to 3 million live particles per dose, according

to the strains. According to immunogenicity in animal models, some vaccines(Pasteur 1173 P2 and D anish 1331) are called “ strong” strains, w hereas G laxo strain1077 and Toky o 172 are called “ w eak” (Smith et a l., 1979). It is dif ficult to demonstratethat one strain is clearly superior to another in the protection of human beings.The incidence of side-effects w ith BC G vaccination differs betw een “ strong” and“ w eak” strains.

Adverse events are predominantly related to infection by the live attenuatedbacterium, and errors in achieving intradermal innoculation – a diff icult field techniq ue.

Mild adverse events

Side-effects of BC G vaccination have been reported for a long t ime in most countriesof the world. A review was published by Lotte et al. in 1984, gathering more than1000 publications. Since then, the only new condition is related to H IV infection.

In 90–95% of vaccine recipients, BC G causes a specific lesion t hat starts a s apapule two or more weeks after vaccination. This then becomes ulcerated andheals after several months leaving a scar. The duration of suppuration may alterthe willingness of mothers to allow their children to receive other antigens(Lo evinsohn & G arealla, 1990). More serious local react ions hav e also beendescribed (Lotte et al., 1984): limited lupoid reaction, lasting a few months, keloids,and real tuberculous lupus (1/200 000 inoculations) have been reported

(Misery & C ombemale, 1993; Marrak et al., 1991).

2. Adverse events follow ingBC G vaccine


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M i ld react ions a re most ly loca l w i th o r wi thout regiona l mani fes ta t ions .Local reactogenicity differs between vaccines, varying with both strain andnumber of viable bacilli. Thus the P asteur and C openhagen strains have generallybeen found to be more reactogenic than the Toky o, G laxo or B razilian (Moreau)strains (Milstien, 1990). There w ere several report s in the late 1980s of “ outbreaks”of B C G reactions, manifested as large ulcers and local lymphadenopathy orsuppurative lymphadenitis. At this time, changes in vaccine availability led manyprogrammes to switch from the less reactogenic G laxo1077 to the more reactogenicPasteur 1173P2 strain w ithout staff b eing not ified o f the necessary change in dosageit implied (in Austria: H engster et al., 1992; in India: K abra et al., 1993; in Jamaica:N oah et al., 1990; in Mo zambique: WER , 1988; in Zimbabw e: WER , 1989).

Axil lary or cerv ical lymphadenit is usually heals spontaneously and it is best not totreat the lesion if it remains non-adherent to the skin. An adherent or fistulatedlymph gland, however, may be drained and an anti-TB drug may be instilled locally.Some authors recommend systemic treatment of severe persistent lesions with

erythromycin (Bandhari et al., 1980), while others have tried systemic treatmentw ith isoniazid (H anley et al., 1985) and local streptomy cin with aspiration (Kuyucuet al., 1998). H ow ever, lesions have persisted for one month aft er therapy w ith eitherdrug , and placebo-contro lled trials of treatment are still needed (H anley et al., 1985).

Local and regional suppurati ve lymphadenit is is now becoming rare, especiallyw hen BC G inoculations are performed by w ell-trained staff, w ith a standardiz edfreeze-dried vaccine and a clearly stated individual dose depending o n the age of thevaccinated subjects.

Severe adverse events

O steiti s may occur as a B C G complication. BC G osteitis/osteomy elitis is another ofthe rare and severe consequences of B C G vaccination, and has been reported,in particular in Scandinavia and Eastern Europe, typically associated withchanges in BC G vaccine strain. Thus there w as a report of an increase in osteitis to35 per million in C zechoslovakia after a shift fro m the P rague to R ussian strainBC G (Lotte, 1988). B oth Finland and Sweden reported increases in osteitisafter 1971, w hen they shifted to a G othenburg strain prod uced in D enmark.Sweden reported rates as high as 1 in 3000 vaccine recipients, which declined rapidlyw hen the national pro gramme shifted to a D anish (C openhagen 1331) vaccine strain(Lotte, 1988).

Those have been described mostly in Scandinavian countries and seem to be linkedto the G öteborg strain. According t o K röger et al. (1994), the incidence rate of suchcomplications ranged from 15 to 73 per 100 000 vaccinated between 1971 and 1978.D itt mann (1992) q uot es a freq uency betw een < 0.1 and 30 per 100 000 vaccinerecipients. These accidents were also described rarely after injection of the Pasteuror Japanese strains.


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Tuberculous meningitis

The complication due to BC G has been described (Tardieu et al., 1988) but this isalso exceptional.

Generali zed i nfecti on due to B C G vaccination has also been reported, sometimesbeing fatal. Sy stemic BC G -itis is a recognized but rare consequence of BC Gvaccination, and traditionally has been seen in children with severe immunedeficiencies. A recent multicentre study has identified the syndrome in children w ithsevere combined immuno deficiency (SC ID ), chronic granuloma tous disease,D i G eorge syndrome and homozy gous complete or partial interferon gamma receptordeficiency (Jouan guy, 1996; Joua nguy 1997; C asano va, 1995). I ts fr equ ency isreported as less than 5 per million vaccine recipients, reflecting the rarity of theunderlying conditions (Lotte, 1988). If not properly managed, these cases may befatal.

Accord ing to M and e, 1980, th e first case w as report ed in 1953, 30 years aft erBC G had f irst been applied to man. Betw een 1954 and 1980, 34 cases w ere publishedin the global literature, and the Lotte et al. study estimates the incidence as 2.19 perone million vaccine recipients. N evertheless, three recent C anad ian cases w erereported in 1998. Severe and generalized B C G infection that may occur inimmunocompromised individuals should be treated with anti-tuberculous drugsincluding isoniazid and rifampicin (Romanus et al., 1993).

BCG in HIV-infected infant

There has been particular concern over the implications of H IV fo r the safety o f

BC G vaccination, after early case reports of systemic BC G -itis in individuals w ithAI D S (Anon , 1985). A series of stud ies w as initiated in Af rica to co mparereactogenicity in infants born to H IV-positive and H IV-negative w omen. O nly o nestudy found a significant excess of reactions among the H IV “ exposed” and positiveinfants. This occurred following the mistaken administration of more than twice therecommended d ose of B C G Pasteur vaccine. Four out of 13 H IV-infected infantshad “ mild” reactions (e.g. lymphadenitis, three infants) or “ moderate” reactions(abscess or f istula, one infant) in comparison to 16 of 166 infants born toH IV-uninfected mothers (p = 0.04) (O ’B rien, 1995). In general the data available todate have supported the WH O policy of exempting only individuals with sy mptomat icH IV infection (AID S) from routine BC G vaccination at birth (WH O , 1987).

The main concern is currently linked w ith the H IV infection. A recent study conductedby O ’B rien et al. (1995) has conf irmed the absence of severe adverse events inasympto matic children infected with H IV and immunized at birth. Sy mptoms ofimmunodeficiency rarely appear before several months of age in neonates infectedat b irth . N evertheless, Talbo t et al. (1997), reviewed t he literature published betw een1980 and 1996, and gathered 28 cases of generalized infection by BC G ; 24 of themoccurred in immunocompromised children, and 9 of t hem w ere AID S cases.The mortality w as 78%, but it has not been possible to estimate the part at tributableto AID S in these deaths. Moreover, Talbot et al. have show n that t hese systemicinfections could also occur after revaccination, and that they were not responsive tostandard treatment.


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To prevent any r isk of genera l ized infect ion w ith B C G in these pat ients ,WH O recommends giving BC G to neonates as soon as possible after birth in countriesw here tuberculosis is an important public health prob lem, except in the case of childrenw ith clinical sy mptoms of AID S (SPA and EP I, 1987). These recommendations aresupported by the findings o f several studies, among o thers in Rw anda (WER , 1992).

There are several observations of adverse events fo llow ing BC G administration as atherapy for bladder cancer. The vaccine is administered intravesically and the dosesused in this indication are much higher than those used for infant immunization.The most frequent complications are pulmonary, hepatic, bone marrow, and jointinfections, but a lary ngeal tumour has also been reported. G eneral signs such asfever and inflammatory signs are common (Sicard et al., 1992)

Around 1.5 billion subjects had already been vaccinated before EP I w as launched in1974. Ar oun d 100 000 000 neonat es have b een vaccinat ed each y ear w ithB C G since then. Very f ew adverse events have been reported, considering these

figures.

References

Anon. (1985). D isseminated My cobacterium bovis infection from BC G vaccinationof a patient with Acquired Immunodeficiency Syndrome. MMWR: Morbidi ty and M ortalit y Weekl y Report , 34:227–228.

Bhandar i B , Khurana R , Mandowwara SL (1980) . Management o f pos t-BC G lymphadenitis. I ndian Journal of Pediatr ics , 47:367–70.

WER (1989). B C G -associa ted lym phadenit is in infants – Zimbab w e.Week ly Epidemiological Record , 48:37;1-3.

WER (1992). B C G immuniza t ion and paedia t r ic H IV in fec t ion .Week ly Epidemiological Record , 67:129–32.

C C D R (1998). D isseminat ed Bacille C almette-G uérin infection: Three recentC anadian cases. Canada Communi cable D isease Repor t , 24:9–14.

C asanova JL , Jouang uy E, L amhamedi S, Blanche S, Fischer A (1995).Imm unological cond itions of children with B C G disseminated infection (letter).

L ancet , 346:581.

C olebunders RL , Iz aley L, M usampu M, Pauw els P, Francis H , Ry der R (1988).B C G vaccine abscesses are unrela ted to H IV infect ion [let ter].JAM A: The Journal of the Ameri can M edical A ssociati on , 259:352.

D ittm ann S (1992). Immuno logical preparations. M eyer’s side eff ect of D rugs ,12th Ed . MN G D ukes ed. E lsevier Science Pub lishers, 791–840.

H anley SP, G umb J, Macfarlane JT (1985). C omparison of ery thromy cin and isoniaz idin treatment of adverse reactions to BC G vaccination. Br it ish M edical Journal,

290:970.


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H engster P, Schnapka J, Fille M, M enardi G (1992). O ccurrence of suppurat ivelymphad enitis after a change of B C G vaccine. Archives of D isease in Chi ldhood ,67:952–55.

WH O (1995). Immuniz at ion pol icy . G lobal Pro gramme for Vaccines andImmunization . G eneva, World H ealth O rganizat ion (WH O /EP I/G EN /95.03RE V.1).

Jouanguy E, Altare F, Lamhamedi S, et al (1996). Interferon-receptor deficiency inan infant w ith fatal B acille G almette G uerin infection. The N ew England Journal of M edicine , 335:1956–1961.

Jouang uy E, L amhamedi-C herradi S, Altare F, et al. (1997). Part ial interferonby receptor 1 deficiency in a child w ith tuberculoid bacillus C almette G uerininfection and a sibling with clinical tuberculosis. Journal of Cli nical I nvesti gati on ,100:2658–2664.

Kabra SK , Jain Y, Seth M V (1993). BC G associated adenitis. L ancet , 341:970.

K röger L, Brand er E, K orppi M et al (1994 ). O steitis after new born vaccinationw ith three different B acillus C almette-G uérin vaccines: tw enty n ine y ears ofexperience. Pedi atr ic I nf ecti ous D isease Journal , 13:113–122.

Kuyucu N, K uyucu S, O cal B, Teziç T, U lus S. Comparison of oral eryt homy cin,local administration of streptomycin and placebo therapy for non-suppurative BC Glymphadenitis (1998). Pediatr ic I nfect ious D isease Journal , 17: 6524-5.

Lo tte A, Wasz-H ockert O , Po isson N , D umitrescu N , Verron M, C ouvert E (1984).

A bibliography o f the complications of B C G vaccination: a comprehensive list o fthe w orld literature since the introd uction of B C G up to July 1982. Advances in Tuberculosis Research , 21:194–245.

Lo tte A, Wasz-H ockert O , Po isson N , D umitrescu N , Verron M, C ouvert E (1984).BC G C omplications: estimates of the risks among vaccinated subjects and statisticalanalysis of their main characteristics. Adv ances in Tuberculosis Research , 21:107–193 .

Lot te A, ten D am H G , H enderson R (1988). Second IU ATLD study o n complicationsinduced by intradermal BC G vaccination. Bulletin of the I nternational U nion Against

Tuberculosis and L ung D isease , 63(2):47–59.

Lo evinsohn B , G arealla ET (1990). BC G ulcers and their effect on mother’s willingnessto allow their children receive other antigens. Transact ions of t he Royal Society of Tropical M edicine and H ygiene , 84:430.

WER (1988). Lymphadenitis associated w ith B C G Immunization, M ozambiq ue.Week ly Epidemiological Record , 63:381–388.

Marrakh, R ouissi R, Kharfi M, K ammoun N (1991). Un cas de lupus tuberculeuxcompliquant la vaccination par le BC G . L a Tunisie Medicale , 69:651–4.

Mande R (1980). Bécégites généralisées mortelles. Sem H ôp Paris , 56:470–72.


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WH O (1990). Milstien JB, G ibson JJ. Q uality control of BC G vaccine by WH O :a review of factors that influence vaccine effectiveness and safety. Bulletin of the World H ealth O rganization, 68:93–108.

Misery L , C omb emale P (1993). U rticaire systémique révélatrice d’un lupustuberculeux post-vaccinal, Annals de dermatogie et venerologie , 120:233–5.

N oah P K , Smickle MF, P rabhakar P, Pand e D , Jonhson B , Ashley D (1990).O utbreak of Bacillus C almette-G uérin associated ly mphadenitis and abscesses inJamaican children. Pediatr ic I nfecti ous D isease Journal , 9:890–3.

O ’Brien KL, R uff AJ, Louis MA, Desormeaux J, Joseph D J, McBrien M, C oberly J,Bo ulos R, H asley N A (1995 ). B aci llus C almette-G uérin complica t ions inchi ldren bor n to H IV-1-infected w omen w ith a review o f the l i tera ture.Pediatrics , 95:414–418.

Ray C S, Pr ingle D , Legg W, Mbengeranw a O L (1999). Lympha denit isassociated w ith BC G vaccination: a report of an outbreak in H arare, Zimbabw e.Centr al Af ri can Journal of M edicine , 34:281-286.

Romanus V, Fasth A, Tordai P, Wiholm BE (1993). Adverse reactions in healthy andimmunocompromised chi ldren under six years o f age vaccinated with theD anish BC G vaccine, strain C openhagen 1331: implications for the vaccination po licyin Sweden. Acta Paediatr ica , 82:1043–52.

Sicard D , B lanche P, D ebre B, Z anaret M (1992). P seudo-tumeur lary ngée liée à uneBécégite. Presse médical e , 21:1039.

Smith D , H arding C , C han J, et al (1979). Potency of 10 BC G vaccines organizedby the IABS. Journal of Biological Standardization , 7:179–97.

Smith K C , Starke JR (1999). Bacille C almette-G uérin Vaccine. in P lotkin,S & O renstein, W, eds. Vaccines . Philadelphia, Pennsylvania, WB Saunders C ompany,1999:111–139.

WER (1987). Specia l Pro gramme on AI D S and Expand ed P rogramm e onImmuniz ation. Joint Statement. C onsultation on human immunodeficiency virus androutine childhood immunization. Weekly Epidemi ological Record , 62:297–299.

Talbot E, P erkins MD , Silva SFM, Fro thingha m R (1997). D isseminated B acilleC almette-G uérin disease after vaccination: case report and review. Clini cal I nfectious D iseases , 24:1139–46.

Tardieu M, Truffo t-P ernot C , C arr iere JP, D uf ic Y, Land rieu P (1988).Tuberculous meningi t is due to B C G in tw o previously heal thy chi ldren.L ancet , 440–41.

WER (1987). WH O P o l icy : G loba l Pro gramme on AI D S and ExpandedProgramme on Immuniza t ion – jo in t s ta tement : consul ta t ion on human

immunodef ic iency virus (H IV) and routine chi ldhood immuniz at ion.Week ly Epidemiological Record , 297–309.


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The vaccines

The four types of cholera vaccines currently available are:

1 . The original ki l led cholera vaccine given parentera lly , consist ing of a

heat-killed, phenol-preserved mixed suspension of Inab a and O gaw a subty pesof V ib ri o cholerae, Serovar 01 (D itt man , 1992). This vaccine is no longerrecommended fo r use, and WH O requirements have been discontinued.

2. Tw o new cholera vaccines given orally (Sack et al., 1999).

Killed whole V. chol erae 01 in combination w ith purified recombinant Bsubunit of cholera to xin (WC /rB S). The vaccine is prepared fro mfour strains of killed V. cholerae , including a heat-killed classic Inaba,a heat-killed classic O gaw a, a fo rmalin-killed E l Tor I naba a nd afor malin-killed classic O gaw a. This vaccine is licensed in Argentina,G uatemala, H onduras, N icaragua, N orw ay, Peru, Salvador and Sw eden.

An attenuated live oral cholera vaccine, containing the genetically

manipulated V. cholerae 01 strain 103-H gR . This vaccine is licensed inArgentina, Canad a, Peru, Philippines and Sw itzerland. It cont ainsaspartame (a phenylalanine derivative, which is added as a sweetener).The buffer contains sodium bicarbonate, ascorbic acid, which serves toneutralize gastric acid.

3. As a resul t o f techno logy t ransfer, a var ian t o f the w ho le-cel l vacc inebut without the B subunit has been produced and tested in Viet Nam(Trach et a l., 1997) and looks pro mising fo r mass campaigns in the future.

Mild adverse events

Side-effects from parent eral whole-cell cholera vaccine are similar to those fromwhole-cell typhoid vaccine, although somewhat less severe (Benenson et al., 1968).Approximately 50% of vaccine recipients develop a soreness and inflammation atthe site, and 10 to 30% develop generalized symptoms of fever and malaise.Symptoms usually last one to three days, although some individuals experience adelayed react ion and develop a sore arm between days four and seven(Sack et al., 1999).

Mild post-vaccination gastrointestinal symptoms were reported with equalfrequency for both vaccine and placebo recipients in rando mized, placebo-contro lled,doub le-blind trials of the reactogenicity of oral B S/WCV that is currently licensed

using the recommended immunization schedule of two doses two weeks apart(Begue et al., 1995).

3. Adverse events follow ingcholera vaccine


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Follow ing administra t ion o f the currently- l icensed C VD 103-H gR str a in ,gastrointestinal sympto ms w ere reported w ith equal frequency for vaccine recipientsand placebo recipients in randomized, placebo-controlled, double-blind trialsconducted in North American and European populations using 5x108 CFU dose(Cry z et al., 1990; K ot loff et al., 1992). In d eveloping countries, side-effects w erealso identical in vaccine recipients and placebo group, using 5x109 C F U d o se(Arehawaratana et al., 1992; Simanjutak et al., 1992; Lagos et al., 1998).

Live oral cholera vaccine 103-H gR w as safe in H IV-positive subjects (Perry, 1998)and was wel l- to lera ted even in infants as young as 3 months of age(Lagos et al., 1998; 1999).


The ori ginal parenteral k i l led cholera vaccin e is no longer recommended.When in use, life-threatening reactions used to be extremely rare, but allergic

anaphylactic reactions w ere possible follow ing its administrat ion. D ittmann (1992),cited occasional reports of neurological and psychiatric reactions. H e also reportedone case of G uillain-Barré synd rome; tw o cases of myo carditis and tw o cases ofmyocardial infarction as well as fatal anaphylactic reaction, acute renal failure andpancreatitis.

There are no specific contraindications for k il led oral vaccines . The safety of thevaccines in pregnant women or immunosuppressed people has not been studied.Because this is a killed oral vaccine, the risk seems minimal (Sack et al., 1999).

No severe adverse events related to the administration of li ve oral vaccines have

been reported.

References

Arehaw aratana P S, Singharaj P, Tay lor, et al. (1992). Safety and immunogenicity ofdifferent immunizat ion regimens of C VD 103-H gR live oral vaccine in soldiers andcivilians in Thailand. Journal of I nfecti ous D iseases , 164:1042–8.

B egue RE , C astellares G , Ruiz R, et al. (1995). C ommunity -based assessment o fsafety and immunogenicity of t he whole cell plus recombinant B subunit (WC /rBS)oral cholera vaccine in Peru. Vaccine , 13:691–4.

B enenson AS, Joseph P R, O seasohn R O (1968). C holera vaccine field trial inEast Pakistan. 1. Reaction and antigenicity studies. Bull etin of t he World H ealth O rganization, 38:347–57.

C ry z SJ, Levine MM, K aper JB (1990). Rand omized double-blind placebo-contro lledtrial to evaluate the safety and immunogenicity of t he live oral cholera vaccine strainC VD 103-H gR in adult Swiss. Vaccine , 8:577–80.

D ittmann S (1992). Immunob iological preparations. In M eyler’s Side Ef fects of D rugs ,12th ed. Elsevier Science, 1992:791–814.


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Kotlo ff KL, Wasserman SS, O ’D onnell S, et al. (1992). Safety and immunogenicityin N orth Americans of a single dose of live oral cholera vaccine C VD 103-H gR:Results of a placebo-contro lled, double blind crossover trial. I nfection and I mmunity ,60:4430–2.

La gos R , L osonsky G , Abrego P, et al. (1998). Tolerancia, immunog enicidad ,excreción y transmissión de la vacuna ant i-cólera ora l viva a tenuada ,C VD 103-H gR. Estudio pareado do ble ciego en niños chilenos de 24 à meses.Boleti n M edico del H ospital I nfanti l de M exico , 53: 214–220.

Lagos R , San Martin O , Wasserman SS, P rado V, Lo sonsky G A, Bustamente C ,Levine MM (1999). Palatability, reactogenicity and immunogenicity of engineeredl ive ora l cholera vaccine C VD 103-H gR in C hilean infants and t odd lers .Pediatr ic I nfect ious D isease Journal . 18(7): 624–30.

P erry RT, Ilo w e C V, et al. (1998). A singles dose of live oral cho lera vaccineC VD 103-H gR is safe and immunogenic in H IV-infected and non-infected adults inMali. Bull etin of the World H ealth O rganization , 76(1):63–71.

Sack D A, C adoz M (1999). C holera vaccines. In P lotkin SA, O renstein WA, eds.Vaccines , 3rd ed. P hiladelphia, PA, WB Saunders C ompany, 1999:639–49.

Simanjutak SC , et al. (1992). Safety and imm unogenicity of single do se live ora lcholera vaccine C VD 103-H gR in 5–9 y ears o ld I ndo nesian chi ldren.L ancet , 340:689–94.

Trach D D , C lemens JD , K e N T, et al. (1997). Field tr ial of a locally pr od uced,

killed, oral cholera vaccine in Viet Nam. L ancet , 349:231–235.


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Vaccines

Available vaccines against diphtheria, pertussis and tetanus for use in infants andyoung children contain the following active ingredients (Mortimer Jr et al., 1999;Wassilak et al., 1999; Edw ard s et al., 1999):

D iphtheria and tetanus toxo ids.

Vaccine against pertussis of one of the two types:

whole-cell vaccine, inactivated bacterium Bordetella pertussis ;

acellular vaccine, consisting of betw een one and five purified proteins ofthe bacterium.

Preserving agents (e.g. thiomersal or phenoxyethanol), stabilizing agents(e.g. gelatin or polysorbate 80) and adjuvants such as aluminium hyd roxide oraluminium phosphate.

Vaccines against diphtheria, pertussis and t etanus (D PT) are combined so that theycan be administered to the child in a single injection. For adults, the vaccines usedare generally a combination of only diphtheria and tetanus, w ith low er concentrationsof the diphtheria toxoid (Td) or tetanus toxoid (TT) only for pregnant women inorder to control neonatal tetanus.

a) DIPHTHERIA TOXOID

D iphtheria toxoid is a preparation of inactivated diphtheria toxin. U sually it isavailable as a preparation adsorbed with aluminium hydroxide or phosphate andcombined w ith ot her toxoids or vaccines. The amount o f toxoid present is measuredin flocculating units (Lf), and t he immunizing potency in I nternational U nits

(IU ) per dose (these values are measured in d ifferent w ays and do not convert directly).WH O recommendations stipulate a potency o f not less than 40 IU per dose up to theage of seven years.

Mild adverse events

Fifty years ago, efforts to maintain protection against diphtheria in children andadults met with unacceptable local and systemic reactions. In general, these weretype IV delayed hypersensitivity reactions to the diphtheria proteins. Purifying thetoxoid, adsorbing it on an aluminium hydroxide and reducing its concentration(Mortimer Jr et al., 1990) considerably reduced the frequency of such reactions.

4. Adverse eventsfollow ing diphtheria,

tetanus and pertussis vaccines


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Reactions to adsorbed diphtheria toxoid are more frequent among people who havealready received several boosters (Edsall et al., 1954). Their frequency varies withthe toxoid concentration and the level of diphtheria toxin antibodies present in theblood prior to vaccination.

Mild reactions include:

Lo cal reactions, light to mo derate: redness, pain and hardening at t he injectionpoint (11% to 38%).

Systemic reactions: transient fever (1%), malaise, aches, flushing.


G eneralized urticaria or pruritus have been reported and, rarely, anaphylacticreactions. Recent data on adverse reaction to diphtheria toxoid alone are scarce,since it is usually comb ined w ith tetanus toxo id for adults and w ith pertussis vaccinefor children under seven years of age.

b) TETANUS TOXOID

Tetanus toxoid is a preparation of inact ivated toxin. The toxo id is available in a plain(unadsorbed) form or adsorbed with aluminium phosphate or hydroxide, alone or incombination with other toxoids or vaccines. The potency of tetanus toxoid,expressed in International U nits varies widely according to t he preparation and t hemanufacturer, but WH O stipulates not less than 60 IU per dose. The frequency andgravity of local reaction to tetanus vaccination increases with the number of dosesadministered and with age (Myers et al., 1982). The risk of local reaction and sterile

abscess increases when an injection of adsorbed vaccine puts the adjuvant in contactw ith the subcutaneous tissue (EP I, 1982; Mark, 1999). This is of par ticular impo rtancein the programme of prevention o f neonatal tetanus through immunization of pregnantwomen in developing countries.

Mild adverse events

Minor local reactions such as pain and erythema are the most f requent and are foundin 25% to 85% of cases (Mortimer Jr et al., 1999). In some cases, a nodule can format the point of injection and remain for several weeks. A sterile abscess appears in6 to 10 cases per million doses administered.

Systemic reactions occur with booster injections in 0.5% to 10% of cases;such reactions entail fever, malaise, shivering, general aches and headaches.


A llergic reacti ons

Reactions such as generalized urticaria and anaphylaxis, are rare (1 to 6 casesper million doses administered). An Arthus-type hypersensitivity reaction(hypersensitivity to immune complexes) and serious local reactions can occur inhy per-immunized persons, i.e. persons w ho have high t itres of ant i-tetanus antibody

before the vaccination.


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Brachial neuri ti

This defined as dysfunction limited to the upper extremity nerve plexus,without involvement of other peripheral or central nervous system structure(AAP, 1997) has been reported after administration of tetanus toxoid (relative risk

of 5 to 10; 0.5 to 1 cases per 100 000 doses administered) (Vaccine Safety C ommittee,1994). It is usually associated with the administering of multiple doses (Rutledge &C art er, 1986).

Gui llai n-B arrésyndrome

This appears w ithin six weeks of vaccination, and has been associated w ith the tetanuscomponent. An American study reviewed 306 cases of the syndrome in adults andchildren, and concluded that , if such an association exists, it is very rare (Tutt le et al.,1997)

c) COMBINED DIPHTHERIA AND TETANUS TOXOIDS

C ombined diphtheria and t etanus vaccine w ith reduced diphtheria content is givento subjects aged seven years and over. The intensity and frequency of local andsystemic reactions increase with age, with the number of doses administered andw ith the concentration o f to xoid (My ers et al., 1982; C D C , 1996; N C C I, 1998).Thus, reducing d iphtheria content, the number and severity of reactions are reduced.The available data suggest that both diphtheria and tetanus toxoids contribute to theadverse reactions.

Mild adverse events

The Td vaccine causes local reactions, pain, induration and erythema in 10% to75% of cases. In some cases, a nodule can develop at the point of injection andremain there for several w eeks. A sterile abscess appears in 6 to 10 cases per milliondoses administered. Fever and other systemic reactions (muscular aches andheadaches) occur in 10% of cases.


The remarks on allergic reactions, brachial neuritis and G uillain-Barré syndrome inthe above section on tetanus apply also to the Td vaccine.

d) PERT

USSIS

VACCINES

Tw o classes of pert ussis vaccine are currently availab le: w hole-cell vaccines andacellular vaccines.

The whole-cell vaccines are suspensions of killed B. pertussis organisms at aconcentration of more than 4 IU.

The acellular vaccines are made from purified antigens of B. pertussis . All thecurrent vaccines contain pertussis toxoid (3.2 to 40µg per do se) and most cont ainfilamento us agglut inin (2.5 - 34.4 µg per dose). O ther antigens in the vaccinesmay include pertactin (1.6 - 23.4 µg per dose), fimbriae 2 (0.8 to 5 µg per dose)and fimbriae 3 (5 µg per d ose), (C D C , 1997).


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The adverse reactions fo llow ing injection o f pertussis vaccines, in comb ination w ithdiphtheria and tetanus toxoids, are listed in the two sections below.

e) COMBINED DTPVACCINES CONTAINING WHOLE-CELL PERTUSSIS VACCINE

Mild adverse events

The whole-cell component of pertussis is largely but not solely responsiblefor react ions occurr ing a f ter administra t ion of comb ined D TP vaccine(C od y, 1981; Scheifele, 1994; G upta , 1991; C herry, 1996). A study compa ringD T and D TP vaccination of under-six year olds show ed significantly low er rates forD T w ith respect t o sensitivity, redness, oedema, fever, dro w siness, irritation, vomiting,loss of appetite and persistent w eeping, except screaming (Cody, 1981).

In another study comparing a placebo arm was included in six month old childrenw ho had received tw o d oses of D TP previously (Lo ng, 1990). D TP caused

significantly more reactions of all types, except oedema of more than 5 cm,a temperature in excess of 39.4° C and screaming.

Minor local reactions such as pain, oedema and erythema occur in 40% to 80% ofcases w hen D TP vaccine is administered. In rare cases, a nodule can form at thepoint of injection and remain there several weeks. A sterile abscess appears in6 to 10 cases per million doses administered.

Mild syst emic react ions consist o f temperature over 38° C and irr i ta t ion(40% to 75%), drow siness (33% to 62%), loss o f appetit e (20% to 35%), and vomit ing(6% to 13%).

The frequency of local reactions tends to increase with the number of dosesadministered, w hile sy stemic reactions (C od y, 1981; C ommun icable diseases inC anad a, 1992; 1994) w ith the exception o f f ever (C herry, 1996), diminish w ithsubsequent do ses. Local reactions are more intense when the intramuscular injectionof adsorbed vaccines introduces aluminium salt into subcutaneous tissue (Ipp, 1989).


Specific severe adverse events are described:

Persistent, inconsolable crying for more than three hours (mostly frompain, 1%).

Temperature in excess of 40.5° C (0.3%).

U nusual screams (0.1%).

C onvulsions (usually related to fever, one case in 12 500 does administered)(Farrington et al., 1995).

H y pot onic–hy porespo nsive episodes (one case in 1750 do sesadministered)(C od y, 1981).


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Anaphylactic reactions are rare (two cases in 100 000 doses administered)(Edw ards et al., 1999; CD C , 1996).

C onvulsions are more frequent w hen there is a personal history (with a relative risk

of 6.4) or a family history (relative risk of 2.4) of convulsions in the child(Edw ards et al., 1999; Livengoo d, 1989). There w as an increased relative risk fo rconvulsions 0–3 day s after D TP vaccinatio n (Farrington, 1995).

Systematic administering of acetaminophen or any appropriate antipyretic at thetime and at 4 and 8 hours after immunizat ion decreases the subsequent incidence offebrile and local reactions (AAP, 1997). It may also be of benefit if there is a personalor family history of convulsions (Ipp et al., 1987; C D C , 1987).

The U S Vaccine Safety C ommittee agreed in 1994 that there was insufficient evidenceto conclude that pertussis vaccine could cause permanent brain damage (Edw ards etal., 1999). Furthermore, the experts rejected the alleged causal link betw een D TPvaccine and autism, infant spasms, Reye syndrome and sudden infant death sy ndrome.

f) DPT COMBINED VACCINES CONTAINING ACELLULAR PERTUSSIS VACCINE

Mild adverse events

In general, vaccines containing the acellular pertussis component causes the sameadverse effects, but less frequently, than vaccines containing whole cell pertussiscomponent. (Edw ards et al., 1999; C D C , 1997). Studies tend to show that thefrequency of reactions containing the acellular component of pertussis does notexceed the frequency follow ing injection o f a vaccine w ithout the pertussis component

(D T or Td vaccines) (G ustaf sson, 1996). Studies show considerable differencesbetween children receiving first doses (at two, four and six months), for all slight tomoderat e reactions except vomiting (see table 4) (Mills et al., 1998; D ecker et al.,1995; D ecker & Edw ard s, 1996).


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Table 4: Percentage of mild to moderate reactions within 24 hoursfollowing a dose of DTP

a) 13 different acellular pertussis vaccines, each cont aining 1 to 4 antigens, all comb ined w ithdiphtheria and tetanus toxoids.

b) Whole-cell pertussis vaccine combined with Lederle diphtheria and tetanus toxoids.


Studies to estimate the frequency of severe and rare reactions are continuing.Even w hen convulsions, persistent w eeping, temperature in excess of 40° C andepisodes of hypotonia and hyporeactivity have occurred after injection of acellularvaccines, minor and major reactions are reduced by more than half w hen w hole-cellvaccine is used (Edw ards et al., 1999).

Several studies have demonstrated the safety of substituting a vaccine containing theacellular pertussis component as a booster for a child who began the course ofvaccination with a vaccine containing the whole cell component (Pichichero et al.,1997; H alperin et al., 1996; Feldman et al., 1992). In part icular, admin istering abooster (fourth dose) of acellular pertussis vaccine to children whose course ofvaccination had begun with acellular vaccine produced more local reactions than

w hen they had previously b een given who le-cell vaccines. H ow ever, even thoughthe frequency of local and systemic reactions related to acellular vaccine tends torise w ith the number of d oses administered, they are less frequent than w hen a whole-cell vaccine is used.


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References

American Academy of P edia tr ics (1997). In : P eter G , ed.1997 Red book : Repor t of t he Commit tee on I nf ect ious D iseases , 24th ed. Elk G rove Village, IL:American Academy of Pediatrics. 1997:394–407, 518–523, 687.

C D C (1987). C enters for D isease C ontrol and P revention. Advisory C ommitteeon Im munization P ractices (AC IP ). P ertussis immunization; family historyof convulsions and use of ant ipyret ics . M M WR: Mo rb i d i t y and Mo r t al i t y Week ly Report , 36:281–2.

C D C (1996) C enters for D isease C ontrol and P revention. Advisory C ommittee onIm munizat ion P ractices (AC IP ). U pdate: vaccine side effects, adverse reactions,contraindications and precautions. MMWR: M orbidity and Mortality Weekly Report ,45(RR-12):22–31.

C D C (1997). C enters for D isease C ontrol and P revention. Advisory C ommittee onImmuniz ation P ractices (AC IP ). Pertussis Vaccination: U se of acellular pertussisvaccines among Infants and young children. MMWR: Morbid i ty and M orta l i ty Week ly Report , 46(RR-7):1–16.

C herry JD (1996). H istorical review of pertussis and t he classical vaccine.Journal of I nf ecti ous D iseases , 174,supt 3:S259–S263.

C ody C L, B araff L J, C herry JD , et al. (1981). N ature and rates of adverse reactionsassoc ia ted w i th D TP and D T immuniza t ions in in fan ts and ch i ldren .Pediatrics , 68:650–60.

D ecker MM, Edw ards K M, Steinhoff M C , et al. (1995). Comparison of 13 acellularpertussis vaccines: adverse reactions. Pediatrics , 96:557–66.

D ecker M M, E dw ards K M (1996). The multicenter acellular pertussis trial:An overview. Journal of I nf ect ious D iseases , 174, supt 3:S270–S275.

Edsall G , Altman JS, G aspar AJ (1954). C ombined tetanus-diphtheria immunizationof adults: Use of small doses of diphtheria toxoid. American Journal of Publ ic H ealth ,44:1537–45.

Edw ards KM, D ecker MD , Mort imer Jr EA (1999). Pertussis vaccine. In P lotkin S,O renstein W, eds. Vaccines , 3rd ed., WB Saund ers C ompany, 1999:293-344.

WER (1982). Expanded Programme on Immunization. Reactions to tetanus toxoid.Week ly Epidemiological Record , 57:193–4.

Farr ington P, Pugh S, C olville A et al. (1995). A new method for active surveillanceof adverse events from D TP and MM R vaccines. L ancet , 345: 567–9.

Feldman S, Perry S, Andr ew M, et al. (1992). C omparison o f acellular (B ty pe)and whole-cell pertussis component diphtheria-tetanus-pertussis vaccines as the

first booster immunization in 15–24 month-old children. Journal of Pedi atr ics ,121:857–61.


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G upta R K , Relyveld EH (1991). Adverse reactions aft er injection o f adsorb eddiphtheria-pertussis-tetanus (D PT) vaccine are not due only to pertussis organismsor pertussis components in the vaccine. Vaccine , 9:abstract.

G ustafsson L, H allander H O , O lin P, et al . (1996). A contro lled trial of atw o-component acellular, a five-component acellular, and a w hole-cell pertussisvaccine. N ew England Journal of M edicine , 334:349–55.

H alperin SA, Eastwo od B J, Barreto L, et al. (1996). Adverse reactions and antibodyresponse to four doses of acellular or whole cell pertussis vaccine combined withdiphtheria and tetanus toxoids in the first 19 months of life. Vaccine , 14:767–72.

Ipp MM et al. (1987). Acetaminophen prophylaxis of adverse reactions followingvaccination of infants with diphtheria-pertussis-tetanus toxoids-polio vaccine.Pediatr ic I nf ecti ous D isease Journal , 6:721–5.

Ipp MM , G old R , G oldbach M, et al. (1989). Adverse reactions to diphtheria, tetanus,pertussis-polio vaccination at 18 months of age: effect of injection site and needlelength. Pediatrics , 83:679–82.

Livengood JR, Mullen JR, White JW, et al. (1989). Family history of convulsionsand use of pertussis vaccine. Journal of Pediatr ics , 115:527–31.

Lo ng S, D eforest A, Smith D G , et al. (1990). Lo ngitudinal study of adverse reactionsfollowing diphtheria-tetanus-pertussis vaccine in infancy. Pediatrics , 85:294–302.

Mark A, C arlsson RM , G ranstrom M (1999). Subcutaneous versus intramuscular

injection fo r booster D T vaccination of ad olescents. Vaccine , 17:2067–72.

Mills E, G old R , Thipphaw ong J , et al (1998). Safety and immuno genicity o f acombined f ive-component pertussis-diphtheria- tetanus-inact iva tedpoliomyelitis-H aemophilus b conjugate vaccine administered to infants at two,four and six months of age. Vaccine , 16:576–85.

Mor timer Jr EA, Kharton M (1999). D iphtheria toxoid. in P lotkin S, O renstein W.Vaccines , 3rd ed. P hiladelphia, PA, WB Saund ers C ompany, 1999:140–157.

My ers MG , Beckman C W, Vosdingh R A et al. (1982). P rimary immunization w ith

tetanus and d iphtheria toxoids. Reactions rate and immunogenicity in older childrenand adults. JAMA: The Journal of t he Ameri can M edical Associati on , 248:2478–80.

N ational C onsultative C ommittee on Immunizat ion (1998). Canadian I mmunization Guide , 5th edition, D irectorate G eneral for H ealth, D isease Cont rol Laborato ry,H ealth C anada , 1998:69, 75, 93–94.

P ichichero ME , D eloria MA, Rennels MB, et al (1997). A safety and immunogenicitycomparison of 12 acellular pertussis vaccines and one whole-cell pertussis vaccinegiven as a fourth dose in 15 to 20 month-old children. Pediatrics , 100:772–88.


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Rut ledge SL, C arter O (1986). N eurologic complications of immunizat ions.Journal of Pediat ri cs , 109:917–924.

Scheifele D W et al. (1994). Role of w ho le-cell pertussis vaccin e in severe local

reactions to the preschool (fifth) dose of diphtheria-pertussis-tetanus vaccine.Canadian M edi cal A ssociat ion Journal , 150:29–35.

Tuttle J et al. (1997). “ The r i sk o f G ui ll a in-Barré synd rome a f terTetanus-toxo id-C ontaining Vaccines in Adults and C hildren in the U nited States” ,Ameri can Journal of Public H ealth , 87:2045–8.

Vaccine Safety C ommittee (1991). Adverse effects of pertussis and rubel la vaccines: A report of the Commi tt ee to Rev iew the Adverse Consequences of Pertussis and Rubella Vaccines . Institute of Medicine (IO M). Washington D C , National AcademyPress.

Vaccine Safety C omm itt ee (1994 ). A dv er se Ev en t s A ssoci at ed w i t h C hi ld hood Vaccin es. Ev id ence Beari ng on C ausali ty. Institute of Medicine.Washington, D .C , N ational Academy P ress.

Vaccine Safety C omm itt ee (1994 ). D T P v acci nes an d chr on i c ner v ou s system dysfunction: A new analysis . (Supplement.) Institut e of M edicine (IO M).Washington, D .C ., N ational Academy P ress.

Wassilak SG F, O renst ein WA, Sut ter RW (1999). Teta nus t ox oid .In P lotkin S, O renstein W. Vaccines , 3rd ed. P hiladelphia, PA, WB Saunders C ompany,1999:441–474.


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Vaccine preparation

Several H aemophilus inf luenzae ty pe b (H ib) conjugate vaccines have been developedand licensed, resulting in extensive experience in their use in Europe and the Americas.All these vaccines utilize the same hapten, polyribosylribitol phosphate (PRP).

H ow ever, the vaccines differ in the protein carrier used, the size of the poly saccharide,the type of linkage and immunogenicity (Ward & Zangwill, 1999). Four differentty pes of carrier have been used – diphtheria to xoid (PR P -D ), tetanus toxoid(PRP-T), a non-toxic variant of d iphtheria toxin (H bO C ), and the outer membraneprotein complex of serogroup B N eisseri a meningit id is (PRP -O MP ). Thiomersal isused as a preservative in some preparations and adjuvant is added in some.

Mild adverse events

Lo calized reactions are common fo llow ing administrat ion of H ib vaccines.Within 24 hours of vaccination, recipients may experience pain and tenderness at the

injection site. These reactions are generally mild and transient. In most cases,they spontaneously resolve within two to three days and further medical attention isnot required (Fritzell & Plotkin, 1992). Mild systemic reactions, including fever,rarely occur fo llow ing administra tion of H ib vaccines (2%) (Valdheim et al., 1990).

Serious adverse events

Serious adverse events follow ing administrat ion of H ib vaccine are uncommo n,making it one of the safest vaccines currently available. In a study including4459 Navajo infants, there were no differences in the type and frequency of seriousadverse reactions occurring among those receiving H ib conjugate vaccine and t hosereceiving a placebo (CD C , 1991). Research has also show n the use of H ib vaccines

to be safe in H IV-infected individuals (Leroy et al., 1996; D ockrell et al., 1998).

Anaphylaxis

Anaphylaxis was not reported during the pre-licensure clinical trials. Since then,post-marketing surveillance has identified five possible cases of anaphylaxis(Milstien et al., 1987; Strat to n et al., 1994). H ow ever, no report s of anaph y laxisfollow ing H ib vaccination have been published. Aft er review ing available data,the Institute of M edicine (IO M) concluded that there is not enough evidence toaccept or reject a causal relationship betw een H ib vaccines and anaphy laxis(Stratton et al., 1994).

5. Adverse events associatedwith

H aemophi lus inf luenzae type b (H ib) vaccine


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Gui l lai n–Bar résyndrome

N o contro lled studies have been conducted to explore the risk of G BS fo llowingH ib vaccination. G BS w as not reported in any of t he pre-licensure clinical trials.The Institute of M edicine identified seven cases of G BS that occurred fo llow ing H ibvaccination, however, three of the individuals had received multiple vaccines andone had an implausible onset interval. Therefore, the I O M concluded there wasinadequate evidence to accept or reject a causal relationship betw een H ib vaccinesand G BS (Stratto n et al., 1994).

Thrombocytopenia

D uring one H ib conjugate vaccine trial, a case of thrombocy topaenia was reported;however, a subsequent study found the vaccine had no effect on platelet count(Lepow et al., 1984; Strat ton et al., 1994). Since that time, post-marketing surveillancehas identified several possible cases of thro mbocy topenia follow ing H ib vaccination

(Milstien et al., 1987; Stratton et al., 1994). The Institute of Medicine reviewedavailable data and concluded there was inadequate evidence to accept or reject acausal relationship betw een H ib vaccines and thro mbocy topenia (Stratt on et al.,1994).

Transverse myeli ti s

The vaccine adverse event report ing system has identified in the U SA three possiblecases of t ransverse myelitis (TM) follow ing H ib vaccinat ion (Stratt on et al., 1994).H ow ever, there have been no reports of TM fo llow ing H ib vaccination published inthe literature and no cases of TM were reported in pre-licensure trials. Therefore,

the Institute of Medicine concluded that the data was inadequate to accept or rejecta causal relationship betw een H ib vaccines and TM (Strat ton et al., 1994).

Vaccination of persons with human immunodeficiency virus infection was welltolerated except for mild soreness at the site of injection that was reported by someindividuals (Kroon et al., 1997)

Combi ned H ib v acci nes

Hib–DPT: A combination of H aemophilus influenzae type b vaccine–diphtheriatoxoid conjugate with diphtheria–tetanus–acellular pertussis vaccine did notresult in significant differences in safety (Kovel et al., 1992). The rates of localand systemic adverse events did not differ according to the site of injection,arm versus thigh, or the concurrent or combined administration of D TP(Scheifele et al., 1992).

The safety profile of combined H bO C –D TP is comparable to that o f thevaccines co-administered at separate injection sites. The incidence of localand systemic reactions is similar (Madore et al., 1990; Paradiso et al., 1993;B lack et al., 1993; C D C , 1993). O ne exception is for sw elling aft er the firstdose, which is more common w ith the combined product H b–O C , 8.0% versus4.3% with separate products (Black et al., 1991). This has not been found inother studies.


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The administration on the same day of either MMR vaccine or D PT+ O P Vvaccine together w ith PRP -O MP C did not result in an increase in the rates offever or irritab ility (D ashefsky et al., 1990). After P RP -T vaccine, no seriousside-effects were observed and the rate of adverse reactions was consistentwith the concurrent administration of diphtheria–tetanus–pertussis vaccine inG ambian infant s (Mulho lland et al., 1994), French children (Fritzell & Plotkin,1994), and in a British accelerated schedule (Booy et al., 1992; Begg et al.,1995).

Hib–DPT–IPV: PRP-T vaccine mixed in the same syringe withdiphtheria–tetanus–pertussis–enhanced inactivated poliovirus vaccine resultedin the same rate of local and systemic side-effects as for children receivingD TP –IP V only, except fo r irritability and use of acetaminophen after thesecond dose. These were slightly but significantly more frequent in theD TP–IP V–PRP-T group (D agan et al., 1994). PRP-T w as given concurrentlyor combined with PTP and IPV to healthy children at two, four and six

mont hs (G old et al., 1994). C omb ination r esulted in more local redness(18% vs. 11%, p


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D agan R , Bo tujansky C , Watemberg N , et al. (1994). Safety and immunogenicity inyoung infants of H aemophilus b-tetanus protein conjugate vaccine, mixed in thesame syringe with diphtheria–tetanus–pertussis-enhanced inactivated poliovirusvaccine. Pediatr ic I nf ecti ous D isease Journal , 13:356–61.

D ashefsky B , Wald E, G uerra N , Buers C (1990). Safety , to lerabi l i ty andimmunogenicity of concurrent administration of H aemophilus inf luenzae type bconjugate vaccine (meningococcal pro tein conjugate) with either measles–mumps–rubella vaccine or oral poliovirus vaccines in 14- to 23-month-old infants.Pediatrics , Sup:682–9.

D ockrell D H , Po land G A, Mitchell PS, et al. (1998). Eff ect of H aemophilus inf luenzae ty pe b immunization on H IV viremia in H IV-seropositive adults. Journal of A cqui red I mmune D efi ciency Syndrome and H uman Retr ovir us , 18:512–14.

Fritzell B, Plotkin SA (1992). Efficacy and safety of a H aemophilus inf luenzae typeb capsular polysaccharide-tetanus protein conjugate vaccine. Journal of Pediat ri cs ,121:355–62.

G lobal P rogramme for Vaccines and I mmunizat ion (G PV) (1998). The WH O positionpaper on H aemophilus inf luenzae t ype b conjugate vaccines. Weekly Epidemiological Record , 73:64–8.

G old R , Scheifele D , Bar reto L , et al. (1994). Safety and immunogenicity ofH aemophilus inf luenzae vaccine (tetanus toxo id conjugate) administered concurrentlyor combined with diphtheria and tetanus toxoids, pertussis vaccine and inacti vated poliomyeli t i s v accin e to healthy in fant s at t w o, four and six m onth s of age.

Pediatr ic I nf ect ious D isease Journal , 133:348–55.

K ovel A, Wald ER , G uerra N , Serdy C , Meschievitz C K (1992). Safety andimmunogenicity of acellular diphtheria–tetanus–pertussis and H aemophilus conjugatevaccines given in combination or at separate injection sites. Journal of Pediatr ics ,120:84–7.

K roo n FP, van D issel JT, Rijkers G T, La bad ie J, van Furt h R (1997).Antibody response to H aemophil us inf luenzae type b vaccine in relation to thenumber of CD4+ T lymphocytes in adults infected with human immunodeficiencyvirus. Cli nical I nfecti ous D iseases , 255:600–6.

Lepow ML , Samuelson JS, G ordon LK (1984). Safety and immunogenicity ofH aemophilus inf luenzae type b-polysaccharide-diphtheria toxoid conjugate vaccinein adults. Journal of I nfecti ous D iseases , 150:402–6.

Leroy V, Lad ner J, N sengumuremy i F, et al. (1996). Safety of H aemophilus inf luenzae conjugate vaccine in children bo rn to H IV-1 infected mo thers: Kigali (Rw anda),1992–1994. Vaccine , 14:177–8.

Mado re D V, Johnson C L, P hipps DC , et al. (1990). Safety and immunogenicity ofH aemophilus inf luenzae ty pe b oligosaccharide-C RM conjugate vaccine in infants

aged 15 to 23 months. Pediatrics , 86:527–34.


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Milstien JB, G ross TP, Kuritsky JN (1987). Adverse reactions reported fo llow ingreceipt of H aemophilu s inf luenzae type by vaccine: an analysis after 1 year ofmarketing. Pediatrics , 80(2):270–4.

Mulholland EK , B y ass P, C ampbell H , et al. (1994). The immunogenicity andsafety of H aemophilus inf luenzae type b-tetanus toxoid conjugate vaccine inG ambian children. Annals of Tropical Pediat ri cs , 14:183–8.

Paradiso P R, H ogerman D A, Madore D V, et al. (1993). Safety and immunogenicityof a combined diphtheria, tetanus, pertussis and H aemophilus inf luenzae type bvaccine in young infants. Pediatrics , 92:827–32.

Schei fele D , B jornson G , B arreto L , Meekison W, G uasparini R (1992).C ontrolled trial of H aemophilus inf luenzae type b diphtheria, tetanus and pertussisvaccines, in 18-month-old children, including comparison of arm versus thighinjection. Vaccine , 10:455–60.

Stratton K R, H ow e C J, Johnston RB , Jr., eds. (1994 ). Adverse events associat ed w it h chi ld hood v accin es. Ev id ence beari ng on causal i t y . Washington, D C ,National Academy Press.

Valdheim C M, G reenberg D P, Marcy SM, et al. (1990). Safety evaluation ofPRP-D H aemophilus inf luenzaety pe b conjugate in children immunized at 18 monthsof age and older: Follow-up study of 30 000 children. Pediatr ic I nfecti ous D isease Journal , 9:555–61.

Ward JI, Zangwill KM (1999). H aemophil us inf luenzae vaccines. In Plotkin SA,

O renstein WA, eds. Vaccines , 3rd ed. P hiladelphia, PA, WB Saunders C ompany,1999:183–221.


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The vaccines

Inactivated hepatitis A vaccine is prepared from a cell-culture-adapted virus,purified from cell lysates by ultrafiltration and exclusion gel chromatography orother methods, formalin inactivated, adsorbed to an aluminium hydroxide adjuvant,

and prepared w ith or w ithout 2-phenoxy ethanol as a preservative. The antigen contentof one vaccine is determined by reactivity in a quantitative immunoassay forH AV antigen and final vaccine potency (per dose) is expressed as an enzyme-linkedimmunosorbent assay (EL ISA) units (El.U .). The titer varies from 360 El.U forchildren to 1440 El.U for adults. For other vaccines, the antigen content is expressedas units (U) of hepatitis A ant igen (C D C , 1996) and varies from 25 to 160 antigenunits. Several live attenuated hepatitis A vaccines are currently under developmentand tw o are licensed in C hina, but add itional contro lled trials w ith att enuated vaccinesare needed for better assessment of bot h safety and efficacy (WH O , 1995).

Mild adverse events

D ata co ncerning adverse events are derived fr om pre-licensure clinical studies.No serious adverse events have been attributed definitively to hepatitis A vaccine.

Among adults, the most frequently reported side-effects occurring within 3 daysafter the 1440 El.U . dose were (C D C , 1996):

Soreness at the site of injection (56%).

H eadache (14%).

Malaise (7%).

In clinical studies among children, the most frequently reported side-effects were

Soreness at the injection site (15%).

Feeding problems (8%).

H eadache (4%).

Injection site induration (4%).

Balcarek et al., (1995) found minor local reactions (erythema, induration, soreness)in 29.8% of the pre-school children immuniz ed w ith 360 El.U ., most of them aft erthe first d ose. Minor sy stemic side-effects that resolved spontaneously w ere reportedby parents of 47% of the children, including fever, malaise, anorexia and headache.All objective adverse events normalized within 48 hours.

6. Adverse events follow inghepatitis A vaccine


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Among the 9200 persons who have received the other vaccine, no serious adverseevents were reported. Among adults the most frequent side-effects that occurredw ithin 5 day s follow ing vaccination include tenderness (53%), pain (51%), and w armth(17.3%) at the injection site (53%) and headache (16.1%). Among children,the most commo n side-effects repor ted w ere pain, (19%), tenderness (17%) andw armth (9%) at the injection site (C D C , 1996).

Systemic reactions that include fatigue, fever, diarrhoea and vomiting occur in lessthan 5% of vaccine recipients (Feinstone et al., 1999).

The safety of hepatitis A vaccine during pregnancy has not been established.Since the vaccine is prepared from inactivated virus, the risk to the developing fetusis likely t o be negligible. H ow ever, it should not be given to pregnant w omen unlessthere is a definite risk of infection. Safety of hepatitis A vaccine in patients withchronic liver disease has been assessed during a five-site survey, with a control groupof healthy people. Symptoms were generally categorized as mild to moderate in

severity and all resolved spontaneously (Keefe et al., 1998)

Severe adverse reactions

Post-licensure reports of severe adverse events, without regard to causality,received b y the vaccine manufacturer, have included anaphy laxis, G uillain–Barrésyndrome, brachial plexus neuropathy, transverse myelitis, multiple sclerosis,and erythema multiforme. Most of these events have occurred among adults,and approximately one third have occurred among persons receiving other vaccinesconcurrently. For serious adverse events for which background incidence data areknow n (e.g. G uillain–Barré syndro me and brachial plexus neuropathy ) the rates for

vaccine recipients are not higher than would be expected for an unvaccinatedpopulation.

A case of leukocytoclastic vasculitis has been described after vaccination, whichresolved witho ut therapy (C one et al., 1996).

No serious adverse events were reported from approximately 40 000 children whow ere administered a do se of 360 El.U . hepatitis A vaccine in a pro tective efficacystudy (Innis et al., 1994; Sandman et al., 1995).

Combi ned vacci nes

When hepatitis A and B vaccines are given in a combined form, the incidence ofadverse events has generally been similar to that for hepatitis B vaccine.


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References

B alcarek K B, B agley MR , P ass RF, Schi f f E R, K rause D S (1995).Safety and immunogenicity of an inactivated hepatitis A vaccine in preschool children.

Journal of I nfecti ous D iseases , 171(Suppl 1): S70–2.

C D C (1996). C enters for D isease Co ntrol and P revention. P revention of hepatitisA through active or passive immunization. Recommendations of the AdvisoryC ommittee on I mmunization P ractices (AC IP ). MMWR: M orbidity and Mortality Week ly Report , 45(RR-15):1–30.

C one L , Sneider R , N azemiR, D ietrich EJ (1996). Vasculitis related t o hepatitis Avaccination. Brief report. Cli ni cal I nfecti ous D iseases , 22:596.

Feinstone SM, G ust ID (1999). H epatitis A vaccine. In P lotkin SA, O renstein WA,eds. Vaccines , 3rd ed. P hiladelphia, PA, WB Saund ers C ompany, 1999:650–671.

Innis BL, Snitbhan R, Kunasol P et al. (1994). Protection against hepatitis A byan inactivated vaccine. JAM A: The Journal of t he Ameri can M edical Associati on ,271:28–34.

Keeffe EB, Iwarson S, McMahon BJ, et al. (1998). Safety and immunogenicity ofhepatitis A vaccine in patients with chronic liver disease. H epatology , 27:881–6.

N ational consultative committee on immunization (1998). Canadian I mmunization Guide , 5th edition, D irectorate G eneral for H ealth, D isease Co ntrol Labo ratory,H ealth C anada , 1998:69, 75, 93–94.

Sandman L , D avidson M , Kr ugman S (1995). In activat ed hepatitis A vaccine:A safety and immunogenicity study in health professionals. Journal of I nfecti ous D iseases , 171(Suppl1):S50–2.

WH O (1995). Memorandum f rom a WH O meeting: Public health control of hepatitisA. Bull eti n of the World H ealth O rganizati on, 73:15–20.


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Vaccine preparation

H epatitis B vaccines (H BV) are composed of highly purified preparations of hepatitisB “ s” antigen (H B sAg). This is a glycopro tein that is a component of the outerenvelope of hepatitis B virus, and is also fo und as 22-nm spheres and tubular fo rms

in the serum of people with acute and chronic infection. Vaccines are prepared byharvesting H Bs Ag f rom the plasma of people w ith chronic infection (plasma derivedvaccine) or by inserting plasmids containing the viral gene in yeast or mammaliancells (recombinant D N A vaccine). An adjuvant, aluminium phosphate o r aluminiumhydroxide, is added to the vaccines that are sometimes preserved with thiomersal.The concentrat ion of H Bs Ag varies from 2.5 to 40 µg per dose, according to w hichmanufacturer is used and the target population (C D C , 1996; Maho ney et al., 1999).More than half a billion people have been immunized in t he w orld since the beginningof the implementation of the universal programmes, with a very effective vaccinewhich is considered extremely safe.

Mild adverse reactions

In general, there are minimal reactions, such as local pain, myalgia and transientfever, mostly w ithin 24 hours. C hildren have few er adverse reactions than adults(


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Anaphylacti c reactions

The estimated incidence of anaphylaxis among vaccine recipients is one per600 000 vaccine doses distributed. N o serious, severe or f ata l anaphy lactic reactionhas been reported. Further vaccination w ith hepatitis B vaccine is contraindicated inpeople w ith a history of anaphy laxis to a previous dose (C D C , 1996).

Gui l lai n–Bar résyndrome

There has been a suggested po ssible associa t ion betw een G uil la in–Barrésynd rome (G BS) and receipt of the first do se of plasma-derived vaccine in theU S (C D C , 1991). In 1991, G uillain–Barré syndro me w as reported at a very low rate (0.5 per 100 000 vaccine recipients), w ith no deaths in all reported cases amongadults. An estimated 2.5 million adults received one or more doses of recombinant

vaccine during the period 1986–1990. C urrent available data indicate no demonstrab leassociation between receipt of either plasma-derived or recombinant vaccine andG B S .

There are at least three controversial adverse events associated with hepatitis Bvaccines: the relationship of hepatitis B vaccine to diabetes, to demyelinating d iseases(e.g. multiple sclerosis) and chronic fatigue syndrome (Mahoney et al., 1999).Estab lishing a causal relationship betw een these adverse events and hepatitis B vaccineis difficult: these events are rare, occur in the absence of hepatitis B vaccination andhave their peak incidence in the older age groups who did not receive hepatitis Bvaccine as part of routine childhood vaccination. A recent review by the Food and

D rug Administration (FD A) of case reports in the Vaccine Adverse Events ReportingSystem for the years 1991 to 1994 concluded that there were no unexpected adverseevents in neonates and infants given hepatitis B vaccine. This was despite the use ofat least 12 million doses of vaccine in these age groups (Mahoney et al., 1999).

D emyelati ng di sorders

A few articles mention isolated demyelinating cases follow ing hepatitis B vaccination(Shaw, 1988; H erro elen, 1991; M aha ssin, 1993; Trevisan i 1993; N ad ler, 1993;Tartaglino, 1995). In France, over the years up to 1999, popular press and televisionprogrammes raised concern that hepatitis B immunization might be linked with new cases or flare-ups of multiple sclerosis or other demyelinating diseases.

A position paper from WH O w as published pointing out the “ Lack of evidencetha t h epatitis B vaccine causes multiple sclerosis” (Wkly Epid em Rec, 1997).C ompared to the background rate of multiple sclerosis in France, which is 1 to3 cases per 100 000 persons, the no tif ication rate of demyelinating d iseases in temporalassociation with hepatitis B vaccination was 0.6 per 100 000 during the period fromD ecember 1994 and D ecember 1996. O bservat ions in other countries show similarpatterns to that observed in France: 0.1 to 0.8 cases of demyelinating diseaseper 100 000 vaccine recipients (Austra lia, B elgium, C anad a, G ermany, I ndia,U nited K ingdom, U nited States).


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A national pharmaco-vigilance survey was initiated in France in 1994, after thereport to the N ational Agency fo r D rugs of several neurological disorders evokingmultiple sclerosis after hepatitis immunization. Three studies have been conductedin adul ts , two in neuro logy wards in France , the th i rd one based on the“ G eneral Practitioners Research D atabase” of t he U nited K ingdom Ministry ofH ealth. The three studies did no t f ind a statistically significant increase in the risk ofthe first episode of central demyelination after immunization. The possibility of anassociation is being explored w ith further studies. N o adverse event of this ty pe hasbeen reported so far in infants (Levy-Bruhl et al., 1999).

The Viral H epatitis Prevention B oard ’s activities are incorporated into t he WH OC ollaborative Centre on Prevention and C ontrol of H epatitis at the U niversity ofAntwerp, Belgium. A meeting of the Board organized in September 1998 made thefollow ing conclusions: “ the available data, although limited, did not demonstrate acausal association between hepatitis B immunization and central nervous systemdemy elinating disease, including mult iple sclerosis” . Therefore, the group support ed

the WH O recommendat ions that all countries should have universal infant and/oradolescent immunization pro grammes, and cont inue to immunize adults when facingincreased risk of hepatit is B, as appropriate (H all et al., 1999; H alsey et a l., 1999).

Chroni c fati gue syndrome

In C anada , during 1993–94 a rumour w as also raised that vaccination againsthepatitis B w as responsible for chro nic fatigue syn drom e (D elage, 1993) but noepidemiological dat a have ever confirmed this allegatio n (C anadian M edicalAssociation, 1993).

H air l oss

H air loss has been report ed after rout ine immunizat ion, especially hepatitis B(Wise et al., 1997). H air loss is a commo n event; it may be extremely diff icult toconfirm a causal association w ith H BV administration.

D iabetes

C laims have been made that administration o f vaccines including hepatitis B vaccinecan cause type I diabetes (juvenile or insulin-dependent d iabetes mellitus – ID D M)in rat s (C lassen, 1996) and child ren (C lassen, 1997). The consensus of currentprofessional opinion accepts there is no link (Karvonene 1999; Jefferson, 1998).In Finland, elimination of mumps by immunization has coincided with a decrease inID D M (H y oty, 1993). Studies in Sweden failed to find an increase in diabetes afterstopping B C G (D ahlq uist, 1995) or pertussis immunizat ion (H eijbel, 1997).Similar studies and results have been do cumented in Sw eden (Blom, 1991) andC anada (Parent, 1997). A panel review of all the evidence to date w as held in theU nited States. This also found no associat ion (Inst itute, 1999).


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References

Andre FE (1989). Summary on safety and efficacy data on a yeast-derivedh

Informacion Suplementaria en Seguridad en Vacunas Who Part 2 2000

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