Evidence based pediatrics - part 2 ppsx

IMMUNIZATIONSCHEDULES The Canadian schedule for routine immunization of children is given in Table 3–1.1The combined diphtheria, tetanus, acellular pertussis, inactivated polio and Haemo

118 American Academy of Pediatrics Screening for elevated blood lead levels American Academy of Pediatrics Committee on Environmental Health Pediatrics 1998;101:1072–8.

119 Daniel K, Sedlis M, Polk L, et al Childhood lead poisoning, New York City, 1988 MMWR 1990;39:1–7.

CHAPTER 3

ImmunizationRonald Gold, MD, MPH, FRCPC

O

Immunization prevents disease and saves lives It is also one of the few health interventionsthat saves more money than it costs Successful implementation of childhood immunizationprograms requires that both the health professionals involved in administering vaccines andparents be knowledgeable about the risks of the diseases and the benefits as well as the risks

of the vaccines In particular, it is extremely important that the true precautions and traindications are understood

con-The only absolute contraindications to immunization are as follows:1,2

• Anaphylaxis to a previous dose of vaccine

• Anaphylaxis to a constituent of a vaccine (eg, severe allergic reaction to influenza andyellow fever vaccines after eating eggs or allergy to neomycin in the case of inactivatedpolio vaccine[IPV] or mumps-measles-rubella [MMR] vaccine)

• Pregnancy, in the case of MMR

• Immunodeficiency, in the case of MMR

Precautions which may indicate deferral of immunization include the following:

• Recent administration of immunoglobulin, in the case of MMR (see1,3for details)

• Moderate or severe acute illness with or without fever

Conditions which are not contraindications to immunization are as follows:1,2

• Local reaction to previous dose of vaccine

• Mild acute illness with or without fever

• Convalescent phase of an acute minor illness

• Current antimicrobial therapy

• Recent exposure to infection

• Prematurity

• Personal or family history of allergy

• Family history of convulsions, sudden infant death syndrome (SIDS)

• Convulsion, hypotonic–hypo-responsive (HHR) episode, or high fever (≥40.5°C)within 48 hours or persistent inconsolable crying lasting ≥3 h after prior dose of diph-theria-pertussis-tetanus (DPT) vaccine

• Pregnancy, in the case of hepatitis B and influenza vaccines

• Diagnosis of multiple sclerosis, any other autoimmune disorder, or muscular dystrophyViral respiratory and gastrointestinal infections are very common in children less than

2 years of age Studies have demonstrated that there is no increase in adverse events and nodiminution of the immune responses if vaccination is performed while a child has a minorillness Deferral of vaccination because of minor illness is all too common but should beavoided because children whose vaccinations are delayed have an increased probability of notbeing fully immunized

IMMUNIZATIONSCHEDULES

The Canadian schedule for routine immunization of children is given in Table 3–1.1The

combined diphtheria, tetanus, acellular pertussis, inactivated polio and Haemophilus zae type b vaccine is now used in all Canadian provinces and territories Differences exist

influen-between jurisdictions regarding at what age the second dose of MMR and at which gradeschool–based hepatitis B vaccination should be administered Information on schedules forchildren whose immunization did not begin in early infancy can be found in the CanadianImmunization Guide The routine immunization schedules differ between the United Statesand Canada because (1) the combined vaccine is not yet available, (2)a sequential killed–livepolio vaccine schedule is recommended, and (3) both hepatitis B and varicella vaccines arerecommended for infants in the United States (Table 3–2).4,5

Epidemiology

Since 1983, less than five cases of diphtheria have been reported annually in Canada, almostall of which were in adults who had been either partially immunized or not immunized atall Diphtheria is still a severe disease—the case fatality rate is 5 to 10 percent

Diphtheria Toxoid

Diphtheria toxoid (D) is available in Canada and the United States, either separately or bined with one or more vaccines, including tetanus toxoid (T), acellular pertussis vaccine(aP), and (IPV) The combination recommended for routine immunization in Canada is D,

com-T, aP, and IPV, DTaP-IPV, which is used to dissolve lyophilized Haemophilus influenzae type

b vaccine (tetanus toxoid conjugate polyribose-phosphate, [PRP-T]) The resulting nation, DTaP-IPV/PRP-T, is administered as a single injection The recommended vaccine

combi-in the United States is DTaP scombi-ince combcombi-inations with IPV and/or Haemophilus b (Hib) cine are not yet licensed.4

vac-For children over 7 years old and adults, a reduced amount of diphtheria toxoid is used(2 Lf units per dose rather than 12 to 25 Lf units) to minimize local reactions in persons who

Table 3–1 Routine Immunization of Infants and Children in Canada

tivated polio vaccine; Hib = Haemophilus influenzae type b conjugate vaccine: tetanus toxoid conjugate (PRP-T)

used with combined DTaP-IPV in Canada; MMR = measles mumps rubella vaccine, first dose on or after first birthday, second dose either at 18 mo or at 4 to 6 y, depending on province; Td = adult tetanus, diphtheria vac- cine with reduced dose of diphtheria toxoid for those ≥ 7 years of age; HB = hepatitis B vaccine: 3 doses at 0, 1, and 6 months either in infancy or in preadolescence, depending on province.

have previously been vaccinated.6–8The adult formulation is usually combined with Td orwith Td and IPV (Td-IPV).

Adverse Events

The most common reaction caused by diphtheria toxoid is redness, swelling, pain, and derness at the site of the injection The pain may cause babies to cry and be irritable Localreactions are much more common in children and adults receiving boosters of the diphthe-ria toxoid than in infants receiving the first three doses

ten-Efficacy

Diphtheria toxoid prevents disease in most children and adults who are fully immunized.Those who do get diphtheria in spite of being fully vaccinated have a milder illness with fewercomplications

Evidence for the efficacy of diphtheria toxoid includes

• trials in school children in Toronto, which demonstrated a 75 percent reduction in theincidence of diphtheria in vaccinated compared to unvaccinated children;9

• the virtual disappearance of diphtheria cases in all countries in which immunization

of infants and children is routine;10–13

• milder disease and fewer complications in fully immunized persons.14

Indirect evidence supporting the effectiveness of diphtheria toxoid is provided by thecurrent experience in Russia, Ukraine, and other states of the former Soviet Union.13Amarked decrease in the number of children being vaccinated was followed by epidemics ofdiphtheria; over 100,000 cases of diphtheria and more than 1,200 deaths occurred in Russiaand Ukraine since 1990.13

Recommendations

There is good evidence to support the recommendation of routine immunization of all dren with diphtheria toxoid, including one well-designed controlled trial without random-ization, dramatic declines in disease incidence in all countries within a short period ofintroduction of mass immunization, and resurgence of epidemics when vaccination coveragedeclines (Table 3–3) The optimal schedule of boosters for adults remains to be determined

chil-TETANUS

Epidemiology

The frequency of tetanus has declined in all countries with successful immunization grams Since 1985, there have been fewer than five cases per year in Canada Most cases oftetanus now occur in persons over 60 years who have never been vaccinated

pro-Table 3–3 Summary of Quality of Evidence Supporting Use of DTaP-PV and Hib Vaccines Immunizing Agent Quality of Evidence Recommendation

Tetanus Toxoid

Tetanus toxoid is supplied in Canada and the United States either by itself or combined withone or more other vaccines, including diphtheria toxoid, pertussis vaccine, and IPV (See sec-tion above on “Diphtheria Toxoid” for description of combinations available in Canada.)

Adverse Events

Redness, swelling, pain, and tenderness at the site of injection are the most common tions occurring after administration of tetanus toxoid.15The likelihood of local reactionsincreases with the number of doses given.16Severe local reactions after boosters occur in lessthan 2 percent of adults, primarily in those who have too many boosters, that is more thanonce every 10 years.17

reac-Other reactions following tetanus vaccination include swollen lymph glands (especiallythose near the site of injection), fever, headache, and muscle aches

Allergic reactions (usually hives) do occur but are rare.18As tetanus toxoid is usuallygiven in combination with other vaccines, the exact factor causing a reaction may not be easy

to identify Severe allergic reactions are much less common in infants and young childrenthan in adults.19

Adverse neurologic events have been reported following administration of tetanus oid The frequency of neurologic reactions is estimated to be less than one per million doses

tox-of vaccine, making it impossible to determine whether the association is coincidental orcausal.20

Efficacy

Routine immunization of U.S soldiers during World War II resulted in a 30-fold reduction

in the incidence of tetanus occurring after war wounds, compared with World War I.21grams to prevent tetanus of newborns in the developing countries confirm that tetanus tox-oid is extremely effective; in a double-blind controlled trial, no disease was seen in infantsborn to mothers who had received at least two doses of tetanus toxoid compared with a rate

Pro-of 78 per 1,000 live births in control infants.22Tetanus is extremely rare in all countries witheffective programs for vaccination of children.23

Recommendations

There is good evidence to support the recommendation of routine immunization of all dren with tetanus toxoid including the reduced incidence of tetanus in U.S military per-sonnel in World War II compared with World War I;21the dramatic declines in incidence inall countries within a short period of introduction of mass immunization;23and random-ized, double-blind controlled trials confirming the efficacy of tetanus toxoid in preventingneonatal tetanus in the developing countries (see Table 3–3).22The optimal schedule ofboosters for adults remains to be determined

Epidemiology

Introduction of routine immunization with DPT in the 1940s resulted in a 90 percentdecrease in reported cases of pertussis, from an average of 17,463 cases reported annually inthe immediate prevaccine era to 4,900 cases per year for 1986 through 1995.24The actualnumber of cases is 10 to 15 times greater than the reported number because of incompletereporting of the disease by physicians.25

The introduction of routine DPT vaccination was also followed by a significant change

in the age distribution of pertussis In the prevaccine era, the peak incidence of pertussisoccurred in children 1 to 5 years of age and less than 15 percent of reported cases occurred

Immunization 43

in infants.26With routine vaccination, the peak incidence switched from young children toinfants less than 1 year of age, among whom approximately 50 percent of reported casesoccurred Concurrently, there has been a significant increase in the proportion of casesoccurring in adolescents and young adults.27

Approximately 85 percent of Canadian children have received 4 doses of DPT by 2 years

of age and >90 percent have received 5 doses by 6 years of age.24However, disease continues

to occur, along with epidemics every 3 to 5 years.24,25 The lack of change in the intervalbetween epidemics is strong evidence that routine vaccination, as presently practiced with aprimary series of DPT at 2, 4, and 6 months followed by boosters at 18 months and at 4 to

6 years, has failed to interrupt the transmission of Bordetella pertussis in the population.26

Acellular Pertussis Vaccine

The new acellular pertussis vaccines consist of purified proteins extracted from the bacteria.The acellular vaccines differ in both the number and concentration of the following proteinspurified from B pertussis: pertussis toxoid (PT), filamentous hemagglutinin (FHA), pertactin

(PRN, formerly designated 69 kD protein), and fimbriae (FIM) 2 and 3 (Table 3–4) TheCanadian acellular pertussis vaccine contains PT, FHA, PRN, and both FIM 2 and FIM 3 Ithas completely replaced the use of whole-cell pertussis vaccine throughout Canada The rou-tine immunization schedule did not change with the replacement of whole-cell by acellularpertussis vaccine (see Table 3–1) The Canadian vaccine has not yet been licensed in theUnited States, where four acellular pertussis vaccines from other manufacturers are avail-able.4

Adverse Events

The frequency of adverse effects after whole-cell and acellular pertussis vaccines are marized in Table 3–5 These results were obtained from Canadian studies comparing whole-cell pertussis (DPT–IPV/PRP–T) with acellular pertussis combination vaccines(DTaP-IPV/PRP-T), given at 2, 4, and 6 months of age.28Both local and systemic adverseevents were two to four times less common after acellular vaccine The severity of reactionswas also significantly less with acellular vaccine Similar results have been obtained with allacellular pertussis vaccines.29,30

sum-Severe allergic reactions such as anaphylaxis have been described after immunizationwith whole-cell pertussis vaccine With both whole-cell and acellular pertussis vaccines that

Table 3–4 Components of B pertussis Involved in Pathogenesis of Disease and Immunity

Role of pertussis proteins in Pertussis proteins Attachment to mucosa Immunity

are currently available, the occurrence of anaphylaxis has been so rare that it is not possible

to calculate the risk Naturally, any child who has an allergic reaction of any kind after tussis or any other vaccine should not receive the same vaccine again until the cause of thereaction has been identified by appropriate evaluation

per-Other severe reactions that may occur after both whole-cell and acellular pertussis cines include prolonged crying, “collapse” reaction (also known as hypotonic–hypo-respon-sive episode), and convulsions All these events are less frequent after immunization withacellular than with whole-cell pertussis vaccine.31About 1 in 100 infants have nonstop, incon-solable crying or screaming lasting more than 3 hours after administration of whole-cell vac-cine, but this reduction is much less frequent after acellular pertussis vaccines There is noevidence that prolonged crying is caused by a neurologic reaction, and recovery is complete.Hypotonic–hypo-responsive episodes occur most often after the first dose of DPT andalmost never after the fourth or fifth dose.32They occur about once in every 1,750 DPT injec-tions Symptoms begin within 12 hours of the injection and may last up to 1 day The infantbecomes pale, floppy, and less responsive than normal The cause of HHE is unknown.Infants with HHE recover completely and can receive additional doses of pertussis vaccinewithout risk of recurrence of HHE.33,34

vac-Any vaccine which can induce fever can precipitate febrile convulsions in susceptiblechildren The incidence of convulsions after whole-cell pertussis vaccination is between 1 in1,700 vaccinations and 1 in 10,000 vaccinations.35,36Convulsions are more common after thethird and fourth doses than after the first two doses Febrile convulsions do not cause per-manent brain damage and do not increase the risk of epilepsy or any other disorder of thebrain.37 Immunization is not associated with an increased incidence of afebrile convul-

sions.38

Immunization 45

Table 3–5 Incidence of Adverse Events after Whole-Cell or Acellular Pertussis Combined Pentavalent Vaccines in Canadian Infants

Incidence of Adverse Events (%)

Febrile seizures, prolonged crying, and HHE have been observed following the istration of acellular pertussis vaccine.31,39,40The rates of such reactions appear to be lowerwith acellular than with whole-cell pertussis vaccine.31However, since none of the reactionsthat occurred after whole-cell vaccine are known to cause permanent brain damage, it isunlikely that damage will occur after administration of the acellular vaccine.

admin-Many other conditions have been blamed on the pertussis vaccine Such allegations arebased on anecdotes rather than scientific studies There are no valid scientific studies whichdemonstrate a causal link between pertussis vaccine and encephalopathy, brain damage,autism, infantile spasms, epilepsy, mental retardation, learning disorders, hyperactivity,SIDS, asthma, or atopic diseases.1,41,42

The only contraindication to administration of pertussis vaccine is an anaphylactic tion to a previous dose

reac-Efficacy

Routine vaccination of infants and young children has resulted in a marked decline in thefrequency of pertussis in every country with effective childhood vaccination programs Con-versely, discontinuation or declines in vaccine coverage have resulted in large epidemics inJapan, Sweden, the United Kingdom, and the newly independent states of the former SovietUnion.43When vaccine coverage rose again in Japan and England, the incidence of pertus-sis declined.44

Randomized, placebo-contolled studies in Sweden showed that the Canadian acellularvaccine protected 85 percent of infants against pertussis.39,40Similar results were obtainedwith other acellular pertussis vaccines.45

Products containing multiple pertussis antigens are more effective than those with PTalone or PT plus FHA against pertussis The Canadian vaccine is also very effective against milddisease.39,40The results from recent efficacy trials have confirmed that there are antibody cor-relates of protection; vaccinated children with high antibody levels against PT, PRN, and FIMhad a much lower secondary attack rate after household exposure to pertussis than did vacci-nated children with low titers The titer of antibody to FHA did not correlate with protection.46,47Another very important finding of the recent studies is the demonstration that re-infec-tion with pertussis is a common event because of waning immunity, which occurs not only

in vaccinated individuals but also in those with prior pertussis infection.27Such re-infectionmay be asymptomatic, being detectable only by demonstrating a rise in antibodies to per-tussis antigens but may also result in illness with cough.48,49

Because adverse reactions are so much less common with acellular than with whole-cellvaccine, it is possible to give boosters to adolescents and adults It has become increasinglyrecognized that pertussis is very common in adolescents and young adults In fact, the great-est rise in incidence of disease during the 1990s in North America occurred in persons 10 to

29 years of age Approximately 15 to 25 percent of young adults presenting with cough ofmore than 7 days duration have pertussis.50–52

A single booster of either Td or Td-IPV combined with acellular pertussis vaccine hasbeen shown to be safe and highly immunogenic in those between 10 and 60 years of age.53,54Such boosters may prolong the duration of protection against pertussis, thereby resulting in

reduced transmission of B pertussis in the population If routine boosters do reduce the

inci-dence of pertussis in adolescents and adults, infants under 6 months of age who have not yetcompleted the primary series would greatly benefit because of reduced risk of exposure toinfection from siblings and parents

Recommendations

There is good evidence to support the recommendation of routine immunization of all dren with acellular pertussis vaccine, including two well-designed randomized, placebo-con-

chil-trolled trials39,55and one randomized controlled trial without placebo;40several case-controltrials; epidemiologic evidence of dramatic declines in disease incidence in all countrieswithin a short period of introduction of mass immunization and resurgence of epidemicswhen vaccination coverage declines (see Table 3–3) The optimal schedule of boosters foradolescents and adults remains to be determined.

Epidemiology

Within 12 years after the introduction of IPV in 1955, the incidence of paralytic poliodecreased by almost 99 percent in Canada, United States, and all other countries with suc-cessful polio vaccine programs using either IPV or oral polio vaccine (OPV) The global cam-paign to eradicate polio has been remarkably successful.56Indigenous transmission of wildpolioviruses has been interrupted throughout the entire western hemisphere and the regionwas certified as polio free in 1994 Today, the remaining major foci of transmission of wildpolioviruses are in Africa.57Because of the speed and extent of travel in all parts of the world,

we must continue to immunize children until polioviruses have been eliminated worldwide

Polio Vaccine

In Canada, an IPV–only schedule is used.1The change from OPV to IPV was based on theefficacy on an IPV–only schedule, the eradication of wild polio from the western hemisphereand declining risk of importation of wild polio viruses because of the success of the WorldHealth Organization (WHO) polio eradication program in most parts of the world, and thedesire to avoid the risk of vaccine-associated paralytic polio (VAPP) due to OPV

Inactivated polio vaccine contains types 1, 2, and 3 wild-type polio viruses which havebeen killed with formalin The viruses in IPV are grown in either human MRC-5 cells or Verocells

In Canada, IPV is supplied either by itself or in combination with the following vaccines:DTP-IPV, DTaP-IPV, DT-IPV, or Td-IPV Both DPT/IPV and DTaP-IPV can be used to dis-solve the lyophilized Hib vaccine so that all five vaccines can be administered as a single injec-tion

In the United States, either IPV-only or sequential IPV-OPV schedules are mended by the American Academy of Pediatrics.5Oral polio vaccine consists of attenuatedstrains of live type 1, 2, and 3 polio viruses grown on monkey kidney cell cultures

recom-Adverse Events Associated with IPV

Other than minor pain and redness at the injection site, side effects with IPV are extremelyrare Current methods of production and testing before release of each batch of IPV ensurethat there is no live polio virus in the vaccine

In 1960, some batches of rhesus monkey kidney cells used to grow polio virus were covered to be infected with a monkey virus called simian virus 40 (SV40) Live SV40 was sub-sequently found in some batches of both IPV and OPV, which had been used in many parts

dis-of the world Vaccine production methods were altered in order to ensure that SV40 was notpresent in cells used to grow polio viruses All polio vaccines, both IPV and OPV, used since

1963 have been free of SV40

Simian virus 40 is a papovavirus, a group of viruses known to cause cancer in severalspecies of animals No differences in death rates from all causes or in cancer deaths have beendetected among groups who had received vaccine containing SV40 compared with thosegiven vaccine free of SV40.58A workshop on SV40 at the National Institutes of Health (NIH)concluded that there is no evidence of harm to humans as a result of exposure to SV40 inpolio vaccines.59

Immunization 47

Adverse Effects

Paralytic poliomyelitis following the use of monovalent type 3 OPV was first described in

1962.60Vaccine-associated paralytic polio also occurs with trivalent OPV For petent infants receiving their first dose of OPV, the risk of VAPP is estimated to be 1 case per750,000 children vaccinated.61The risk decreased nearly 20–fold with subsequent doses.There is also a risk of VAPP in household and community contacts of children vaccinatedwith OPV because the vaccine virus is excreted in the stool for several weeks The risk in con-tacts is much lower than in vaccinated children The risk of VAPP is more than 3,000-timeshigher in immunodeficient persons, especially those with agammaglobulinemia orhypogammaglobulinemia.62The risk of VAPP is eliminated entirely by an IPV-only sched-ule The IPV-OPV sequential schedule is estimated to reduce the risk of VAPP by 95 percent.63

immunocom-Efficacy

Field trials of the original IPV showed that it offered protection against paralytic polio in 55percent of school children after one dose, 80 percent after two doses, 91 percent after threedoses, and 96 percent after four doses.64Current vaccines are much more potent than theoriginal Salk vaccine and have been shown to be 90 percent effective after just two doses.65Protection lasts for many years following vaccination with IPV.66

The experience in Sweden, Finland, the Netherlands, France, and some Canadianprovinces (Ontario, Nova Scotia, Newfoundland) has demonstrated that paralytic polio can

be eliminated by the use of IPV alone.66–71Even though the virus has been brought back intothese countries many times over the past 50 years by travelers infected with polio, only threesmall outbreaks of paralytic polio have occurred All cases involved small groups of peoplewho had refused immunization for religious reasons No disease occurred in those who hadbeen vaccinated.72

The eradication of polio from the western hemisphere and many other parts of the worldled to a change from OPV to IPV in all of Canada to avoid the very small risk of paralyticpolio associated with OPV

Recommendations

There is good evidence to support the recommendation of routine immunization of all dren with IPV, including a large well–designed randomized, placebo–controlled trial inschool children and strong epidemiologic evidence of elimination of paralytic polio and oferadication of indigenous transmission of wild polio viruses in all countries which have highvaccine coverage with IPV (see Table 3–3)

Epidemiology

Before 1985, Hib was the most common cause of bacterial meningitis in children out the world Every year, in Canada, about 1,500 cases of Hib meningitis occurred in chil-dren under 5 years of age and an equal number of other forms of invasive Hib disease.However, Hib infections have almost disappeared in countries such as Canada where Hibvaccine is part of the routine immunization schedule.73–75

Haemophilus b vaccine is the purified capsular polysaccharide, PRP Because the pure saccharide is not sufficiently immunogenic in infants, current vaccines are composed of thepolysaccharide covalently bound to a protein carrier such as tetanus toxoid (PRP-T), diph-theria toxoid (PRP-D), a nontoxic form of diphtheria toxin produced by a mutant strain of

Meningococcus (PRP-OMP) The conjugated vaccines are safe and highly immunogenic in

infants The Hib vaccine currently used in Canada is PRP-T

Adverse Events

Haemophilus b vaccines are extremely safe When given as a separate injection, Hib gated vaccines cause local redness and pain in 5 to 15 percent of infants Local reactions aremilder and much less common than those seen after DPT vaccine The addition of the Hibvaccine to DPT, DPT-IPV, DTaP or DTaP-IPV vaccines has no bearing on the frequency andseverity of side effects.28,76

conju-The only contraindication to Hib vaccine is the occurrence of a severe allergic reaction

to a previous dose of the vaccine Children who have such allergic reactions after tions should be seen and evaluated by a physician to identify the cause of the reaction

vaccina-Efficacy

Antibodies against PRP that are induced by Hib vaccine protect children in two ways

• The vaccinated child is protected against invasion by Hib.76,77

• The vaccinated child is less likely to become a carrier of Hib, thereby reducing mission of Hib in the population.78,79

trans-The efficacy of Hib vaccines has been shown to be over 95 percent in randomized,placebo-controlled trials.76,77Active surveillance has demonstrated greater than 99 percentreduction in incidence in Scandinavia, United States, and Canada following introduction ofroutine immunization, regardless of which conjugate vaccine is used.77However, in certainnative populations that have extremely high carriage rates and high incidence of disease, dif-ferences in efficacy between different conjugates have been observed.80For such populations,conjugates such as PRP–OMP, which induce antibodies after the first dose at 2 months ofage, may be required

Recommendations

There is good evidence to support the recommendation of routine immunization of all dren with conjugated Hib vaccine, including many well-designed randomized, placebo–con-trolled trials, and epidemiologic evidence of dramatic declines in disease incidence in allcountries within a short period of introduction of mass immunization (see Table 3–3)

Epidemiology

Before measles vaccine became available, almost everyone got measles by 18 years of age Anaverage of 350,000 cases occurred every year in Canada and there were 50 to 75 deaths, 5,000hospital admissions, and 400 cases of encephalitis

Since licensure of measles vaccine in 1963, there has been a dramatic decline in theannual number of cases in every country with routine immunization programs In 1998,there were only 12 laboratory-confirmed cases of measles reported in Canada, a decline of

>99.99 percent since the prevaccine era.81

The measles virus is highly contagious and is able to survive in small droplets in the airfor at least several hours This survival ability ensures airborne spread, which explains thehigh level of contagiousness of the virus.82The secondary attack rate among susceptible per-sons exposed at home to a child with measles is over 90 percent.83

Immunoglobulin Prophylaxis

Administration of immunoglobulin (Ig) after exposure can prevent or attenuate the ity of measles, if given less than 6 days after exposure to measles Immunoglobulin is rec-

sever-Immunization 49

ommended, if the person exposed to measles is at increased risk of severe disease and/orcomplications of measles:

• An infant less than 12 months old

Adverse Events

Side effects after measles vaccine, whether given by itself or combined with mumps andrubella vaccine, are usually mild When children are given a second dose of measles vaccine,

no reactions occur in those who are immune as a result of the first dose.86

The most common side effect is fever In a placebo-controlled, randomized, cross-overstudy in identical twins, about 2 percent had fever of≥39.4°C occurring 8 to 10 days aftervaccination and lasting 24 to 48 hours.87The fever may be high enough to cause seizures

in children who are susceptible to febrile seizures Rash occurs in about 2 percent of twinsand lasts 1 to 2 days The frequency of sides effects in the Finnish twin study are lower thanthe rates in almost all other studies because the twin study was one of the very few toinclude a placebo, thereby enabling more accurate assessment of events attributable to thevaccine

The illness caused by the vaccine (fever and rash for 1 to 2 days in 2 percent of ents)87is much less severe than the actual illness associated with measles (fever, rash, cough,and bronchitis lasting 7 to 10 days in 100 percent of cases).88

recipi-Severe adverse events after measles vaccine are rare The risk of encephalitis aftermeasles vaccine is less than one per one million doses, lower than the background incidence

of encephalitis.89Measles itself, on the other hand, causes encephalitis in about 1 of every1,000 cases In countries where all children are vaccinated against measles, measlesencephalitis has disappeared.90As subacute sclerosing panencephalitis (SSPE) has disap-peared in countries with effective vaccine programs, it seems unlikely that the vaccine causesSSPE.91Transient thrombocytopenia during the month following vaccination with MMRoccurs rarely

Egg Allergy and Measles Vaccination

In the past, it was recommended that children who have allergic reactions after eating eggsshould not be vaccinated with measles or mumps vaccines, unless skin testing was performedand a special vaccine schedule was used However, review of all the studies about vaccinat-ing children with egg allergy has shown that they can be safely vaccinated with measles andmumps vaccine without the need for special precautions.92,93

Measles is often very severe in persons with problems involving the immune system.Moreover, the original measles vaccine caused pneumonia in a few children with leukemia.Therefore, it is recommended that measles vaccine not be given to persons with severe dis-orders of the immune system However, measles vaccine is recommended and has beenshown to be safe for children with HIV infection or with AIDS

Immunoglobulin (Ig) and other blood products may contain antibodies to the measlesvirus that will interfere with measles vaccine Vaccination must be delayed for 3 to 11months, depending on the type and dose of Ig or blood product used

Mumps Vaccine

Mumps vaccine is a live attenuated virus vaccine produced in chick embryo cell cultures.After passing all tests for potency and safety, the virus is lyophilized Trace amounts ofneomycin remain in the vaccine Mumps vaccine is most often combined with measles andrubella vaccines to produce MMR vaccine

Because exposure to sunlight or heat will kill the mumps vaccine virus, it must be erated at the proper temperature (5 to 8°C) Improper storage remains a problem and may

refrig-be responsible for many of the vaccine failures

Side effects of mumps vaccine

Side effects of the Jeryl Lynn strain of mumps vaccine have been rare A few children developswelling of the salivary glands 10 to 14 days after vaccination Meningitis has been reported

to occur at a rate of 1 case per 800,000 doses No permanent brain damage has occurred afterthe rare cases of meningitis or encephalitis caused by mumps vaccine

Mumps vaccine can be given, without any special precautions, to children with eggallergy (see section on “Measles Vaccine”)

Efficacy

Over 90 percent of those vaccinated are protected against mumps The vaccine provides thesame protection, whether given separately or combined with measles and rubella vaccines.Because fewer antibodies are induced by the vaccine than by the natural infection, therehas been concern about the duration of protection after vaccination Small outbreaks ofmumps still occur, mainly in vaccinated teenagers and young adults (aged 13 to 25 years).101

It has not been determined whether this vaccine failure is due to lack of response to the cine or to gradual loss of immunity Introduction of a routine two-dose schedule of MMRvaccine should reduce the occurrence of such outbreaks.100

vac-Recommendations

There is good evidence to support the recommendation of routine immunization of all dren with two doses of mumps vaccine, including epidemiologic evidence of dramaticdeclines in disease incidence in all countries within a short period of introduction of massimmunization (see Table 3–6)

If a pregnant woman is infected with rubella during the first 20 weeks of pregnancy, theprobability of fetal infection is over 80 percent.102If infection occurs in the first 12 weeks of preg-nancy, the baby is usually born with multiple handicaps; if infection occurs between 16 and 20weeks, deafness is usually the only complication Regardless of the timing of onset of infection,the infected fetus almost always sustains damage Infection is fatal in about 20 percent of fetuses,and 10 percent of infected babies die of complications during the first year of life

Rubella Vaccine

Rubella vaccine is a live, attenuated vaccine grown in human diploid cells (WI38 cells) Afterpassing all tests for potency and safety, the virus is lyophilized Rubella vaccine can be given

alone, combined with measles vaccine (MR), or, most commonly, as measles, mumps, rubellavaccine (MMR) Although rubella vaccine is not as sensitive to light and heat as measles vac-cine, it should be refrigerated at 5 to 8°C until it is used.

All women should have a blood test for immunity to rubella, preferably before their firstpregnancy If the blood lacks antibodies to rubella and the woman is not pregnant, she should

be immunized with rubella vaccine or MMR Women should not become pregnant for 3months after vaccination to allow immunity to develop

If the woman is already pregnant and tests reveal that she lacks antibodies, vaccinationshould be delayed until after delivery of the baby to avoid potential harm to the fetus How-ever, there have been no cases of CRS in over 1,000 infants born to women who were vacci-nated in the first 2 months of pregnancy.103

Adverse Events

Infants rarely have any side effects after rubella vaccination.104The frequency and severity ofside effects increase with age, as does severity of the disease Following vaccination, a few peo-ple develop mild fever, sore throat, headache, a rash, and swollen glands, just like a mild case

of rubella Most of these reactions are probably due to measles vaccine rather than rubella

or mumps vaccine; the frequency of reactions is the same in children receiving MMR or theplain measles vaccine

The most significant side effect of the rubella vaccine is arthralgia, most often enced by adult women Following vaccination, about 25 percent of adult women have somejoint pain compared with less than 1 percent of vaccinated children The incidence ofarthralgia is twice as high after natural infection than after vaccination A recent random-ized, placebo-controlled trial of rubella vaccination of susceptible women in the immediatepostpartum period failed to confirm any increased risk of chronic arthritis associated withthe vaccine.105

experi-Transient thrombocytopenia during the month after rubella vaccination occurs rarely.104However, the incidence of thrombocytopenia is 10 times higher after natural infection thanafter vaccination

Efficacy

The incidence of rubella and of congenital rubella syndrome have declined by over 99 cent in all countries with routine immunization programs.106Between 1994 and 1996, onlythree cases of congenital rubella syndrome were reported per year, one third of which wereimported.107

per-Recommendations

There is good evidence to support the recommendation of routine immunization of all dren with two doses of rubella vaccine, including epidemiologic evidence of dramaticdeclines in disease incidence in all countries within a short period of introduction of massimmunization (see Table 3–6)

The incidence of infection with hepatitis B virus (HBV) displays very marked geographicvariation In Canada, the United States, and other developed countries, the prevalence ofchronic carriage of hepatitis B surface antigen (HBsAg) is about 0.5 percent.108 In China,Southeast Asia, and parts of Africa, chronic carrier rates are over 10 percent

In Canada, the two most common means of spread are sexual activity and sharing ofneedles by users of injectable drugs.109The infection rate is highest among older teenagersand young adults Infection of infants born to infected mothers still occurs, but the rate isdecreasing

Immunization 53

Prevention of HBV infection with HBIg

Hepatitis B immunoglobulin (HBIg) prevents infection following exposure to HBV Forthose exposed to HBV, HBIg is recommended in the following circumstances:

• Accidental needle-stick or other injury

• Sexual activity with an infected person

• An infant born to an infected mother

HB Vaccine

Hepatitis B vaccine consists of the protein that forms the outer coat of the virus particle,hepatitis B surface antigen (HbsAg) The vaccines currently used in Canada are prepared byrecombinant gene technology

Adverse Events

Pain and tenderness at the site of the injection occur after about 15 percent of vaccinations.The soreness is mild and lasts less than 24 hours.110,111Carefully controlled studies have foundthat other symptoms, such as fever, headache, muscle aches and pain, nausea, vomiting, loss

of appetite, and fatigue occur at the same rates in persons who receive the vaccine as in thosewho are given a placebo.111No causal link between hepatitis B vaccination and chronic fatiguesyndrome has been demonstrated.112Although there have been anecdotal reports associat-ing administration of hepatitis B with onset or exacerbation of multiple sclerosis and a vari-ety of other neurologic and connective tissue disorders, epidemiologic studies have failed todemonstrate any causal links.113

Allergic reactions are rare, occurring after only less than 1 percent of vaccinations Suchreactions may be caused by allergy to yeast proteins or to the preservative, thimerosal.Thimerosal is used as an antiseptic in many contact lens solutions Persons who are allergic

to contact lens solutions may have severe local reactions to HB vaccine

Contraindications

The only reason not to give hepatitis B vaccination is anaphylaxis (hypersensitivity leading

to respiratory distress) or any other severe allergic reaction to a previous dose of the vaccine

Control of Hepatitis B through Vaccination

When HB vaccine first became available, it was recommended for persons at increased risk

of infection with HBV, including the following:

• Health care workers and others at risk of infection because of frequent exposure toblood, as part of their occupation (eg, doctors, nurses, dentists)

• Persons with underlying diseases that require treatment with blood or blood products(eg, hemophilia and chronic kidney failure treated with dialysis)

• Infants whose mothers have chronic HBV infection

• Persons living with someone with chronic HBV infection

• Those travelling to areas with high rates of HBV infection

This approach of targeting high-risk groups has been very effective in reducing the ber of infections in persons in the first three groups listed above However, vaccination ofhigh-risk groups has had little or no effect on the overall rate of HBV infections in Canada

num-or the United States.114

To control HBV infection, medical authorities in both Canada and the United Statesnow recommend immunization of all children.2,112,115Italy, New Zealand, and several Asiancountries have already introduced routine vaccination of all infants Because there is a lag

of 15 to 30 years between infection with HBV and the development of chronic liver ease, several decades must pass before the benefits of routine immunization of children areseen

dis-The current strategy for prevention of HBV infection in Canada focuses on three groups:

1 Pregnant women who are tested for HbsAg so that newborns of such mothers can beprotected as soon as possible with HBIg followed by vaccine

2 School-age children who are vaccinated prior to adolescence so that they are protectedbefore becoming sexually active School vaccination programs have been introduced inall provinces and territories

3 Persons at high risk of infection because of occupational exposure, or life-style orbehavior

The decision to recommend vaccination of all children was based on these facts: the cine is safe, effective, and the vaccination program is affordable It costs more to treat chronicliver disease caused by hepatitis B than to vaccinate all children.116,117In Canada, routine vac-cination of school-age children rather than infants is recommended for the following rea-sons:112

vac-• The rate of HBV infection is very low in children under 12 years of age but begins torise rapidly after 15 years of age

• A product combining diphtheria, tetanus, pertussis, polio, and Haemophilus b vaccines

with HB vaccine is not yet available; a 6-in-1 vaccine would be better for infants tominimize the number of injections they receive

The school vaccination programs in Canada have been very successful, reaching over 90percent of eligible children with three doses of vaccine.110,118Infant vaccination programsmay become routine once combination vaccines become available

Overall, HB vaccine is very effective Over 95 percent of those vaccinated develop bodies and are protected against infection with HBV Those who do become infected despitevaccination appear to be protected against developing chronic HBV infection Studies inTaiwan have documented that the incidence of hepatocellular carcinoma caused by HBV isdecreasing in those cohorts that had been vaccinated as infants.119

anti-The duration of protection is not yet known It does, however, last at least 10 years, andprobably much longer For now, booster doses of vaccine are not considered necessary

Recommendations

There is good evidence to support the recommendation of routine immunization of all dren with hepatitis B vaccine, including randomized, placebo-controlled trials,120–122 epi-demiologic evidence of declines in disease incidence in all countries within a short period

chil-of introduction chil-of mass immunization,123and studies in Taiwan showing a decline amongvaccinated cohorts of primary hepatocellular carcinoma (see Table 3–7).119

parents and/or sick leave benefits incurred by them, the costs of doctor visits, and the agement of the complications of chickenpox.124,125

man-Varicella Vaccine

A live attenuated vaccine was licensed in Canada in December, 1998 The vaccine currentlylicensed in the United States and Canada is unstable unless stored in a freezer at –15°C, whichmay create problems in the distribution of the vaccine

In healthy children, the vaccine is very safe and immunogenic Seroconversion occurs inover 97 percent of children less than 12 years of age after one dose The vaccine is lessimmunogenic in adolescents and adults; two doses, administered 1 month apart, are rec-ommended for susceptible persons over 12 years of age The vaccine prevents chickenpox inover 80 percent of recipients.126Disease is mild in those who are infected in spite of vacci-nation Very mild symptoms, such as low-grade fever and rash around the injection site,develop in less than 10 percent of normal children and adults Chickenpox does occur in vac-cinated persons due to the vaccine strain, but the rate is significantly lower than that fol-lowing infection with wild virus.126

To date, neither the duration of protection nor the need for boosters is known Studies

in Japan suggest that immunity lasts many years.127,128

Recommended Use of Varicella Vaccine

Recommendations for the use of varicella vaccine in Canada have been issued by the NationalAdvisory Committee on Immunization (NACI) and are the same as in the United States Uni-versal vaccination is recommended for all children after the first birthday It can be given con-currently with MMR vaccine A combined MMR-varicella vaccine is under investigation butnot yet available Varicella vaccination is also recommended for adolescents and adults whohave no history of chickenpox It is unlikely that routine serologic testing for susceptibilitywould be cost effective in those without a definite history of chickenpox

Recommendations

There is good evidence from randomized controlled trials that varicella vaccine is effective

in preventing chickenpox and in reducing the incidence of zoster in children, adolescents andadults (Table 3–8) Routine immunization of all children, adolescents and adults without evi-dence of prior infection is recommended

4 Committee on Infectious Diseases Recommended childhood immunization schedule—United States, January-December 1999 Pediatrics 1999;103:182–5.

5 Committee on Infectious Diseases Poliomyelitis prevention: revised recommendations for use of inactivated and live oral polio virus vaccines Pediatrics 1999;103:171–2.

6 Simonsen O, Klaerke M, Klaerke A, et al Revaccination of adults against diphtheria II: Combined diphtheria and tetanus revaccination with different doses of diphtheria toxoid 20 years after primary vaccination Acta Pathol Microbiol Immunol Scand [C] 1986; 94:219–25.

7 Blennow M, Granstrom M, Strandell A Adverse reactions after diphtheria-tetanus booster in year-old schoolchildren in relation to the type of vaccine given for the primary vaccination Vaccine 1994;12:427–30.

10-8 Aggerbeck H, Wantzin J, Heron I Booster vaccination against diphtheria and tetanus in man Comparison of three different vaccine formulations—III Vaccine 1996;14:1265-72.

9 McKinnon N, Ross M, Defries R Reduction of diphtheria in 36,000 Toronto school children as a result of an immunization campaign Canad J Publ Hlth 1931;22:217–23.

10 Munford R, Ory H, Brooks G, et al Diphtheria deaths in the United States, 1959-1970 JAMA 1974;229:1890–3.

11 Griffith A The role of immunization in the control of diphtheria Develop Biol Standard 1979; 43:3-13.

12 Dixon J Diphtheria in North America J Hyg Camb 1984; 93:419–32.

13 Hardy I, Dittmann S, Sutter R Current situation and control strategies for resurgence of theria in newly independent states of the former Soviet Union Lancet 1996; 347:1739–44.

diph-14 Naiditch MJ, Bower AG Diphtheria A study of 1433 cases observed during a ten-year period at Los Angeles County Hospital Am J Med 1954;17:229–45.

15 Mackko MB Comparison of the morbidity of tetanus toxoid boosters with tetanus-diphtheria toxoid boosters Ann Emerg Med 1985;14:33–5.

16 Sisk CW, Lewis CE Reactions to tetanus-diphtheria toxoid (adult) Arch Environ Health 1965;11:34–6.

17 Edsall G, Elliott MW, Peebles TC, et al Excessive use of tetanus toxoid boosters JAMA 1967;202:17–9.

18 Smith RE, Wolnisty C Allergic reactions to tetanus, diphtheria, influenza and poliomyelitis immunization Ann Allergy 1962;20:809–13.

19 Jacobs RL, Lowe RS, Lanier BQ Adverse reactions to tetanus toxoid JAMA 1982;247:40–2.

20 Vaccine Safety Committee Diphtheria and tetanus toxoids Adverse events associated with hood vaccines: evidence bearing on causality In Stratton KR, Howe CJ, Johnston RB editors Research strategies for assessing adverse effects associated with vaccines Washington, DC: National Academy Press; 1994 p.67–117.

child-21 Long AP, Sartwell PE Tetanus in the U.S Army in World War II Bull US Army Med Dept 1947;7:371–85.

22 Newell KW, Duenas Lehman A, LeBlanc DR, et al The use of tetanus toxoid for the prevention

of tetanus neonatorum Final report of a double-blind controlled field trial Bull World Hlth Org 1966;35:863–71.

Immunization 57

23 Izurieta HS, Sutter RW, Strebel PM, et al Tetanus surveillance–United States, 1995-1997 Morb Mortal Wkly Rep 1998;47 (SS2):1-13.

24 Laboratory Center for Disease Control Canadian national report on immunization, 1997 diatr Child Health 1998;3 (Suppl B):20–1B.

Pae-25 Halperin S, Bortolussi R, MacLean D, et al Persistence of pertussis in an immunized population: results of the Nova Scotia Enhanced Pertussis Surveillance Program J Pediatr 1989; 115:686–93.

26 Fine P, Clarkson J Distribution of immunity to pertussis in the population of England and Wales.

J Hyg 1984; 92:21–6.

27 Edwards K Pertussis in older children and adults Adv Pediatr Infect Dis 1998;13:59–77.

28 Mills E, Gold R, Thipphawong J, et al Safety and immunogenicity of a combined nent pertussis-diphtheria-tetanus-inactivated poliomyelitis-Haemophilus b conjugate vaccine administered to infants at two, four and six months of age Vaccine 1998;16:576–85.

five–compo-29 Edwards D, Meade B, Decker M, et al Comparison of 13 acellular pertussis vaccines: overview and serologic response Pediatrics 1995; 96(Suppl):548–57.

30 Decker M, Edwards K, Steinhoff M, et al Comparison of 13 acellular pertussis vaccines: adverse reactions Pediatrics 1995; 96(Suppl):557–66.

31 McDermott C, Grimsrud K, Waters J Acellular pertussis vaccine and whole-cell pertussis vaccine:

a comparison of reported selected adverse events [abstract] 3rd Canadian National nization Conference,Calgary AB, December 2-6, 1998 1998.p.67–8.

Immu-32 Gold R, Scheifele D, Halperin S, et al Hypotonic-hypo-responsive episodes in children ized at 10 Canadian pediatric tertiary-care centers, 1991-1994 Can Comm Dis Rep 1997; 23:73–7.

hospital-33 Miller E Collapse reactions after whole-cell pertussis vaccination Pertussis remains a bigger risk than collapse after vaccination Br Med J 1998; 316:876–80.

34 Vermeer-de Bondt PE, Labadie J, Rumke HC Rate of recurrent collapse after vaccination with whole-cell pertussis vaccine: follow up study Br Med J 1998; 316:902–3.

35 Cody CL, Baraff LJ, Cherry JD, et al Nature and rates of adverse reactions associated with DTP and DT immunizations in infants and children Pediatrics 1981;68:650–60.

36 Griffin M, Ray W, Mortimer E, et al Risk of seizures and encephalopathy after immunization with diphtheria-tetanus-pertussis vaccine JAMA 1990;263:1641–5.

37 Baraff L, Shields W, Beckwith L, et al Infants and children with convulsions and responsive episodes following diphtheria-tetanus-pertussis immunization: follow-up evalua- tion J Pediatr 1988;81:789–94.

hypotonic-hypo-38 Hirtz DG, Nelson KB, Ellenberg JH Seizures following childhood immunizations J Pediatr 1983;102:14–8.

39 Gustafsson L, Hallander H, Olin P, et al A controlled trial of a two-component acellular, a component acellular, and a whole-cell pertussis vaccine N Eng J Med 1996; 334:349–55.

five-40 Olin P, Rasmussen F, Gustafsson L, et al Randomized controlled trial of two-component, component, and five-component acellular pertussis vaccines compared with whole-cell per- tussis vaccine Lancet 1997;350:1569–77.

three-41 Howson C, Fineberg H The ricochet of magic bullets: summary of the Institute of Medicine report Adverse effects of pertussis and rubella vaccines Pediatrics 1992; 89:318–24.

42 National Advisory Committee on Immunization Canadian Immunization Guide Ottawa: Health and Welfare Canada, 4th ed; 1993.p.160.

43 Gangarosa E, Galazka A, Wolfe C, et al Impact of anti-vaccine movements on pertussis control: the untold story Lancet 1998; 351:356–61.

44 Cherry JD The epidemiology of pertussis and pertussis immunization in the United Kingdom and the United States: a comparative study Curr Probl Pediatr 1984;14:1–77.

45 Plotkin S, Cadoz M The acellular pertussis vaccine trials: an interpretation Pediatr Infect Dis J 1997;16:508–17.

46 Storsaeter J, Hallander H, Gustafsson L, et al Levels of anti-pertussis antibodies related to

pro-tection after household exposure to Bordetella pertussis Vaccine 1998;16:1907–16.

47 Cherry J, Gornbein J, Heininger H, et al A search for serologic correlates of immunity to tella pertussis cough illnesses Vaccine 1998;16:1901–6.

Borde-48 Jenkinson D Duration of effectiveness of pertussis vaccine: evidence from a 10-year community study Br Med J 1988;296:612–4.

49 He Q, Viljanen M, Nikkari S, et al Outcomes of Bordetella pertussis infection in different age

groups of an immunized population J Infect Dis 1994;170:873–7.

50 Robertson P, Goldberg H, Jarvie B, et al Bordetella pertussis infection: a cause of persistent cough

in adults Med J Australia 1097;146:522–5.

51 Mink C, Cherry J, Christenson P, et al A search for B pertussis infection in university students.

Clin Infect Dis 1992;14:464–71.

52 Mink C, Sirota N, Nugent S Outbreak of pertussis in a fully immunized adolescent and adult ulation Arch Pediatr Adolesc Med 1994;148:153–7.

pop-53 Begue P, Stagnara J, Vie-Le-Sage F, et al Immunogenicity and reactogenicity of a booster dose of diphtheria, tetanus, acellular pertussis and inactivated poliomyelitis vaccines given concurrently with Haemophilus type b conjugate vaccine or as pentavalent vaccine Pediatr Infect Dis J 1997;16:787–94.

54 Tran Minh N, Edelman K, He Q, et al Antibody and cell-mediated immune responses to booster immunization with a new acellular pertussis vaccine in school children Vaccine 1998;16:1604–10.

55 Greco D, Salmaso S, Mastrantonio T, et al A controlled trial of two acellular vaccines and one whole-cell vaccine against pertussis N Eng J Med 1996;334:341–8.

56 Centers for Disease Control Progress toward global eradication of poliomyelitis, 1997 MMWR 1998;47:414–9.

57 Centers for Disease Control Progress toward poliomyelitis eradication— West Africa, tember 1998 MMWR 1998;47:882–6.

1997—Sep-58 Strickler H, Rosenberg PS, Devesa SS, et al Contamination of polio virus vaccines with simian virus 40 (1955-1963) and subsequent cancer rates JAMA 1998; 279:292-5.

59 Brown F, Lewis AM Simian Virus 40 (SV40): a possible human polyomavirus Dev Biol Stand 1998;94:247–69.

60 Terry L The association of cases of poliomyelitis with the use of type 3 oral poliomyelitis cines Washington, DC: US Department of Health, Education and Welfare; 1962.

vac-61 Strebel P, Sutter R, Cochi S, et al Epidemiology of poliomyelitis in the United States one decade after the last reported case of indigenous wild virus—associated disease Clin Infect Dis 1992;14:568–79.

Immunization 59

62 Sutter RW, Prevost DR Vaccine-associated paralytic poliomyelitis among immunodeficient sons Infect Med 1994;11:426, 429–30, 435–8.

per-63 Centers for Disease Control and Prevention Poliomyelitis prevention in the United States duction of a sequential schedule of inactivated polio virus vaccine followed by oral polio virus vaccine Morb Mortal Wkly Rep 1997;46(RR3):1–25.

Intro-64 Francis TJ, Korns R, Voight R, et al An evaluation of the 1954 poliomyelitis trials [summary report] Am J Publ Hlth 1955; 45:vol 5, Part 2.

65 Faden H, Modlin J, Thomas M, et al Comparative evaluation of immunization with live ated and enhanced potency inactivated trivalent polio virus vaccines in childhood: systemic and local immune responses J Infect Dis 1990;162:1291–7.

attenu-66 Plotkin S IPV for the United States Pediatr Infect Dis J 1995;14:835–9.

67 Bôttiger M Long-term immunity following vaccination with killed polio virus vaccine in den, a country with no circulating polio virus Rev Infect Dis 1984;6(suppl 2):S548–51.

Swe-68 Lapinleimu K Elimination of poliomyelitis in Finland Rev Infect Dis 1984;6(suppl 2):S457–60.

69 Hofman B Poliomyelitis in the Netherlands before and after vaccination with inactivated vaccine J Hyg 1967;65:547–57.

polio-70 Malvy DJ, Drucker J Elimination of poliomyelitis in France: epidemiology and vaccine status Publ Hlth Rev 1993;21:99–106.

71 Varughese PV, Carter AO, Acres SE, et al Eradication of indigenous poliomyelitis in Canada: impact of immunization strategies Can J Publ Hlth 1989:80:363–8.

72 Oostvogel PM, van Wijngaarden JK, van der Avoort HG, et al Poliomyelitis outbreak in an cinated community in the Netherlands, 1992-93 Lancet 1994;344:665–70.

unvac-73 IMPACT Recent trends in pediatric Haemophilus influenzae type b infections in Canada Can Med

Assoc J 1996; 154:1041–7.

74 Grewal S, Scheifele D Haemophilus influenzae type b at 11 pediatric centers, 1996-1997 Can

Commun Dis Rep 1998;24:105–8.

75 Gold R, Scheifele D, Barreto L, et al Safety and immunogenicity of Haemophilus influenzae

vac-cine (tetanus toxoid conjugate) administered concurrently or combined with diphtheria and tetanus toxoids, pertussis vaccine, and inactivated poliomyelitis vaccine to healthy infants at two, four, and six months of age Pediatr Infect Dis J 1994;13:348–55.

76 Peltola H, Aavitsland P, Hansen K, et al Perspective: a five-country analysis of the impact of four

different Haemophilus influenzae type b conjugates and vaccination strategies in Scandinavia.

J Infect Dis 1999;179:223–9.

77 Fritzell B, Plotkin S Efficacy and safety of a Haemophilus influenzae type b capsular

polysaccha-ride–tetanus conjugate vaccine J Pediatr 1992;121:355–62.

78 Takela AK, Eskola J, Leinonen M, et al Reduction of oropharyngeal carriage of Haemophilus zae type b (Hib) in children immunized with a Hib conjugate vaccine J Infect Dis 1991;164:982–6.

influen-79 Murphy TV, Pastor P, Medley F, et al Decreased Haemophilus colonization in children vaccinated with Haemophilus influenzae type b conjugate vaccine J Pediatr 1993;122:517–23.

80 Galil K, Sungleton R, Levine O, et al Reemergence of invasive Haemophilus influenzae type b

dis-ease in a well-vaccinated population in remote Alaska J Infect Dis 1999; 179:101–6.