Background Because of concern about safety and efficacy, nopertussis vaccine has been included in the vaccination programin Sweden since 1979. To provide data that might permit thereintroduction of a pertussis vaccine, we conducted a placebo-controlledtrial of two acellular and one whole-cell pertussis vaccines.
Methods After informed consent was obtained, 9829 children bornin 1992 were randomly assigned to receive one of four vaccines:a two-component acellular diphtheria–tetanus–pertussis(DTP) vaccine (2566 children), a five-component acellular DTPvaccine (2587 children), a whole-cell DTP vaccine licensed inthe United States (2102 children), or (as a control) a vaccinecontaining diphtheria and tetanus toxoids (DT) alone (2574 children).The vaccines were given at 2, 4, and 6 months of age, and thechildren were then followed for signs of pertussis for an additional2 years (to a mean age of 21/2 years).
Results the whole-cell vaccine was associated with significantlyhigher rates of protracted crying, cyanosis, fever, and localreactions than the other three vaccines. The rates of adverseevents were similar for the acellular vaccines and the controlDT vaccine. After three doses, the efficacy of the vaccineswith respect to pertussis linked to a laboratory-confirmed caseof pertussis or contact with an infected household member withparoxysmal cough for >21 days was 58.9 percent for the two-componentvaccine (95 percent confidence interval, 50.9 to 65.9 percent),85.2 percent for the five-component vaccine (95 percent confidenceinterval, 80.6 to 88.8 percent), and 48.3 percent for the whole-cellvaccine (95 percent confidence interval, 37.0 to 57.6 percent).
Conclusions The five-component acellular pertussis vaccine weevaluated can be recommended for general use, since it has afavorable safety profile and confers sustained protection againstpertussis. The two-component acellular vaccine and the whole-cellvaccine were less efficacious.
The most widely used vaccine against pertussis is whole-cellpertussis vaccine, which is given in three primary injectionsin infancy,1 usually followed by booster injections at preschoolage.2 Acellular vaccines, which are likely to cause fewer reactionsthan whole-cell vaccines,3,4 have been in routine use in Japansince 1981, but there was initially little information on theirefficacy.5 In the absence of animal models for the disease,the development of acellular vaccines relied on data from asingle randomized, placebo-controlled trial of two acellularvaccines conducted in Sweden in the mid-1980s.6 The trial didnot include a whole-cell vaccine because of poor public acceptanceof such vaccines in Sweden at that time. The efficacy of twodoses of a one-component vaccine, containing chemically inactivatedpertussis toxin, given to infants ranging from 6 to 12 monthsof age was 54 percent against culture-confirmed pertussis withcough lasting at least one day. The efficacy of a two-componentvaccine, in which the second component was filamentous hemagglutinin,was 69 percent. Both vaccines were about 80 percent effectiveagainst culture-confirmed pertussis with cough lasting at least30 days. After three years of further unblinded follow-up, therelative efficacy was greater for the two-component vaccinethan the one-component vaccine.7 Whether these efficacy estimateswere in the range of those for licensed whole-cell vaccinescould not be established at that time. A number of acellularpertussis vaccines have since become available for study.8,9The present trial compared a two-component vaccine with a five-componentvaccine and with a conventional whole-cell vaccine used in theUnited States, all of which were formulated with diphtheriaand tetanus toxoids. Since a diphtheria–tetanus–pertussis(DTP) vaccine was not routinely administered in Sweden, theinclusion of a control vaccine consisting of diphtheria andtetanus toxoids (DT) alone was ethical.
Methods
Subjects
Parents of infants born in 1992 and living in the catchmentarea of defined child health centers were informed about thetrial by letter. Study nurses contacted parents who expressedinterest in the study, explained the study again orally andin writing, and asked whether the families would like to participate.Infants were excluded from the study if neither parent spokeSwedish, if other difficulties with communication or follow-upwere anticipated, or if the family planned to move from a studyarea before the trial was completed. Infants were also excludedif any of the following were present: serious chronic illnesswith signs of cardiac or renal failure, failure to thrive, progressiveneurologic disease, uncontrolled epilepsy, infantile spasm,immunosuppression, and previous culture-confirmed pertussis.Informed consent was obtained from the parents of all participants.The trial was approved by the ethics committee at the KarolinskaInstitute in Stockholm.
Vaccines
Two experimental vaccines were used. The two-component acellularDTP vaccine (SmithKline Beecham, Rixensart, Belgium) contained25 µg of pertussis toxin inactivated by glutaraldehydeand formalin, 25 µg of formalin-treated hemagglutinin,25 flocculation units of diphtheria toxoid, and 10 flocculationunits of tetanus toxoid in each 0.5-ml dose. The five-componentacellular DTP vaccine (Connaught Laboratories, Toronto) contained10 µg of glutaraldehyde-inactivated pertussis toxin, 5µg of filamentous hemagglutinin, 5 µg of fimbriae2 and 3 combined, 3 µg of pertactin (a 69-kd outer-membraneprotein of Bordetella pertussis that has been shown to conferprotection in animal models10), 15 flocculation units of diphtheriatoxoid, and 5 flocculation units of tetanus toxoid per 0.5-mldose.
The whole-cell DTP vaccine licensed in the United States (ConnaughtLaboratories, Swiftwater, Pa.) contained 5.7 protective unitsof pertussis, 6.65 flocculation units of diphtheria toxoid,and 5 flocculation units of tetanus toxoid. The DT vaccine (SwedishNational Bacteriological Laboratory, Stockholm) contained 15flocculation units of diphtheria toxoid and 3.75 flocculationunits of tetanus toxoid. All vaccines were adsorbed to aluminumsalts. The two-component and five-component acellular vaccinescontained 2-phenoxyethanol as a preservative, whereas the whole-cellvaccine contained thimerosal. The DT vaccine contained no preservative.All children in a group received vaccine from the same batch.Because of logistic problems related to the availability ofa whole-cell vaccine, only the two acellular vaccines and aDT control were used during the first two months of the trial.11
Blinding and Randomization
The vaccines were supplied in identical vials, each of whichwas labeled with a unique computer-generated randomization number.Twelve-unit blocks were used to ensure balanced assignment ofinfants to the three groups randomized during the first twomonths of the trial, and thereafter, 16-unit blocks were usedfor randomization to the four groups. The block sizes were notrevealed to the investigators. Blinding was maintained untildata analysis began in June 1995. The adequacy of blinding waschecked by means of a questionnaire administered to parentsand study nurses 14 days after the third study dose. The possibilityof partial unblinding of the whole-cell–vaccine groupwas raised early in the trial,12 since the DT and acellularvaccines were easily resuspended to homogeneous opaque suspensions,whereas the whole-cell vaccine required vigorous shaking toresuspend. Also, the rates of general symptoms and local reactionswere notably higher after the introduction of the whole-cellvaccine.
Administration of Vaccines
The trial vaccines were given in a series of three intramuscularinjections on the side of the thigh. The first injection wasgiven at 2 months of age (56 to 92 days of age), with the twosubsequent doses scheduled to be given at 8-week intervals (rangebetween doses, 28 to 90 days). Vaccination was deferred if thechild was febrile (temperature, >38.0°C) or had receivedanother vaccine within six days. Contraindications for subsequentdoses were cyanosis, persistent crying for 3 or more hours,fever (temperature, >40.0°C) within 24 hours after adose, shock-like reaction within 48 hours, seizures, and encephalopathy.Inactivated poliovirus vaccine and a vaccine against Haemophilusinfluenzae type b were given two weeks or more after a doseof study vaccine or were given simultaneously in the other leg.
Follow-Up
Nurses were specially trained for the study. Each nurse enrolledapproximately 250 infants and was responsible for vaccinationand standardized follow-up.
Adverse Events
The study nurses telephoned the parents and asked structuredquestions about common adverse events 1 and 14 days after eachdose of vaccine. Serious adverse events were defined as collapse(hypotonic, hyporesponsive episodes13) or generalized allergicreaction within 48 hours after a dose and sudden death, acuteor subacute encephalitis or encephalomyelitis, encephalopathy,convulsions, invasive bacterial infections, other life-threateningevents, and onset of a serious chronic disease within two monthsafter a dose. Serious adverse events and contraindicating eventswere reported to the clinical coordinators. For all study participantswho were hospitalized, hospital records were collected fromthe beginning of the study until two months after the last doseof vaccine or until the child was at least eight months of age.This period was selected to cover invasive bacterial infections14and other unexpected late events.
Ascertainment of Cases and Clinical Follow-Up
The study nurse contacted each household every six to eightweeks. The parents were instructed to call if their child coughedfor more than seven days or if they suspected that whoopingcough was present in the household. In such instances the nursevisited the household, collected standardized clinical information,and obtained nasopharyngeal aspirates from all persons suspectedof having whooping cough. For study children suspected of havingwhooping cough, paired serum samples were collected for diagnosis,with the second sample obtained six to eight weeks after thefirst. A second aspirate was obtained after one week if thefirst culture was negative and symptoms of pertussis persisted.
Serologic Samples
For a study of immunogenicity at one site, venous samples werecollected before vaccination, one month after the third dose,and at 12 months and 2 1/2 years of age. Capillary serum sampleswere collected from all study children at 12 months of age,from children with even randomization numbers at 2 years ofage, and from children with odd randomization numbers at 2 1/2to 3 years of age.
Culture
Nasopharyngeal aspirates were collected as previously reported.15The nasopharyngeal aspirate and the tip of the catheter usedto collect the aspirate were inserted into transport–enrichmentmedium and sent to the local bacteriologic laboratory, usuallyon the day of collection. The aspirate was inoculated onto charcoalmedium with 40 mg of cephalexin per liter according to the methodof Regan and Lowe16 for primary isolation, and the plates wereread after seven days. The enrichment medium was subculturedafter 72 hours and examined four days later. Slide agglutinationwith commercial antiserum specific for B. pertussis and B. parapertussiswas used for the primary identification of isolates. All strainswere sent to the Swedish Institute for Infectious Disease Controlfor biochemical verification and serotyping. Analysis with thepolymerase chain reaction (PCR)17 (and unpublished data) wasused to identify suspected colonies of B. pertussis or B. parapertussisthat could not be subcultured or identified by slide agglutination.
Serologic Analysis
Serum samples were analyzed by a standardized enzyme-linkedimmunosorbent assay,11 with two types of U.S. reference humanantiserum (identified by the Food and Drug Administration aslot 3 for pertussis toxin, filamentous hemagglutinin, and fimbriaeand lot 4 for pertactin) used as controls.18 A reference-linemethod was used to calculate arbitrary units of measure forthe assays.19 Levels of IgA and IgG antibodies against pertussistoxin and filamentous hemagglutinin were measured for diagnosis.A substantial serologic response was defined as an increasein the level of IgG or IgA antibodies of at least 100 percent.The results were accepted if the coefficient of variation ofcontrols within tests was less than 15 percent.
For analysis of the IgG antibody response to vaccination, levelsof IgG antibody against pertussis toxin, filamentous hemagglutinin,pertactin, and fimbriae were determined before and after vaccination.The minimal level of detection was set at 1 arbitrary unit.11Serum samples without measurable antibodies were assigned avalue of 50 percent of the minimal level of detection.
Case Definitions
In the primary case definition, the disease was defined accordingto criteria established by the World Health Organization20 inorder to permit comparisons with other trials and to overcomethe differences in the diagnostic sensitivity of culture andof pertussis-toxin serologic analyses in vaccine and placeborecipients.21 A primary case was defined as the presence ofat least 21 consecutive days of paroxysmal cough plus one ofthe following: culture-confirmed B. pertussis, an increase of100 percent or more in IgG or IgA antibodies against pertussistoxin, an increase of 100 percent or more in IgG or IgA antibodiesagainst filamentous hemagglutinin (in the absence of positiveresults for B. parapertussis on culture or PCR), or documentedcontact with an infected household member with culture-confirmedB. pertussis who began to cough within 28 days before or afterthe onset of cough in the study child. In the secondary casedefinitions, the diagnosis was established by the presence oflaboratory-confirmed pertussis (by culture, serologic analysis,or PCR) with cough for >1, >7, >21, or >30 consecutivedays and paroxysmal cough for >14 or >21 consecutive days.
Statistical Analysis
The true efficacy of all the pertussis vaccines studied wasassumed to be 80 percent. The null hypothesis to be tested wasthat the efficacy of any of the vaccines was 70 percent or less,corresponding to a relative risk of pertussis of 1.5 or greaterfor the comparison of the acellular vaccines with the whole-cellvaccine.11 Hazard ratios obtained by Cox proportional-hazardsregression were used to estimate absolute and relative vaccineefficacy22 with SPSS software for personal computers (SPSS,Chicago). The Kolmogorov–Smirnov two-sample test was usedto compare the distributions between groups of IgG antibodylevels after vaccination. Calculations of chi-square, relativerisk, and differences of paired proportions with 95 percentconfidence intervals were done as appropriate. All analyseswere performed according to plans outlined before blinding wassuspended.11
Results
A total of 24,336 infants were eligible for the study. A totalof 14,507 infants did not participate for the following reasons:parents declined to participate (34.4 percent), parents didnot respond to the letter of invitation and were not reachedby telephone (16.9 percent), parents did not speak Swedish (3.6percent), other known reasons (2.9 percent), medical contraindications(1.1 percent), and the family planned to move from the studyarea (0.7 percent). The remaining 9829 infants (40.4 percent)were randomly assigned to a group at the first injection. Thefour groups did not differ significantly with respect to severalprognostic characteristics (Table 1). A total of 199 childrendid not complete the primary vaccination series because of culture-confirmedpertussis before the third dose (n = 47), withdrawal from thestudy (n = 40), or contraindicating events (11 in the groupgiven two-component acellular vaccine, 18 in the group givenfive-component acellular vaccine, 67 in the group given whole-cellvaccine, and 16 in the group given DT vaccine [control]; overallP<0.001). Later losses to follow-up (as of January 8, 1995)included 205 children (2.1 percent) who moved out of the studyarea and 116 children (1.2 percent) who did not complete follow-upfor other reasons. One child died of sudden infant death syndrome1 day after the first dose of the whole-cell vaccine, and anotherchild died of this syndrome 27 days after the first dose ofthe two-component vaccine. Two deaths — one due to progressiveconvulsions with renal and liver failure and the other to bronchiolitis— occurred 7 and 14 months, respectively, after the thirddose of the DT vaccine. All four deaths were judged to be unrelatedto vaccination.
Table 1. Base-Line Characteristics of the 9829 Infants in the Four Vaccine Groups.
Adverse Events
Serious adverse events developed within 60 days after vaccinationin 48 children, including 2 of the 4 who died. The number ofevents was similar between groups (P = 0.66). Five hypotonic,hyporesponsive episodes occurred among recipients of the whole-cellvaccine: four after the first dose and one after the seconddose. One episode was reported after the third dose in a recipientof the five-component vaccine. There were 24 convulsions (5in the group given two-component vaccine, 7 in the group givenfive-component vaccine, 3 in the group given whole-cell vaccine,and 9 in the group given DT vaccine). Five of the convulsionsoccurred within 48 hours after a dose of vaccine (two in thetwo-component–vaccine group, one in the whole-cell–vaccinegroup, and two in the DT-vaccine group). There were 16 otherserious events, which occurred 4 to 61 days after vaccination:3 invasive bacterial infections (2 in the group given whole-cellvaccine and 1 in the group given two-component vaccine), 2 apparentlylife-threatening events, and 11 serious chronic illnesses (3malignant tumors, 2 cases of hydrocephalus, 2 cases of cardiacfailure, 1 neurologic malformation, and 1 case each of Kawasaki'ssyndrome, suspected Leigh's disease, and psychomotor retardationwith amaurosis).
There were 163 events that contraindicated the administrationof further doses of vaccine, including the episodes of hypotonichyporesponsiveness and convulsions. Protracted crying for threehours or more was noted in 23 recipients of the whole-cell vaccineas compared with 0 to 4 recipients of the other three vaccines(1.1 percent vs. 0 to 0.2 percent, P<0.001). A rectal temperatureof at least 40.0°C was noted within one day of vaccinationin 28 recipients of whole-cell vaccine (1.3 percent) and in2 to 7 recipients of the other three vaccines (0.1 to 0.4 percent).Four recipients of whole-cell vaccine had generalized cyanosison the day of the first dose (P = 0.040 by Fisher's exact two-tailedtest for the comparison with either of the groups given acellularvaccine). Pronounced local reactions with general symptoms contraindicatedthe administration of further trial doses in 13 recipients ofwhole-cell vaccine and 1 recipient of five-component vaccine(P<0.001). The rates of minor general symptoms and localreactions were high in the group given whole-cell vaccine andlow in the other three groups, with no clinically relevant differencesin the low rates between the acellular-vaccine and DT-vaccinegroups (Table 2).
Table 2. General Symptoms and Local Reactions Reported within One Day of a Dose of Vaccine in the Four Groups.
Fourteen days after the third dose, the study nurses could identify53.5 percent of the recipients of whole-cell vaccine but couldnot distinguish between recipients of the acellular vaccinesand the DT vaccine.
Postvaccination Antibody Levels
Paired serum samples obtained before the first dose and onemonth after the third dose were available for 689 study children.Some prevaccination samples contained high levels of maternalantibodies against pertussis. Therefore, as specified in theprotocol,11 before breaking the code, we evaluated only thepostvaccination levels. The frequencies23 of IgG antibody levelsagainst four pertussis antigens are shown in Figure 1A, Figure 1B,Figure 1C, and Figure 1D. Both acellular-vaccine groupshad high levels of antibodies against pertussis toxin (Figure 1A),but the levels in the groups given the five-component vaccinewere significantly lower than those in the group given the two-componentvaccine (P<0.001). Levels of antibodies against pertussistoxin in the whole-cell–vaccine group were very low. Thelevels of IgG antibodies against filamentous hemagglutinin (Figure 1B)were significantly lower in the group given the five-componentvaccine than in the group given the two-component vaccine (P<0.001),and the levels in the group given whole-cell vaccine were muchlower than the levels in either of the acellular-vaccine groups.Levels of antibodies against fimbriae (Figure 1C) and pertactin(Figure 1D) were significantly higher in the group given thefive-component vaccine than in the group given whole-cell vaccine(P<0.001); the flatness of the distribution curves for thesetwo antibodies suggests a nonuniform response to whole-cellvaccine.
Figure 1. Postvaccination IgG Antibody Levels against Pertussis Toxin (Panel A), Filamentous Hemagglutinin (Panel B), Fimbriae 2 and 3 (Panel C), and Pertactin (Panel D) in Recipients of the Two-Component Acellular Vaccine (N = 186), the Five-Component Acellular Vaccine (N = 178), Whole-Cell Vaccine (N = 144), and DT Vaccine (N = 181).
Data are given as reversed distribution curves; the x axis is logarithmic. In all cases the units used in the enzyme-linked immunosorbent assay to measure IgG antibodies are arbitrary.
Efficacy
During the main follow-up period, which lasted an average of21 to 23.5 months after the third dose, 737 cases of pertussiswere diagnosed that met the primary case definition (Table 3).The proportions of culture-confirmed cases were as follows:56 percent in the two-component–vaccine group, 42 percentin the five-component–vaccine group, 59 percent in thewhole-cell–vaccine group, and 73 percent in the DT-vaccinegroup. The proportions of cases confirmed on the basis of anincrease of 100 percent or more in IgG or IgA antibodies againstpertussis toxin were as follows: 29 percent in the two-component–vaccinegroup, 37 percent in the five-component–vaccine group,36 percent in the whole-cell–vaccine group, and 24 percentin the DT-vaccine group. The proportions of cases confirmedon the basis of an increase of 100 percent or more in IgG orIgA antibodies against filamentous hemagglutinin were as follows:13 percent in the two-component–vaccine group, 12 percentin the five-component–vaccine group, 5 percent in thewhole-cell–vaccine group, and 2 percent in the DT-vaccinegroup. The proportions of cases documented only on the basisof contact with an infected household member were as follows:2 percent in the two-component–vaccine group, 9 percentin the five-component–vaccine group, 0 percent in thewhole-cell–vaccine group, and 1 percent in the DT-vaccinegroup.
Table 3. Efficacy of the Vaccines with Respect to Confirmed Cases of Pertussis with >21 Days of Paroxysmal Cough.
The two-component vaccine and the whole-cell vaccine conferredsome protection against laboratory-confirmed typical pertussisbut did not meet the preset standard of at least 70 percentefficacy. The five-component vaccine conferred good protectionagainst typical pertussis. Figure 2 shows that the efficacyof whole-cell vaccine declined during the two years of follow-up,whereas the efficacy of the five-component vaccine was sustained.This vaccine also conferred substantial protection against mildand atypical pertussis, with an estimated efficacy of 77.9 percent(95 percent confidence interval, 72.6 to 82.2 percent) againstlaboratory-confirmed pertussis with at least one day of cough.With the use of the same case definition, the efficacy of thetwo-component vaccine was 42.3 percent (95 percent confidenceinterval, 32.6 to 50.6 percent) and of the whole-cell vaccine,41.2 percent (95 percent confidence interval, 29.7 to 50.9 percent).
Figure 2. Efficacy of the Vaccines against Laboratory-Confirmed or Household-Linked Cases of Pertussis with 21 Days of Paroxysmal Cough, According to the Interval after the Third Dose in the Four-Vaccine Part of the Trial.
Discussion
In this controlled trial the rates of adverse events among childrenwho received an acellular pertussis vaccine and those who receivedthe control DT vaccine with no pertussis component were similar.The acellular vaccines were much less likely to cause reactionsthan the whole-cell vaccine, as shown previously.24,25,26,27The same pattern was observed in an Italian trial, reportedin this issue of the Journal, which used the same whole-cellvaccine, two three-component vaccines, and a different DT-vaccinecontrol.28 A temperature of 40.5°C or higher and convulsionsare contraindications for additional doses of whole-cell vaccine,and the 1994 Red Book29 advises physicians to consider carefullyan individual patient's history before vaccination. Our datasuggest that the medical contraindications for acellular pertussisvaccines, like those for DT vaccine, are few. We found thatthe five-component acellular vaccine was both safe and efficacious.
The whole-cell vaccine produced low antibody responses to allpertussis antigens studied, reflecting the varying serologicresponses reported for licensed whole-cell vaccines.3,30 Bothacellular vaccines were immunogenic with regard to each antigenstudied. because of its higher content of filamentous hemagglutininand pertussis toxin, the two-component vaccine produced higherpostvaccination antibody levels than the five-component vaccine.The anti–pertussis-toxin response to the two-componentvaccine seemed lower than previously reported8 and may reflecta variation in immunogenicity from lot to lot or methodologicdifferences.
Efficacy was determined with unusual accuracy, since a pertussisepidemic occurred during the trial.11 Furthermore, the laboratoryconfirmation of cases was improved by the use of one or twobedside nasopharyngeal aspirates and by the use of serum collectedbefore the episode (i.e., at one or two years of age), beforea significant increase in the serum antibody titer had occurred.Failure to demonstrate a serologic response was expected mainlyin vaccine recipients, for whom exposure to the bacteria couldlead to a rapid increase in antibodies. Because we includedserum obtained before exposure to pertussis, as much as 49 percentof the cases meeting the primary case definition were serologicallyconfirmed among the recipients of the five-component vaccine,as compared with 26 percent among recipients of the DT vaccine.Hence, the issue of the differences in the sensitivity of cultureand serologic methods between groups21 was avoided. Cases confirmedon the basis of an anti–filamentous-hemagglutinin responsealone were evenly distributed between the groups. The exclusionof these potentially false positive cases only marginally changedthe efficacy estimates. In this trial, vaccines with low andhigh rates of efficacy were identified, supporting the impressionthat the case ascertainment was sensitive and essentially notbiased.
The efficacy of the whole-cell vaccine was lower than expected,as was found in the Italian trial.28 The efficacy may even havebeen overestimated because of partial unblinding.7 The decliningefficacy of the whole-cell vaccine might have been avoided ifa fourth dose had been given at 18 months of age, as is donein the United States.29
The efficacy of the Japanese two-component vaccine was lowerthan that of a two-component vaccine that was given in two dosesto children 6 to 12 months of age in our previous placebo-controlledtrial.6,7 The pertussis-toxoid vaccine used in that trial wasas efficacious (with the use of similar case definitions) asa U.S. pertussis-toxoid vaccine given at 3, 5, and 12 monthsof age.9 Such historical comparisons may indicate that the practiceof primary vaccination with three doses before six months ofage without a booster is not optimal. Hence, it is remarkablethat the efficacy of the five-component vaccine was sustainedduring the entire two-year follow-up period. An optimal vaccinationschedule for highly efficacious acellular vaccines may involvetwo primary doses at 2 to 6 months of age, followed by a boosterat 12 to 18 months of age. The five-component vaccine was alsohighly efficacious against mild disease. The data from thisand three other randomized, placebo-controlled trials6,8,28suggest that multicomponent vaccines are more protective againstboth typical pertussis and mild disease than one-component andtwo-component vaccines. The relative contribution of each antigenremains to be shown. improved protection against infection maydiminish the spread of the disease, which in turn should improvethe control of pertussis. Furthermore, a reduction in the numberof doses needed may have economic and public health advantagesthat would lead many countries to switch from whole-cell toacellular vaccines.
Supported by a contract (N01-AI-15125) with the National Instituteof Allergy and Infectious Diseases.
We are indebted to the participating parents and study nurses,whose intimate collaboration formed the backbone of the trial;to the scientific community, public health authorities, andvaccine manufacturers for collaborating in a most constructiveway, which depended on an unusual degree of openness among thepersons assigned to the project by each organization; to WilliamBlackwelder, David Klein, and Mark van Raden, National Instituteof Allergy and Infectious Diseases; and to Francis André,SmithKline Beecham Biologicals, and Luis Barreto, ConnaughtLaboratories, for constructive criticism of the manuscript.
Source Information
From Sachs' Children's Hospital (L.G., P.O., J.S.) and the Swedish Institute for Infectious Disease Control (H.O.H., P.O., E.R.) — both in Stockholm, Sweden.
Address reprint requests to Dr. Olin at the Swedish Institute for Infectious Disease Control, S-10521 Stockholm, Sweden.
References
Moxon ER, Rappuoli R. Haemophilus influenzae infections and whooping cough. Lancet 1990;335:1324-1329. [CrossRef][Medline]
Cherry CD, Brunell PA, Golder GS, Karzon DT. Report of the Task Force on Pertussis and Pertussis Immunization -- 1988. Pediatrics 1988;81:Suppl:939-984.
Noble GR, Bernier RH, Esber EC, et al. Acellular and whole-cell pertussis vaccines in Japan: report of a visit by US scientists. JAMA 1987;257:1351-1356. [Abstract]
Feldman S, Perry S, Andrew M, Jones L, Moffitt JE. Comparison of acellular (B type) and whole-cell pertussis-component diphtheria-tetanus-pertussis vaccines as the first booster immunization in 15- to 24-month-old children. J Pediatr 1992;121:857-861. [Erratum, J Pediatr 1993;123:842.] [Medline]
Cherry JD. Pertussis: the trials and tribulations of old and new pertussis vaccines. Vaccine 1992;10:1033-1038. [CrossRef][Medline]
Ad Hoc Group for the Study of Pertussis Vaccines. Placebo-controlled trial of two acellular pertussis vaccines in Sweden -- protective efficacy and adverse events. Lancet 1988;1:955-960. [Erratum, Lancet 1988;1:1238.] [CrossRef][Medline]
Storsaeter J, Olin P. Relative efficacy of two acellular pertussis vaccines during three years of passive surveillance. Vaccine 1992;10:142-144. [CrossRef][Medline]
Edwards KM, Meade BM, Decker MD, et al. Comparison of 13 acellular pertussis vaccines: overview and serologic response. Pediatrics 1995;96:548-557. [Free Full Text]
Trollfors B, Taranger J, Lagergård T, et al. A placebo-controlled trial of a pertussis-toxoid vaccine. N Engl J Med 1995;333:1045-1050. [Free Full Text]
Shahin RD, Brennan MJ, Li ZM, Meade BD, Manclark CR. Characterization of the protective capacity and immunogenicity of the 69-kD outer membrane protein of Bordetella pertussis. J Exp Med 1990;171:63-73. [Free Full Text]
Gustafsson L, Hallander HO, Olin P, Reizenstein E, Storsaeter J. Efficacy trial of acellular pertussis vaccine: technical report, Trial I, with results of preplanned analysis of safety, efficacy and immunogenicity. Stockholm, Sweden: Swedish Institute for Infectious Disease Control, 1995:20-70. (Contract no. N01-AI-15125.)
Olin P. Acellular pertussis vaccines -- a question of efficacy. J Hosp Infect 1995;30:Suppl:503-507.
Cody CL, Baraff LJ, Cherry JD, Marcy SM, Manclark CR. Nature and rates of adverse reactions associated with DTP and DT immunizations in infants and children. Pediatrics 1981;68:650-660. [Free Full Text]
Storsaeter J, Olin P, Renemar B, et al. Mortality and morbidity from invasive bacterial infections during a clinical trial of acellular pertussis vaccines in Sweden. Pediatr Infect Dis 1988;7:637-645.
Hallander HO, Reizenstein I, Renemar B, Rasmuson G, Mardin L, Olin P. Comparison of nasopharyngeal aspirates with swabs for culture of Bordetella pertussis. J Clin Microbiol 1993;31:50-52. [Free Full Text]
Regan J, Lowe F. Enrichment medium for the isolation of Bordetella. J Clin Microbiol 1977;6:303-309. [Free Full Text]
Reizenstein E, Johansson B, Mardin L, Abens J, Möllby R, Hallander HO. Diagnostic evaluation of polymerase chain reaction discriminative for Bordetella pertussis, B. parapertussis, and B. bronchiseptica. Diagn Microbiol Infect Dis 1993;17:185-191. [CrossRef][Medline]
Meade BD, Deforest A, Edwards KM, et al. Description and evaluation of serologic assays used in a multicenter trial of acellular pertussis vaccines. Pediatrics 1995;96:570-575. [Free Full Text]
Reizenstein E, Hallander HO, Blackwelder WC, Kühn I, Ljungman M, Möllby R. Comparison of five calculation modes for antibody ELISA procedures using pertussis serology as a model. J Immunol Methods 1995;183:279-290. [CrossRef][Medline]
WHO meeting on case definition of pertussis: Geneva, 10-11 January 1991. Geneva: World Health Organization, 1991:4-5. (Issue no. MIN/EPI/PERT/91.1.)
Hallander HO, Storsaeter J, Möllby R. Evaluation of serology and nasopharyngeal cultures for diagnosis of pertussis in a vaccine efficacy trial. J Infect Dis 1991;163:1046-1054. [Medline]
Kalbfleisch JD, Prentice RL. The statistical analysis of failure time data. New York: John Wiley, 1980.
Reed GF, Meade BD, Steinhoff MC. The reverse cumulative distribution plot: a graphic method for exploratory analysis of antibody data. Pediatrics 1995;96:600-603. [Free Full Text]
Anderson EL, Belshe RB, Bartram J. Differences in reactogenicity and antigenicity of acellular and standard pertussis vaccines combined with diphtheria and tetanus in infants. J Infect Dis 1988;157:731-737. [Medline]
Blumberg DA, Mink CM, Cherry JD, et al. Comparison of acellular and whole-cell pertussis-component diphtheria-tetanus-pertussis vaccines in infants. J Pediatr 1991;119:194-204. [CrossRef][Medline]
Englund JA, Glezen WP, Barreto J. Controlled study of a new five-component acellular pertussis vaccine in adults and young children. J Infect Dis 1992;166:1436-1441. [Medline]
Decker MD, Edwards KM, Steinhoff MC, et al. Comparison of 13 acellular pertussis vaccines: adverse reactions. Pediatrics 1995;96:557-566. [Free Full Text]
Greco D, Salmaso S, Mastrantonio P, et al. A controlled trial of two acellular vaccines and one whole-cell vaccine against pertussis. N Engl J Med 1996;334:341-348. [Free Full Text]
Pertussis. In: Peter G, ed. 1994 Red book: report of the committee on infectious diseases. 23rd ed. Elk Grove Village, Ill.: American Academy of Pediatrics, 1994:355-67.
Edwards KM, Decker MD, Halsey NA, et al. Differences in antibody response to whole-cell pertussis vaccines. Pediatrics 1991;88:1019-1023. [Free Full Text]
Roy, K., Hamilton, D., Allen, K. P., Randolph, M. P., Fleckenstein, J. M.
(2008). The EtpA Exoprotein of Enterotoxigenic Escherichia coli Promotes Intestinal Colonization and Is a Protective Antigen in an Experimental Model of Murine Infection. Infect. Immun.
76: 2106-2112
[Abstract][Full Text]
Fry, S. R., Chen, A. Y., Daggard, G., Mukkur, T. K. S.
(2008). Parenteral immunization of mice with a genetically inactivated pertussis toxin DNA vaccine induces cell-mediated immunity and protection. J Med Microbiol
57: 28-35
[Abstract][Full Text]
Aase, A., Herstad, T. K., Merino, S., Brandsdal, K. T., Berdal, B. P., Aleksandersen, E. M., Aaberge, I. S.
(2007). Opsonophagocytic Activity and Other Serological Indications of Bordetella pertussis Infection in Military Recruits in Norway. CVI
14: 855-862
[Abstract][Full Text]
Higgins, S. C., Jarnicki, A. G., Lavelle, E. C., Mills, K. H. G.
(2006). TLR4 Mediates Vaccine-Induced Protective Cellular Immunity to Bordetella pertussis: Role of IL-17-Producing T Cells. J. Immunol.
177: 7980-7989
[Abstract][Full Text]
Vickers, D., Ross, A. G., Mainar-Jaime, R. C., Neudorf, C., Shah, S.
(2006). Whole-cell and acellular pertussis vaccination programs and rates of pertussis among infants and young children.. CMAJ
175: 1213-1217
[Abstract][Full Text]
Halperin, S. A., De Serres, G.
(2006). Has the change to acellular pertussis vaccine improved or worsened pertussis control?. CMAJ
175: 1227-1227
[Full Text]
Elahi, S., Buchanan, R. M., Babiuk, L. A., Gerdts, V.
(2006). Maternal Immunity Provides Protection against Pertussis in Newborn Piglets.. Infect. Immun.
74: 2619-2627
[Abstract][Full Text]
Committee on Infectious Diseases,
(2006). Prevention of Pertussis Among Adolescents: Recommendations for Use of Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis (Tdap) Vaccine. Pediatrics
117: 965-978
[Abstract][Full Text]
Galanis, E., King, A. S., Varughese, P., Halperin, S. A.
(2006). Changing epidemiology and emerging risk groups for pertussis.. CMAJ
174: 451-452
[Full Text]
Niedziela, T., Letowska, I., Lukasiewicz, J., Kaszowska, M., Czarnecka, A., Kenne, L., Lugowski, C.
(2005). Epitope of the Vaccine-Type Bordetella pertussis Strain 186 Lipooligosaccharide and Antiendotoxin Activity of Antibodies Directed against the Terminal Pentasaccharide-Tetanus Toxoid Conjugate. Infect. Immun.
73: 7381-7389
[Abstract][Full Text]
Halperin, S. A.
(2005). Pertussis--a disease and vaccine for all ages.. NEJM
353: 1615-1617
[Full Text]
Poland, G. A.
(2005). The Growing Paradigm of Preventing Disease: Vaccines To Prevent Herpes Zoster and Pertussis in Adults. ANN INTERN MED
143: 539-541
[Full Text]
Bisgard, K. M., Rhodes, P., Connelly, B. L., Bi, D., Hahn, C., Patrick, S., Glode, M. P., Ehresmann, K. R., and the Pertussis Investigation Team,
(2005). Pertussis Vaccine Effectiveness Among Children 6 to 59 Months of Age in the United States, 1998-2001. Pediatrics
116: e285-e294
[Abstract][Full Text]
Pichichero, M. E., Rennels, M. B., Edwards, K. M., Blatter, M. M., Marshall, G. S., Bologa, M., Wang, E., Mills, E.
(2005). Combined Tetanus, Diphtheria, and 5-Component Pertussis Vaccine for Use in Adolescents and Adults. JAMA
293: 3003-3011
[Abstract][Full Text]
van Amersfoorth, S. C. M., Schouls, L. M., van der Heide, H. G. J., Advani, A., Hallander, H. O., Bondeson, K., von Konig, C. H. W., Riffelmann, M., Vahrenholz, C., Guiso, N., Caro, V., Njamkepo, E., He, Q., Mertsola, J., Mooi, F. R.
(2005). Analysis of Bordetella pertussis Populations in European Countries with Different Vaccination Policies. J. Clin. Microbiol.
43: 2837-2843
[Abstract][Full Text]
Hallander, H. O., Advani, A., Donnelly, D., Gustafsson, L., Carlsson, R.-M.
(2005). Shifts of Bordetella pertussis Variants in Sweden from 1970 to 2003, during Three Periods Marked by Different Vaccination Programs. J. Clin. Microbiol.
43: 2856-2865
[Abstract][Full Text]
Cherry, J. D.
(2005). The Epidemiology of Pertussis: A Comparison of the Epidemiology of the Disease Pertussis With the Epidemiology of Bordetella pertussis Infection. Pediatrics
115: 1422-1427
[Abstract][Full Text]
Mattoo, S., Cherry, J. D.
(2005). Molecular Pathogenesis, Epidemiology, and Clinical Manifestations of Respiratory Infections Due to Bordetella pertussis and Other Bordetella Subspecies. Clin. Microbiol. Rev.
18: 326-382
[Abstract][Full Text]
Tozzi, A. E., Pastore Celentano, L., Ciofi degli Atti, M. L., Salmaso, S.
(2005). Diagnosis and management of pertussis. CMAJ
172: 509-515
[Abstract][Full Text]
Baughman, A. L., Bisgard, K. M., Edwards, K. M., Guris, D., Decker, M. D., Holland, K., Meade, B. D., Lynn, F.
(2004). Establishment of Diagnostic Cutoff Points for Levels of Serum Antibodies to Pertussis Toxin, Filamentous Hemagglutinin, and Fimbriae in Adolescents and Adults in the United States. CVI
11: 1045-1053
[Abstract][Full Text]
Hijnen, M., Mooi, F. R., van Gageldonk, P. G. M., Hoogerhout, P., King, A. J., Berbers, G. A. M.
(2004). Epitope Structure of the Bordetella pertussis Protein P.69 Pertactin, a Major Vaccine Component and Protective Antigen. Infect. Immun.
72: 3716-3723
[Abstract][Full Text]
Advani, A., Donnelly, D., Hallander, H.
(2004). Reference System for Characterization of Bordetella pertussis Pulsed-Field Gel Electrophoresis Profiles. J. Clin. Microbiol.
42: 2890-2897
[Abstract][Full Text]
Nilsson, L., Kjellman, N.-I. M., Bjorksten, B.
(2003). Allergic Disease at the Age of 7 Years After Pertussis Vaccination in Infancy: Results From the Follow-up of a Randomized Controlled Trial of 3 Vaccines. Arch Pediatr Adolesc Med
157: 1184-1189
[Abstract][Full Text]
Skowronski, D. M., Remple, V. P., Macnabb, J., Pielak, K., Patrick, D. M., Halperin, S. A., Scheifele, D.
(2003). Injection-Site Reactions to Booster Doses of Acellular Pertussis Vaccine: Rate, Severity, and Anticipated Impact. Pediatrics
112: e453-459
[Abstract][Full Text]
Le Saux, N., Barrowman, N. J., Moore, D. L., Whiting, S., Scheifele, D., Halperin, S., for Members of the Canadian Paediatric Society/ He,
(2003). Decrease in Hospital Admissions for Febrile Seizures and Reports of Hypotonic-Hyporesponsive Episodes Presenting to Hospital Emergency Departments Since Switching to Acellular Pertussis Vaccine in Canada: A Report From IMPACT. Pediatrics
112: e348-348
[Abstract][Full Text]
Cohn, J. N
(2003). Interaction of -blockers and angiotensin receptor blockers/ACE inhibitors in heart failure. Journal of Renin-Angiotensin-Aldosterone System
4: 137-139
[Abstract]
Cherry, J. D.
(2003). The Science and Fiction of the "Resurgence" of Pertussis. Pediatrics
112: 405-406
[Full Text]
Bruss, J. B., Siber, G. R.
(2002). Quantitative Priming with Inactivated Pertussis Toxoid Vaccine in the Aerosol Challenge Model. Infect. Immun.
70: 4600-4608
[Abstract][Full Text]
Roduit, C., Bozzotti, P., Mielcarek, N., Lambert, P.-H., del Giudice, G., Locht, C., Siegrist, C.-A.
(2002). Immunogenicity and Protective Efficacy of Neonatal Vaccination against Bordetella pertussis in a Murine Model: Evidence for Early Control of Pertussis. Infect. Immun.
70: 3521-3528
[Abstract][Full Text]
SHINA, A., HART, C. A., STENTON, M. D., DAWSON, S., MCCRACKEN, C. M., BINNS, S. H., GASKELL, R. M., WINSTANLEY, C.
(2002). Distribution of fim3 and flaA TTGE sequence types amongst isolates of Bordetella bronchiseptica from different host animals. J Med Microbiol
51: 557-587
[Abstract][Full Text]
Canthaboo, C., Xing, D., Wei, X. Q., Corbel, M. J.
(2002). Investigation of Role of Nitric Oxide in Protection from Bordetella pertussis Respiratory Challenge. Infect. Immun.
70: 679-684
[Abstract][Full Text]
Salmaso, S., Mastrantonio, P., Tozzi, A. E., Stefanelli, P., Anemona, A., Atti, M. L. C. d., Giammanco, A., the Stage III Working Group,
(2001). Sustained Efficacy During the First 6 Years of Life of 3-Component Acellular Pertussis Vaccines Administered in Infancy: The Italian Experience. Pediatrics
108: e81-81
[Abstract][Full Text]
Donnelly, S., Loscher, C. E., Lynch, M. A., Mills, K. H. G.
(2001). Whole-Cell but Not Acellular Pertussis Vaccines Induce Convulsive Activity in Mice: Evidence of a Role for Toxin-Induced Interleukin-1{beta} in a New Murine Model for Analysis of Neuronal Side Effects of Vaccination. Infect. Immun.
69: 4217-4223
[Abstract][Full Text]
Liese, J. G., Belohradsky, B. H., Walker;, A. M., Cherry, J. D., Olin, P.
(2001). The Science and Fiction of Pertussis Vaccines. Pediatrics
107: 611-612
[Full Text]
Tozzi, A. E., Anemona, A., Stat, D., Stefanelli, P., Biol, D., Salmaso, S., Biol, D., Atti, M. L. C. d., Mastrantonio, P., Giammanco, A., the Progetto Pertosse Study Group,
(2001). Reactogenicity and Immunogenicity at Preschool Age of a Booster Dose of Two Three-Component Diphtheria-Tetanus-Acellular Pertussis Vaccines in Children Primed in Infancy With Acellular Vaccines. Pediatrics
107: 25e-25
[Abstract][Full Text]
Braun, M. M., Mootrey, G. T., Salive, M. E., Chen, R. T., Ellenberg, S. S., the VAERS Working Group,
(2000). Infant Immunization With Acellular Pertussis Vaccines in the United States: Assessment of the First Two Years' Data From the Vaccine Adverse Event Reporting System (VAERS). Pediatrics
106: 51e-51
[Abstract][Full Text]
Ellenberg, S. S., Temple, R.
(2000). Placebo-Controlled Trials and Active-Control Trials in the Evaluation of New Treatments. Part 2: Practical Issues and Specific Cases. ANN INTERN MED
133: 464-470
[Abstract][Full Text]
Ekwueme, D. U., Strebel, P. M., Hadler, S. C., Meltzer, M. I., Allen, J. W., Livengood, J. R.
(2000). Economic Evaluation of Use of Diphtheria, Tetanus, and Acellular Pertussis Vaccine or Diphtheria, Tetanus, and Whole-Cell Pertussis Vaccine in the United States, 1997. Arch Pediatr Adolesc Med
154: 797-803
[Abstract][Full Text]
Rowe, J., Macaubas, C., Monger, T. M., Holt, B. J., Harvey, J., Poolman, J. T., Sly, P. D., Holt, P. G.
(2000). Antigen-Specific Responses to Diphtheria-Tetanus-Acellular Pertussis Vaccine in Human Infants Are Initially Th2 Polarized. Infect. Immun.
68: 3873-3877
[Abstract][Full Text]
Hausman, S. Z., Burns, D. L.
(2000). Use of Pertussis Toxin Encoded by ptx Genes from Bordetella bronchiseptica To Model the Effects of Antigenic Drift of Pertussis Toxin on Antibody Neutralization. Infect. Immun.
68: 3763-3767
[Abstract][Full Text]
Gilbert, P. B
(2000). Some statistical issues in the design of HIV-1 vaccine and treatment trials. Stat Methods Med Res
9: 207-229
[Abstract]
Leef, M., Elkins, K. L., Barbic, J., Shahin, R. D.
(2000). Protective Immunity to Bordetella pertussis Requires Both B Cells and CD4+ T Cells for Key Functions Other than Specific Antibody Production. J. Exp. Med.
191: 1841-1852
[Abstract][Full Text]
Kosters, K., Riffelmann, M., Dohrn, B., von Konig, C. H. W.
(2000). Comparison of Five Commercial Enzyme-Linked Immunosorbent Assays for Detection of Antibodies to Bordetella pertussis. CVI
7: 422-426
[Abstract][Full Text]
Mattoo, S., Miller, J. F., Cotter, P. A.
(2000). Role of Bordetella bronchiseptica Fimbriae in Tracheal Colonization and Development of a Humoral Immune Response. Infect. Immun.
68: 2024-2033
[Abstract][Full Text]
McGuirk, P., Mills, K. H. G.
(2000). A Regulatory Role for Interleukin 4 in Differential Inflammatory Responses in the Lung following Infection of Mice Primed with Th1- or Th2-Inducing Pertussis Vaccines. Infect. Immun.
68: 1383-1390
[Abstract][Full Text]
Heininger, U., Schmidt-Schläpfer, G., Cherry, J. D., Stehr, K.
(2000). Clinical Validation of a Polymerase Chain Reaction Assay for the Diagnosis of Pertussis by Comparison With Serology, Culture, and Symptoms During a Large Pertussis Vaccine Efficacy Trial. Pediatrics
105: 31e-31
[Abstract][Full Text]
Nygren, M., Reizenstein, E., Ronaghi, M., Lundeberg, J.
(2000). Polymorphism in the Pertussis Toxin Promoter Region Affecting the DNA-Based Diagnosis of Bordetella Infection. J. Clin. Microbiol.
38: 55-60
[Abstract][Full Text]
Ryan, E. J., McNeela, E., Murphy, G. A., Stewart, H., O'hagan, D., Pizza, M., Rappuoli, R., Mills, K. H. G.
(1999). Mutants of Escherichia coli Heat-Labile Toxin Act as Effective Mucosal Adjuvants for Nasal Delivery of an Acellular Pertussis Vaccine: Differential Effects of the Nontoxic AB Complex and Enzyme Activity on Th1 and Th2 Cells. Infect. Immun.
67: 6270-6280
[Abstract][Full Text]
Cherry, J. D., Olin, P.
(1999). The Science and Fiction of Pertussis Vaccines. Pediatrics
104: 1381-1383
[Full Text]
Abomoelak, B., Huygen, K., Kremer, L., Turneer, M., Locht, C.
(1999). Humoral and Cellular Immune Responses in Mice Immunized with Recombinant Mycobacterium bovis Bacillus Calmette-Guerin Producing a Pertussis Toxin-Tetanus Toxin Hybrid Protein. Infect. Immun.
67: 5100-5105
[Abstract][Full Text]
Salmaso, S., Tozzi, A. E., Atti;, M. L. C. d., Cherry, J. D.
(1999). Observer Bias in Acellular Pertussis Vaccine Trials. Pediatrics
104: 997-997
[Full Text]
Bruss, J. B., Siber, G. R.
(1999). Protective Effects of Pertussis Immunoglobulin (P-IGIV) in the Aerosol Challenge Model. CVI
6: 464-470
[Abstract][Full Text]
Lee, C.-Y., Thipphawong, J., Huang, L.-M., Lee, P.-I., Chiu, H.-H., Lin, W., Debois, H., Harrison, D., Xie, F., Barreto, L.
(1999). An Evaluation of the Safety and Immunogenicity of a Five-Component Acellular Pertussis, Diphtheria, and Tetanus Toxoid Vaccine (DTaP) When Combined With a Haemophilus influenzae Type b-Tetanus Toxoid Conjugate Vaccine (PRP-T) in Taiwanese Infants. Pediatrics
103: 25-30
[Abstract][Full Text]
Cherry, J. D., Heininger, U., Stehr, K., Christenson, P.
(1998). The Effect of Investigator Compliance (Observer Bias) on Calculated Efficacy in a Pertussis Vaccine Trial. Pediatrics
102: 909-912
[Abstract][Full Text]
Heininger, U., Cherry, J. D., Stehr, K., Schmitt-Grohe, S., Uberall, M., Laussucq, S., Eckhardt, T., Meyer, M., Gornbein, J., the Pertussis Vaccine Study Group,
(1998). Comparative Efficacy of the Lederle/Takeda Acellular Pertussis Component DTP (DTaP) Vaccine and Lederle Whole-Cell Component DTP Vaccine in German Children After Household Exposure. Pediatrics
102: 546-553
[Abstract][Full Text]
He, Q., Minh, N. N. T., Edelman, K., Viljanen, M. K., Arvilommi, H., Mertsola, J.
(1998). Cytokine mRNA Expression and Proliferative Responses Induced by Pertussis Toxin, Filamentous Hemagglutinin, and Pertactin of Bordetella pertussis in the Peripheral Blood Mononuclear Cells of Infected and Immunized Schoolchildren and Adults. Infect. Immun.
66: 3796-3801
[Abstract][Full Text]
Nilsson, L., Kjellman, N.-I. M., Bjorksten, B.
(1998). A Randomized Controlled Trial of the Effect of Pertussis Vaccines on Atopic Disease. Arch Pediatr Adolesc Med
152: 734-738
[Abstract][Full Text]
Mastrantonio, P., Stefanelli, P., Giuliano, M., Rojas, Y. H., Ciofi degli Atti, M., Anemona, A., Tozzi, A. E.
(1998). Bordetella parapertussis Infection in Children: Epidemiology, Clinical Symptoms, and Molecular Characteristics of Isolates. J. Clin. Microbiol.
36: 999-1002
[Abstract][Full Text]
Poulain-Godefroy, O., Mielcarek, N., Ivanoff, N., Remoue, F., Schacht, A.-M., Phillips, N., Locht, C., Capron, A., Riveau, G.
(1998). Bordetella pertussis Filamentous Hemagglutinin Enhances the Immunogenicity of Liposome-Delivered Antigen Administered Intranasally. Infect. Immun.
66: 1764-1767
[Abstract][Full Text]
Simondon, F., Iteman, I., Preziosi, M. P., Yam, A., Guiso, N.
(1998). Evaluation of an Immunoglobulin G Enzyme-Linked Immunosorbent Assay for Pertussis Toxin and Filamentous Hemagglutinin in Diagnosis of Pertussis in Senegal. CVI
5: 130-134
[Abstract][Full Text]
Mills, K. H. G., Ryan, M., Ryan, E., Mahon, B. P.
(1998). A Murine Model in Which Protection Correlates with Pertussis Vaccine Efficacy in Children Reveals Complementary Roles for Humoral and Cell-Mediated Immunity in Protection against Bordetella pertussis. Infect. Immun.
66: 594-602
[Abstract][Full Text]
Edwards, K., Adam, H. M.
(1998). Acellular Pertussis Vaccines. Pediatr. Rev.
19: 68-70
[Full Text]
Stehr, K., Cherry, J. D., Heininger, U., Schmitt-Grohe, S., Uberall, M., Laussucq, S., Eckhardt, T., Meyer, M., Engelhardt, R., Christenson, P., the Pertussis Vaccine Study Group,
(1998). A Comparative Efficacy Trial in Germany in Infants Who Received Either the Lederle/Takeda Acellular Pertussis Component DTP (DTaP) Vaccine, the Lederle Whole-Cell Component DTP Vaccine, or DT Vaccine. Pediatrics
101: 1-11
[Abstract][Full Text]
Mahon, B. P., Sheahan, B. J., Griffin, F., Murphy, G., Mills, K. H.G.
(1997). Atypical Disease after Bordetella pertussis Respiratory Infection of Mice with Targeted Disruptions of Interferon-gamma Receptor or Immunoglobulin µ Chain Genes. J. Exp. Med.
186: 1843-1851
[Abstract][Full Text]
Pichichero, M. E., Deloria, M. A., Rennels, M. B., Anderson, E. L., Edwards, K. M., Decker, M. D., Englund, J. A., Steinhoff, M. C., Deforest, A., Meade, B. D.
(1997). A Safety and Immunogenicity Comparison of 12 Acellular Pertussis Vaccines and One Whole-Cell Pertussis Vaccine Given as a Fourth Dose in 15- to 20-Month-Old Children. Pediatrics
100: 772-788
[Abstract][Full Text]
Committee on Infectious Diseases,
(1997). Acellular Pertussis Vaccine: Recommendations for Use as the Initial Series in Infants and Children. Pediatrics
99: 282-288
[Abstract][Full Text]
Mollnes, T. E., Harboe, M.
(1996). Recent Advances: Clinical immunology. BMJ
312: 1465-1469
[Abstract][Full Text]
Levine, M. M
(1996). The legacy of Edward Jenner. BMJ
312: 1177-1178
[Full Text]
(1996). ACELLULAR PERTUSSIS VACCINE: A NEW ERA FOR INFANTS. JWatch General
1996: 5-5
[Full Text]
Greco, D., Salmaso, S., Mastrantonio, P., Giuliano, M., Tozzi, A. E., Anemona, A., Ciofi degli Atti, M. L., Giammanco, A., Panei, P., Blackwelder, W. C., Klein, D. L., Wassilak, S. G.F., The Progetto Pertosse Working Group,
(1996). A Controlled Trial of Two Acellular Vaccines and One Whole-Cell Vaccine against Pertussis. NEJM
334: 341-349
[Abstract][Full Text]
Edwards, K. M., Decker, M. D.
(1996). Acellular Pertussis Vaccines for Infants. NEJM
334: 391-392
[Full Text]
Ellenberg, S. S., Foulkes, M. A., Midthun, K., Goldenthal, K. L.
(2005). Evaluating the Safety of New Vaccines: Summary of a Workshop. Am. J. Public Health
95: 800-807
[Abstract][Full Text]
A correction has been published: N Engl J Med 1996;334(18):1207.
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