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
Background. A household contact substudy was performed as part of a prospective, cohort pertussis vaccine efficacy trial in Germany.
Design. Infants received four doses of either the Lederle/Takeda acellular pertussis component diphtheria-tetanus toxoids (DTP) vaccine (DTaP) or Lederle whole-cell component DTP vaccine at 3, 4.5, 6, and 15 to 18 months of age (Wyeth-Lederle Vaccines and Pediatrics, Pearl River, NY). An open control group received three doses of diphtheria and tetanus toxoids vaccine (DT) at 3, 4.5, and 15 to 18 months of age. Vaccine efficacy rates were calculated using a number of principal and ancillary case definitions for primary, secondary, and noncases by analyzing secondary attack rates in study infants after exposure to pertussis in the household using 7- to 28- and 7- to 42-day postexposure observation periods and the inclusion and the exclusion of noncases who received macrolide antibiotics or trimethoprim-sulfamethoxazole during the exposure period.
Results. During a 3.5-year study period, 10 271 infants (DTP or DTaP, n = 8532; DT, n = 1739) were enrolled and actively followed along with all household members for cough illnesses. Depending on the case definition, 160 to 519 household exposures to pertussis were identified. In general, secondary attack rates in DT recipients were low and this was primarily because of the frequent use of antimicrobial prophylaxis. Using the principal case definitions and the exclusion of noncases who received macrolide antibiotics or trimethoprim-sulfamethoxazole during the exposure period and the 7- to 42-day observation period, the efficacy of DTP against cough illness of ≥7 days duration caused by Bordetella pertussis was 84% (95% confidence interval [CI] = 65–93) and that of DTaP was 58% (95% CI = 30–75). Using similar criteria, the efficacy against typical pertussis (≥21 days of cough with either paroxysms, whoop, or posttussive vomiting) was 94% (95% CI = 77–99) and 86% (95% CI = 62–95) for DTP and DTaP, respectively. The efficacy against any cough illness (with or without) laboratory confirmation was 54% (95% CI = 32–69) and 38% (95% CI = 13–56) for DTP and DTaP, respectively.
Conclusion. This household contact substudy within our cohort study, with active investigator-generated surveillance, was a severe test of vaccine efficacy. Both vaccines (DTP and DTaP) are better at preventing typical pertussis than mild illness. When case definitions similar to those in other recent trials are used, the Lederle/Takeda vaccine has an efficacy similar to other multicomponent DTaP vaccines.
- Bordetella pertussis
- acellular pertussis vaccine
- whole cell pertussis vaccine
- household contact
- vaccine efficacy
In December 1994, we completed a longitudinal cohort, vaccine efficacy trial in which infants were vaccinated with the Lederle/Takeda acellular pertussis component diphtheria-tetanus toxoids (DTP) vaccine (DTaP), Lederle whole-cell component DTP vaccine, or diphtheria and tetanus toxoids vaccine (DT). Cohort data including attack rates and multiple efficacy analyses from this trial have recently been published.1 Efficacy against laboratory confirmed Bordetella pertussis infection with cough ≥7 days was 83% and 72% for DTP and DTaP, respectively; when the clinical case definition was more stringent (requiring ≥21 days of cough with either paroxysms, whoop, or posttussive vomiting [PWV]), the efficacy point estimates increased to 93% for DTP and 83% for DTaP.
The attack rate for pertussis is known to be high with documented close exposure; therefore, household contact studies have been used to evaluate the efficacy of pertussis vaccines for more than 50 years.2–6 When active prospective surveillance is performed, the household contact technique is a severe test for a candidate vaccine. In our cohort efficacy trial, prospective clinical surveillance and laboratory study for illnesses caused byBordetella infections were performed on family members as well as vaccinees. This has allowed us to carry out a household contact efficacy investigation, which is the subject of this report. The objectives of this report are: 1) to compare DTP and DTaP vaccine efficacy as determined after household exposure with that determined in the cohort analysis using identical case definitions; and 2) to demonstrate the importance of case definitions (primary cases, household contact cases, and household contact noncases) in resulting efficacy determinations in household contact trials.
The overall methods of this trial have been presented elsewhere1 and will be summarized below; household contact specific information will be presented in depth.
Enrollment, Immunization Schedules, and Vaccines
The study was performed in 227 sites that were mainly pediatric office practices. From May 1991 through January 1993, healthy 2- to 4-month-old infants received a first dose of either DTaP or DTP in a double-blind, randomized manner or DT vaccine in an open arm of the trial after informed consent had been obtained from a parent. Second and third doses of DTaP and DTP were given at least 6 weeks after the preceding dose and the fourth dose at 15 to 18 months of age. DT recipients received a second dose at least 6 weeks after the first dose and the third dose at 15 to 18 months of age.
The Lederle/Takeda DTaP vaccine (Wyeth-Lederle Vaccines and Pediatrics, Pearl River, NY) contains 40 μg pertussis protein with ∼86% filamentous hemagglutinin (FHA), 8% toxoided pertussis toxin (PT), 4% pertactin, and 2% fimbriae-2 per dose (0.5 mL). It also contains 9.0 Lf diphtheria toxoid, 5.0 Lf tetanus toxoid, aluminum 0.23 mg, and thimerosal 1:10 000 per dose.
The DTP vaccine (Wyeth-Lederle Vaccines and Pediatrics) is formulated to contain ≥4 protective pertussis units, 12.5 Lf diphtheria toxoid, 5.0 Lf tetanus toxoid, 0.1 mg aluminum, and thimerosal 1:10 000 per dose (0.5 mL).
The DT vaccine was any product licensed in Germany.
Serum Collection and Case Ascertainment
Sera were collected from all DTaP and DTP vaccinees 1 month after the third and fourth doses and from DT recipients at the equivalent time points. To construct antibody kinetic curves, further serum specimens were collected at ∼3-month intervals from randomly preselected subsets of children in each vaccine group. Enzyme-linked immunosorbent assay values against specific B pertussisantigens from these serum samples served as references for diagnosis ofBordetella infection by analysis of a single serum at the time of an illness in a study participant.
All cough illnesses in a vaccinee or a household member were to be reported to the study physicians. In addition, all study families were telephoned by the individual study physicians or their office personnel every 2 weeks. If a cough illness of ≥7 days duration without improvement was reported in any household member, a nasopharyngeal specimen (NPS) for culture and an acute blood sample for serology were obtained. If the cough illness persisted for ≥14 days the vaccinee or family member was seen by one of three investigators from the Central Study Center (Erlangen, Germany). After a standardized history and physical examination were performed, the central investigator made a clinical diagnosis in 1 of 5 categories: definite pertussis, definite pertussis with a complication, probable pertussis, possible pertussis, or not pertussis.
Identified cough illnesses were monitored for illness duration and characteristics such as presence of PWV. Convalescent-phase blood samples were collected 6 to 8 weeks after the onset of illness. Per protocol, the follow-up period in a household started 2 weeks after the third dose in DTP and DTaP vaccinees and 2 months after the second dose in DT vaccinees and was continued until December 15, 1994.
Details of culture and polymerase chain reaction (PCR) methods have been previously presented.6,,7 Briefly, calcium alginate swabs were used for NPS collection and placed in Regan-Lowe transport medium. After overnight preincubation and shipment to the central laboratory in Erlangen the NPS was further processed on Regan-Lowe agar plates (Unipath/Oxoid, Wesel, Germany) and modified Stainer-Scholte broth. Suspicious colonies were identified as B pertussis or Bordetella parapertussis by oxidase reaction and specific fluorescent antibodies (Difco Laboratories, Detroit, MI). During the final year of the follow-up period of the trial, PCR was also used for diagnosis (performed by Dr. Gabriela Schmidt-Schläpfer in Basel, Switzerland). NPS for PCR were collected using a Dacron nasopharyngeal swab.
Immunoglobulin G and immunoglobulin A serum antibodies against PT, FHA, pertactin, and fimbriae-2 were determined by enzyme-linked immunosorbent assay at Wyeth-Lederle Vaccines and Pediatrics by a modification of the parallel line method8 as previously described.9–11 Microagglutination assays were performed in the Erlangen laboratory using B pertussis strain 460 as the antigen.8
The person with the earliest onset of cough in a household was designated the primary case. All family members with cough illnesses within 7 days of onset of the primary case were considered coprimary cases. Secondary cases included family members with cough onset 7 to 28 days and 7 to 42 days after the onset of illness in the primary case. Vaccinees (DTaP, DTP, and DT recipients) were eligible for analysis if they were not primary or coprimary cases.
In this trial, we analyzed data resulting from 4 definitions of primary cases, 5 definitions of secondary cases, and 3 definitions of noncases in exposed study children. The criteria for the principal analysis are presented in Table 1 and the criteria underlying the ancillary analyses are presented in Table 2.
Antibiotic usage in study children exposed to pertussis was not restricted by the study protocol and therefore, in accordance with clinical practice in Germany, antimicrobial agents frequently were given prophylactically. Because of this, separate analyses with all secondary case definitions were performed after removal of noncases who had received a macrolide or trimethoprim-sulfamethoxazole.
Estimates of vaccine efficacy and 95% confidence intervals (CI) were calculated as described by Orenstein et al.13Study participants who did not fulfill the definition for a case or a noncase were eliminated from specific analyses.
A total of 10 271 children were enrolled (DT, n = 1739; DTP, n = 4259; and DTaP, n = 4273) in this trial; 9938 study infants (97%) completed the primary series (DTaP/DTP, 3 doses; DT, 2 doses) and 9457 children (92%) received the reinforcing dose (DTaP/DTP fourth dose or DT third dose). During the follow-up period there were 1529 cough episodes among household members of study children. Of these, 160 were classified as primary cases as a result of B pertussis infection according to our principal case definition (Table 1). Using the ancillary primary case definition with expanded serologic criteria (primary case definition I, Table 2) there were 199 primary cases and with the clinical case definitions without and with laboratory confirmation (primary case definitions II and III, Table 2) the number of primary cases was 511 and 519, respectively.
In Fig 1 the distribution of secondary cases by time of onset after exposure is presented. Using the principal case definitions (Table 1) there were 41 cases of laboratory confirmedB pertussis infections in children who had a household exposure. Of these, 37 (90%) had a reasonable temporal relationship to the primary case (within 55 days) and 4 cases occurred 359 to 625 days after illness in the primary case; of those with a temporal relationship, 29 (78%) occurred within 28 days of exposure and 35 (92%) occurred within 42 days of exposure.
In Table 3 attack rates and DTaP and DTP vaccine efficacy point estimates against cough illness of ≥7 days duration caused by B pertussis infection using the principal efficacy analysis case definitions (Table 1) are presented; separate analyses were performed using the 7- to 28-day and 7- to 42-day postexposure observation periods. The attack rate in DT recipients was 32% and 47% for the 7- to 28-day and 7- to 42-day observation periods, respectively. DTaP vaccine efficacy for the 7- to 28-day and 7- to 42-day observation periods was 39% (95% CI = −23–70) and 55% (95% CI = 18–75), respectively. For the same observation periods, DTP vaccine efficacy was 71% (95% CI = 30–88) and 80% (95% CI = 54–92), respectively.
In Table 4, an analysis (attack rates and efficacy) similar to that in Table 3 is presented but all noncases who received macrolide antibiotics or trimethoprim-sulfamethoxazole after onset of cough in the primary case have been excluded. During the 7- to 28-day postexposure period, 40 participants are removed and during the 7- to 42-day postexposure period an additional 3 participants are removed. The use of prophylactic antimicrobial agents was more common in DT recipients (35%) than in DTP (20%) or DTaP (30%) vaccinees during the 7- to 42-day postexposure observation period. The removal of these prophylactically treated noncases results in a slight increase in the point estimates of efficacy for both vaccines. Using the 7- to 42-day postexposure period, the efficacy point estimate of DTaP vaccine increased from 55% to 58% and that of DTP vaccine from 80% to 84%. There is, however, a marked increase in the attack rate in DT recipients. In DT recipients the attack rate increased from 47% to 73%. In DTP and DTaP vaccinees the increases were from 9% to 12% and 21% to 30%, respectively. The use of macrolide antibiotics or trimethoprim-sulfamethoxazole among secondary cases was also analyzed. Of the 11 and 16 cases among DT recipients for the respective 7- to 28-day and 7- to 42-day observation periods, 7 (64%) and 10 (63%), had received a macrolide or trimethoprim-sulfamethoxazole between onset of exposure and the end of the observation period. However, for the 7- to 28-day observation period in only 1 of the 11 cases was use of antimicrobials started before onset of symptoms. Of the 5 additional cases among DT recipients in the 7- to 42-day observation period, 1 had received antimicrobial prophylaxis. The percentage of antimicrobial use among DTP vaccinees was 17% for both observation periods as compared with 25% (7 to 28 days) and 31% (7 to 42 days) in DTaP vaccinees. There was no prophylactic use of antimicrobials reported in DTP or DTaP recipients after household exposure.
Using the 7- to 42-day exposure period and the exclusion of noncases who received macrolides or trimethoprim-sulfamethoxazole, we examined vaccine efficacy for the time periods before and after the booster dose. With the principal case definitions, DTP efficacy before the fourth dose was 76% (95% CI = 45–90) and after the fourth dose it was 91% (95% CI = 66–98). The corresponding figures for DTaP were 60% (95% CI = 15–81) and 55% (95% CI = 15–76), respectively.
We observed the effect of antimicrobial use (macrolides or trimethoprim-sulfamethoxazole) in primary cases on efficacy. Of the 160 family exposure situations, antimicrobial use occurred in 62 (39%) of the primary cases. This antimicrobial use was most common in primary cases in which the vaccinee received DT (71%) compared with 22% and 39% in DTP and DTaP situations. The use or nonuse of antimicrobials in primary cases had no significant effect on the attack rate in DT vaccinated children or on vaccine efficacy.
In Table 5, DTP and DTaP vaccine efficacy against typical pertussis (≥21 days of PWV) because of B pertussis is presented. Using this secondary case definition, the prophylactic use of antimicrobial agents had minimal effect on vaccine efficacy. Ignoring use of antimicrobial agents in exposed study children, efficacy rates were 84% for DTaP and 93% for DTP; when participants with use of antimicrobial agents were excluded, the corresponding figures were 86% and 94%.
In addition to the analyses presented in Tables 3–5, all other possible combinations of primary, secondary, and noncase definitions were analyzed. When both observation periods (7 to 28 days and 7 to 42 days) and the inclusion or exclusion of noncases in which antimicrobial agents had been used prophylactically are included there are an additional 234 possible efficacy calculations for each vaccine. However, because many of the primary, secondary, and noncase combinations result in only minimal differences in efficacy, only data for selected important combinations are presented in Table 6 using the 7- to 42-day observation period and the exclusion of noncases who received macrolides or trimethoprim-sulfamethoxazole.
In Table 6, efficacy against cough illness of ≥7 days duration with laboratory confirmation using 2 primary, 1 secondary, and 2 noncase definitions is presented. When the primary and secondary case definitions include all serology (ancillary I and ancillary I) the efficacy of both vaccines is decreased compared with values presented in Table 4. The decrease is more marked in DTP recipients than in DTaP recipients. DTP vaccine efficacy decreased from 84% to 70% whereas DTaP decreased from 58% to 51%. The use of the ancillary II noncase definition, in which exposed children with any respiratory illness not meeting the case definition are removed from the data set, results in lower vaccine efficacy values in all comparisons.
Using a clinical definition as well as a laboratory-confirmed definition for the primary case (ancillary III) increases the number of primary cases from 117 (Table 4) to 387 (Table 6) but the calculated efficacy for either vaccine is only minimally affected.
In the analysis of laboratory confirmed typical pertussis (≥21 days of PWV) the inclusion of any serology (PT, FHA, pertactin, fimbriae-2, or agglutinins) for the diagnosis of the primary cases or the secondary cases had no appreciable effect on the efficacy point estimates for either vaccine (Table 5 versus 6). The removal of noncases with any respiratory illness not meeting the secondary case definition results in a lowering of vaccine efficacy; this effect is more marked in DTaP recipients than in DTP recipients.
The efficacy of DTP and DTaP against any cough illness with or without laboratory confirmation using 2 primary case definitions and 2 noncase definitions is also presented in Table 6. As can be seen in comparison with the data in Table 4 the reduction in efficacy with the use of this clinical definition for secondary cases is more marked in DTP vaccine recipients than in DTaP vaccine recipients. In all instances (Table 6) the percentage of exposed children with cough illnesses not meeting the secondary case definitions is greater in DTP and DTaP vaccinees than it is in DT recipients.
Fine14 and Fine and colleagues4,,5have pointed out that the point estimates of vaccine efficacy vary considerably based on case definitions and many other facets of study design and analysis. This is evident in recent trials with acellular pertussis vaccines in which household contact analyses has been performed.15–21 In addition to our trial, household contact subanalyses were performed in only two other cohort efficacy trials in which laboratory analysis included serologic evidence of infection as well as culture positivity.17,,20,22,23 Of these three trials ours is unique in that detection of possible cases was investigator determined prospectively (telephone calls every 2 weeks) in addition to parent reporting.1,,22,23
In our trial, we have considered a total of 240 variations in study criteria. Using different criteria, point estimates for DTaP vaccine efficacy varied from 31% to 86% and for DTP vaccine from 36% to 94%.
At the present time there is no scientifically established time period for case inclusion or exclusion for household contact studies. In most studies, a 28- to 30-day exposure window has been used and this was presumably based on knowledge of the case to case interval during pertussis outbreaks.2–4,6,15,17,19,21,24 However, the frequency distribution of cases by week after exposure as demonstrated by Fine and associates5 indicates that approximately one-third of cases have their onset >28 days after exposure. In our trial (Fig 1), 78% of cases occurred within 28 days of exposure and 92% within 42 days of exposure. Based on these data it is our opinion that the 42-day exposure period and not lesser intervals should be used in household contact analyses.
Although it was demonstrated more than 20 years ago that erythromycin administration was effective in preventing secondary cases of pertussis25 and this observation was confirmed on several occasions more recently,26–29 it is surprising that the use of erythromycin and other effective antimicrobial agents have not been considered more carefully in the analyses of household contact studies. In our trial, we were initially concerned with the low attack rate in DT recipients (Table 3). However as can be seen (Table 3 versusTable 4) this low attack rate was attributable to macrolide or trimethoprim-sulfamethoxazole use. The attack rate of 73% (Table 4) and 81% (Table 6) observed when noncases who received macrolide antibiotics or trimethoprim-sulfamethoxazole were excluded is consistent with data from the preantibiotic era.2,,3 In three recent household contact efficacy analyses of acellular pertussis vaccines, the attack rate in unvaccinated children was 85% in the Stockholm trial,20 56% to 65% in the Mainz trial,15 and 92% in the Götenborg trial.17 In the latter trial it was pointed out that prophylactic antimicrobials were not used; whereas in the former two trials the use of prophylactic antimicrobials was not mentioned.
In a separate analysis in the Mainz trial, it was noted that antimicrobial treatment of the primary case led to a decreased attack rate in unvaccinated contact study participants.30 Similar findings were reported by Onorato et al6 and vaccine efficacy against typical pertussis was higher in the subgroup in which primary cases had been treated with erythromycin. In our trial the use of antimicrobial agents in primary cases had no significant effect on the attack rate in DT vaccinated recipients nor on vaccine efficacy. In recent years it has been noted that the spectrum of clinical manifestations of B pertussis infections in unvaccinated children is broad and that a significant percentage of cough illnesses last for 3 weeks or less.7,,31 It has also been recognized that protection induced by pertussis vaccines is to a large measure quantitative rather than qualitative.4 This fact is clearly demonstrated in four of the recent efficacy trials utilizing cohort design.1,,22,23,32 In our cohort analysis, efficacy of the DTaP vaccine decreased from 83% to 73% when mild cases (<21 days of cough) were included in the analysis.
In household contact studies, the usual practice is to count all children with symptoms who do not meet the case definition as noncases. This has been of concern to us because the practice tends to inflate efficacy (Table 6). For each analysis category (primary case and secondary case definitions) in Table 6 it is noted that using the ancillary II noncase definition results in removal of a greater percentage of DTP and DTaP recipients than DT vaccinees. This indicates that a significant number of those removed from the DTP and DTaP groups are in fact children with mild pertussis and not children suffering from unrelated respiratory illnesses. The removal of these children from the data set universally decreases the calculated vaccine efficacy for both vaccines. These findings make a strong case for using any cough illness regardless of laboratory confirmation for the secondary case definition. It is likely that the true efficacy of the two pertussis vaccines in this trial against B pertussis-induced cough illness is in the range of 50% to 54% for DTP and 31% to 38% for DTaP.
A comparison of determined efficacy for selected important case definitions in the cohort and household contact analyses is presented in Table 7. As can be seen, the efficacy of DTP vaccine is almost identical in the two studies when the B pertussis-specific laboratory criterion is used. For typical pertussis, the efficacy of DTaP vaccine is also similar. However, when mild B pertussis-induced illnesses are included the point estimate of DTaP is lower in the household contact study compared with the cohort analysis. This difference is most likely because of a greater opportunity for observer bias in the whole cohort as compared with the more closely observed household contact group.33
During our trial there was considerable illness caused by B parapertussis as well as B pertussis in study participants.1,,33 In our cohort analysis we found that DTaP but not DTP had modest efficacy against illness caused by B parapertussis. However when serologic criteria included significant antibody responses to antigens other than PT that could occur in B parapertussis infections the calculated efficacy decreased for both vaccines. This decrease was more pronounced in DTP vaccinees. In the present household contact analysis similar findings are noted.
Previously a Japanese DTaP vaccine with the same Takeda acellular pertussis component as that in the Lederle/Takeda vaccine was analyzed for its efficacy in a household contact study.19 This study in Japan was a predominantly retrospective study and the majority of the diagnoses in primary or secondary cases were not laboratory confirmed. Reported efficacy against typical pertussis was 98% (95% CI = 84–99) and against all illnesses 81% (95% CI = 64–90). These efficacy estimates are substantially higher than those observed in our present trial as well as the results in our cohort analyses. These different findings indicate the shortcomings of retrospectively as compared with prospectively obtained data.
In summary, this household contact substudy within our cohort study, with active investigator generated surveillance, was a severe test of vaccine efficacy. It is clear that both vaccines (DTP and DTaP) are better at preventing typical pertussis than mild illness. It is unfortunate that in other recent trials the World Health Organization clinical case definition (≥21 days of paroxysmal cough) was used as the primary case definition because this leads to less careful observation of mild illnesses (observer bias) and therefore overestimates efficacy.34 When case definitions similar to those in other trials were used and allowances were made for observer bias the Lederle/Takeda vaccine has an efficacy similar to other multicomponent DTaP vaccines and the Lederle whole cell component DTP vaccine has greater efficacy than the DTP vaccine evaluated in Sweden and Italy.1,,23,32
This study was sponsored by Wyeth-Lederle Vaccines and Pediatrics, Pearl River, New York.
We thank the staff of Wyeth-Lederle Praxis Vaccines and Pediatrics and Quintiles Ltd and to the Study Advisory Board for their contributions to this trial. The laboratory assistance by Carmen Lorenz and Regina Rost and the secretarial assistance of Ilse Reiff, Ingeborg Boatey, Gerlind Baierlacher, Monika Reissinger, Jutta Heinrich, and Sheila Walton is highly appreciated.
The Pertussis Vaccine Study Group consists of: W. Müller, Augsburg; A. Neugebauer, Neusäβ; K. Sailer, Augsburg; H. Keller, Aschaffenburg; U. Kircher, Gersfeld/Rhön; B. Netzel, München; H. Sachsenhauser-Kratzer, Mering; M. Thelen, Planegg; B. and K. E. Buck, Ottobrunn; G. Nath, Krumbach; E. Clapier, Landsberg/Lech; P. Gelius, Marktredwitz; B. Graf zu Castell, Kaufering; H.-J. Hess, Freyung; E. Maas-Doyle, Erlangen-Tennenlohe; H. P. R. Mayer, Bamberg; K. Renner, Marktoberdorf; I. Seltsam, Gemünden; G. Seuwen, Kempten/Allgäu; N. Totzauer, Münchberg; A.-M. Zange, München; I. Bernsau, Stadtbergen; W. Knipping, Ottobrunn; Ch. Neumayer, Dachau; G. Salzer, Regensburg; R. E. Ullner, Dorfen; G. Bergen, Haβfurt; J. Haselhuber, Landshut; N. Herrmann, Ansbach; U. John-Grafe, Steinbach/W.; M. Kaiser, Augsburg; H. Lehn, Dachau; M. Mayer, Würzburg; G. Pitz, Kempten/Allgäu; H. Preidel, Olching; P. Schäffler, Baldham/München; H. Schweppe-Nickl, Postbauer-Heng; H.-Ch. Sengespeik, München; Th. Hangen and W. Geltinger, Landshut; A. Angst, Kaufbeuren; L. Boctor, Erlangen; H. Lichtenstern, Pocking; M. Pieringer, Regensburg; H. Reploh, Bad Tölz; A. Vahle, Landshut; G. Börzsönyi, Freising; R. Haas, Rosenheim; K.-H. Leppik and W. Eberhardt, Erlangen; D. Woiczechowski, Tirschenreuth; E. Berz, München; G. Dorn, C. Hager, Ingolstadt; G. Grundherr, Wasserburg/Inn; U. Janssen, Höchberg; Chr. Brückmann, Brannenburg; J. Lussem-Spanel, Dillingen; K. Müller, Bamberg; F. Engelhardt, Nürnberg; W. Pritsch, Kötzting; A. Rudolph, Lichtenfels; I. Tichmann-Schumann and R. Wörnle, München; C. Förster, Neustadt/Cbg.; J. Gaisbauer, Simbach/Inn; I. Hiller, Fürth; U. Lindlbauer-Eisenach, München; T. Kandler and A. Rühl, Nürnberg; R. Benckendorff, Augsburg; J. Helming and H. Singer, Ingolstadt; E. Judex, Regensburg; H. Kollaschinski, Marktredwitz; P. Lautenbach, Herzogenaurach; J. Lehmann, Immenstadt/Allgäu; G. Lysy, Herzogenaurach; A. Neudecker, Mühldorf; R. Schalkhäuser, Ochsenfurt; H. Schilling, Freystadt; H. A. Schmitz, Obing; F. Scholz, Deggendorf; V. Treu, Karlsfeld; G. B. Vit, Schweinfurt; U. Werner-Jung, Kemnath-Stadt; D. Derbacher, Zirndorf; L. Distel, Neustadt/Aisch; U. Klein, Oberaudorf; Ch. Miller, Frauenau; H. Reiniger, Kirchheim-Heimstetten; K.-H. Weigand, R. Müller and U. V. Eichhorn, Deggendorf; A. Busse, Tegernsee; W. Hiemeyer, Kempten/Allgäu; M. Miedaner, Elisabethszell; A. Schneider, Schweinfurt; W. Schuck, Laufach; D. Schweingel, Bayreuth; B. Simon, München; Chr. Sturm, Memmingen; C. Wittermann, Weilheim; W. Stahl, Nürnberg-Eibach; P. Tcherepnine, Roding; W. Müller, Hof; D. Müller-Bühl and R. Ringert, Alzenau; Chr. Dittmann, Mering; S. and I. Habash, Cham; W. Kunz and K. Skrodzki, Forchheim; E. Lippoldmüller, München; J. Mugler, Fürth; M. Schimmer, Hauzenberg; L. Tenderich, Augsburg; U. Heininger, Erlangen; W.-D. Klaiber, Lindau; E. Preissler and W. Theil, Gersthofen; U. Zimmer, Rothenburg o.d.T.; P. Peller, Rosenheim; W. Winter, Dentlein; G. Akinlaja, Schweinfurt; H.-L. Eschenbacher and R. Ulmer, Lauf/Peg.; S. Jobst and H. G. Schatz, Bayreuth; A. and A. Biebl, Barsbüttel; M. Hummel, Irchenrieth; N. Pauly and L. Zimmermann, Aichach; H.-Chr. Kuderna, Aichach; U. Schamberger, Coburg; U. Schreiner, Oberaurach-Unterschleichach; G. Fuhrmann, München; U. Goering, Pegnitz; K. H. Walther, Frankfurt; S. and P. Duttler, Biberbach; R.-P. Garus, Schwabmünchen; W. von Gloeden, Erlangen; R. Schipper, Monheim; J. Mücke, St. Ingbert; M. Schmidt, Nürnberg; F. Abid, Saarbrücken; H. and H. G. Holzner and W. Harr, Königsbronn; A. Schaaff, Eckental-Eschenau; M. Steiner, Saulgau; F. J. Breyer, St. Ingbert; W. Weidner, H. P. Fritz, Weingarten; W. Heffungs, Meckenbeuren; E. Heitz, Bad Waldsee; B. Höhmann, Aalen; K. Jessenberger, Berlin; K.-E. Mai, Tettnang; A. Olischläger, Biberach an der Riβ; B. Seitz, Traben-Trarbach; K. T. Weber, Berlin; A. Ziegler, Augsburg; F. Beer, Markdorf; R. Besser, Kempten; I. Göpfert-Geyer and M. Plieth, Berlin; R. Kratzsch, Nürnberg; F. Maechler, Berlin; Th. Rautenstrauch, Haar/München; K. H. Staudacher, Weingarten; U. Bernsau, Augsburg; P. Brommer, Tann; D. Bulle and W. Raff, Ravensburg; W. Daffner, Nürnberg-Langwasser; G. Grötzinger, Pfaffenhofen; H. Keudel, Unterhaching; R. J. Kühnelt, Berlin; H. Muth, Berlin; W. Pintgen, Geretsried; U.-B. Rupf, Uhlendingen; Ch. Scheurle, Ravensburg; R. Spallek, Bad Wurzach; G. Thomas, München; K.-J. Taube, Berlin; G. Behr-Heinz and S. Heiland, Friedrichshafen; W. Deigendesch, Metzingen; E. Gimpl, Schweinfurt; H. Hilber and A. Freilinger, Au/Hallertau; Th. Morandini, Schönenberg-Kübelberg; D. Schlegel, Welzheim; F. C. Sitzmann, Homburg/Saar; R. Till, Amberg; E. Reiser, Isny/Allgäu; N. Schmidt, Schongau; P. Seidl, Waldkirchen; J. Zimmer, Ehingen; R. Freund, Berlin; H. Litzenbörger, Berlin; D. Lasius, Berlin; E. Dietmair, W. Wagner and P. Wörle, Bobingen; E. Göhre, Berlin; D. Grunert, Nördlingen; M. Rottmann, Stuttgart; E. Schubert, Roth; P. Seyyedi, Lampertheim; A. Steigenberger, Vilsbiburg; J. Gromball and R. Reif, Nürnberg; K. Kirsten, Ettenheim; Chr. Schaefer, Göppingen; L. and J. Viethen, Berchtesgaden; E. Zöller, Idar–Oderstein; D. Kahn, F. Schulze and S. Schartl, Berlin; E. Eidelloth, Lindenberg; A. Renz, Bermatingen; P. Wolff, Pfullendorf; F. Puls, Friedrichshafen; R. Faul, Stuttgart; B. Koch, Ebersberg; W. Conzelmann, Urbach; M. Müller, Ulm; H.-W. Klopp and U. Lorenz, Winterbach; J. Brunnberg, Würzburg; F. Ditlmann, Augsburg; J. Altmann, Immenstadt; K.-W. Weigel, Karlstadt; K.-P. Groβe, Höchstadt/Aisch; P. Treitz, Püttlingen; U. Behre and A. Burgert, Kehl; F. Ladwein, Saarlouis; J. Lauenstein, Lebach; W. Wahlen, M. Büttner and J. Richter, Homburg/Saar; K. Y. Tjhen, Rottenburg; H. Treib, Bous; J. Disselhoff, Offenburg; H.-P. Niedermeier, Erding; G. Stiepani and W. Gröner, Ravensburg; R. Krämer, Illingen; G. Lück-Coerper, Saarlouis; H.-D. Hüwer, Langenselbold; G. Ulbricht and U. Fegeler, Berlin; E. Schrickel, Murnau; M. Walther-Richters, Meitingen; R. Wörrlein and G. Kottsieper, Ansbach; B. Kostadinowa and Th. Unger, Berlin; K. B. Karsten, Dillingen; and the pilot study contributors: P. Jakob, Erlangen; and W. Kasper, Erlangen.
- Received December 30, 1997.
- Accepted March 2, 1998.
Reprint requests to (J.D.C.) Division of Pediatric Infectious Diseases, UCLA School of Medicine, 10833 Le Conte Ave, Los Angeles, CA 90095-1752.
- DTaP =
- diphtheria-tetanus toxoids, acellular pertussis vaccine, adsorbed •
- DTP =
- diphtheria-tetanus toxoids, whole cell pertussis vaccine, adsorbed •
- DT =
- diphtheria and tetanus toxoids vaccine •
- NPS =
- nasopharyngeal specimen •
- PWV =
- paroxysms, whoop, or posttussive vomiting •
- PCR =
- polymerase chain reaction •
- PT =
- pertussis toxin •
- FHA =
- filamentous hemagglutinin •
- CI =
- confidence interval
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- Copyright © 1998 American Academy of Pediatrics