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The new acellular pertussis vaccine combined with diphtheria and tetanus toxoids (DTaP) appears to confer comparable immunity and result in fewer adverse side effects than the traditional whole-cell pertussis combination (DTwP). A total of 1,293 children receiving their fourth dose of vaccine were given either a US-licensed DTwP or one of 12 different DTaP preparations. Some of the children had had DTwP for their first boosters, while others had always been given DTaP. In general, the DTaP vaccine resulted in fewer side effects and similar antibody responses, regardless of the previous vaccine type., ABSTRACT. Objective. To compare the safety and immunogenicity of 12 different acellular pertussis vaccines combined with diphtheria and tetanus toxoids (DTaP) with one licensed diphtheria, tetanus, and whole-cell pertussis vaccine (DTwP) as a fourth-dose booster in children who had previously received DTaP or DTwP primary vaccinations. Methods. Healthy 15- to 20-month-old children were enrolled at six National Institutes of Health Vaccine Treatment and Evaluation Units. All had been randomly assigned to receive three primary doses of DTaP or DTwP at 2, 4, and 6 months of age as part of an earlier National Institutes of Health multicenter trial of DTaP vaccines in the same Vaccine Treatment and Evaluation Units. Parents recorded the occurrence and magnitude of fever; irritability; and injection site redness, swelling, and pain for 3 days after vaccination. Sera obtained before and 1 month after the booster vaccination were analyzed for antibody to pertussis toxin (PT), filamentous hemagglutinin (FHA), fimbriae (FIM), and pertactin (PRN). Diphtheria and tetanus toxoid as well as PT neutralizing (Chinese hamster ovary cell) and whole-cell agglutinating antibodies were measured on a subset of sera. Results. A total of 1293 children contributed fourth-dose reaction data. Reactions were less frequent after DTaP than after DTwP. For children vaccinated with a fourth dose of DTaP, which was the same DTaP as received in the primary series, fever and injection site redness, swelling, and pain increased in prevalence compared with the third dose in the primary series. For children receiving DTaP as a fourth dose, injection site redness and swelling occurred more frequently in DTaP-primed than in DTwP-primed children. Variation in the occurrence of reactions among DTaP vaccines was observed. A total of 1160 paired pre- and postvaccination sera were available for analysis. Serum antibody concentrations before boosting were lower than those obtained 1 month after the primary immunization. After the fourth dose, significant increases in antibodies directed against the included antigens were observed for all vaccines; postbooster vaccination antibody titers differed significantly among the DTaP vaccines. For children primed and boosted with the same DTaP, antibody levels were not directly related to the quantity of antigen included for PT, FHA, and FIM; for PRN, there was a closer relationship. Some DTaP vaccines given as fourth-dose boosters elicited antibody to PRN or FIM in some vaccinees, although the DTaP vaccines were not reported to contain these antigens; these responses were observed more frequently in DTwP-primed children. Agglutinin antibody rises were observed in all groups immunized with four doses of a DTaP vaccine containing FHA or PRN, regardless of whether the vaccine included FIM. Diphtheria and tetanus antibody levels exceeded the presumed protective concentration (0.1 IU/mL for diphtheria and 0.01 IU/mL for tetanus) after the fourth dose for all vaccinees. Conclusion. Although differences were observed in reaction rates among the DTaP vaccines given as a fourth dose, the DTaP vaccines were, in general, associated with fewer adverse events than a US-licensed DTwP. For DTaP vaccines, fever; irritability; and injection site pain, redness, and swelling occurred more frequently after the fourth dose than after the third dose of the same vaccine in the primary series. No DTaP was consistently most or least reactogenic or immunogenic. Although serologic correlates of pertussis immunity are not defined, it is clear that most DTaP vaccines can stimulate comparable or higher serum antibody responses than DTwP for those antigens contained in the vaccine., Pediatrics 1997;100:772-788; acellular, adverse reactions, antibody, diphtheria-tetanus-pertussis vaccine, pertussis vaccine, whole cell, whooping cough. ABBREVIATIONS. DTaP, diphtheria and tetanus toxoids combined with acellular pertussis vaccine; DTwP, diphtheria and tetanus toxoids [...]

The new acellular pertussis vaccines appear to be more effective at inducing an immune reaction than the conventional whole cell vaccine. A group of 1,942 infants were randomly assigned to receive their regular series of three diphtheria-pertussis-tetanus immunizations with one of 13 varieties of acellular pertussis vaccine or the conventional whole cell vaccine. The new vaccines used one or more of four protein components of Bordetella pertussis, the bacterium that causes whooping cough, to stimulate antibody formation. All vaccines stimulated antibodies against the proteins contained in the vaccine. In most cases, antibody levels exceeded amounts formed in response to the whole-cell vaccine. All vaccines produced sufficient antibody levels to diphtheria and tetanus as well. Antibody levels against pertussis components differed among the 13 acellular vaccines, but whether these differences are important is unknown., Objective. To compare the immunogenicity of a licensed conventional whole-cell (WCL) and 13 diphtheria-tetanus-acellular pertussis (DTaP) vaccines that differed in source, method of manufacture, and included antigens; all vaccines included diphtheria and tetanus toxoids. Methods. Healthy infants were enrolled through six university-based vaccine and treatment evaluation units and were randomized to receive one of the study vaccines at 2, 4, and 6 months of age. Sera were obtained before the first immunization and 1 month after the third immunization and were analyzed for antibody to pertussis toxin (PT), filamentous hemagglutinin, fimbriae, pertactin, and diphtheria and tetanus toxins. Chinese hamster ovary cell toxin neutralization assays were performed, and levels of agglutinating antibodies were determined. Results. Of 2342 infants enrolled, 1942 contributed usable preimmunization and postimmunization serum specimens. Each vaccine produced significant increases in antibodies directed against the included antigens; postimmunization antibody titers differed significantly among the DTaP vaccines. For each evaluated antigen, the majority of DTaP vaccines produced antibody responses that equaled or exceeded those produced by WCL. For some antigens (eg, PT), mean antibody levels by vaccine correlated poorly with the quantity of antigen included in each vaccine; for others (eg, fimbriae), there was a close correlation. Conclusion. Although serologic correlates of pertussis immunity are not defined, it is clear that DTaP vaccines can stimulate immune responses that exceed those of licensed whole-cell vaccine with respect to the measured antibodies. Particularly for PT, immunogenicity seems to depend on factors in addition to antigen concentration, possibly including antigen derivation and formulation. No DTaP was most or least immunogenic with respect to all included antigens. Pediatrics 1905,96:548-557; acellular, antibody, diphtheria-tetanus-pertussis, pertussis, vaccine, whole-cell, whooping cough., ABBREVIATIONS. DTP, diphtheria and tetanus toxoids combined with whole-cell pertussis vaccine; PT, pertussis toxin/toxoid; FHA, filamentous hemagglutinin; FIM, fimbrial protein; PRN, pertactin; DTaP, diphtheria and tetanus toxoids combined with acellular [...]

Functional assays of antibody activity and enzyme-linked immunosorbent assays (ELISAs) of pertussis vaccine-induced antibodies correlate well enough with each other that it does not appear necessary to perform both types of tests. Blood samples for the comparisons were taken from infants participating in a clinical trial of the effectiveness of 13 new acellular pertussis vaccines, which use one or more protein components of the pertussis bacteria, and two standard whole-cell pertussis vaccines. ELISA results for four protein components were compared with results from the two functional assays. Results from one of the two assays were strongly associated with the ELISA results for pertussis toxin. Results from the other functional assay were strongly associated with the ELISA results for fimbrial protein. One type of vaccine that lacked fimbrial protein also responded strongly to this second assay. This vaccine had a particularly strong pertussis toxin response, suggesting there may be some crossover response., Objective. To examine the relationships between functional assays and antigen-specific enzyme immunoassays in sera from a multicenter trial of 13 different experimental acellular pertussis vaccines and 2 licensed whole-cell vaccines, and to determine whether correlations previously observed among assays of specimens from pertussis patients and whole-cell vaccines would apply to specimens from infants immunized with purified components in acellular vaccines. Methods. Postimmunization sera were assayed for immunoglobulin G antibodies to pertussis toxin (PT), filamentous hemagglutinin, pertactin (PRN), and a mixture of types 2 and 3 fimbriae (FIM) by enzyme-linked immunosorbent assay, for whole-cell agglutinins (AGGs) and for PT-neutralizing antibodies by the Chinese hamster ovary (CHO) cell assay. Assay results were compared for individual sera, as well as for geometric mean antibody concentrations or titers (GMTs) calculated by vaccine or overall. Results. For the 15 vaccines, the PT GMTs were highly correlated with the CHO assay GMTs (r = .92), and the FIM GMTs were highly correlated with the AGG GMTs (r = .96). For individual postvaccination sera, there was a significant correlation between the CHO titers and levels of antibody to PT whether the 15 vaccines were considered separately (.59 [less than or equal to] r [less than or equal to] .85) or combined (r = .81). For individual sera from infants immunized with the two whole-cell vaccines or any of the four acellular vaccines containing FIM, a strong correlation between AGG titer and FIM antibody was observed whether the vaccines were considered separately (.83 [less than or equal to] r [less than or equal to] .91) or together (r = .86). One vaccine without detectable FIM produced a measurable AGG response; for this vaccine, a moderate but significant correlation (R = .58) between PRN antibody and AGG titer was observed. Conclusion. These data indicate that appropriate antigen-specific enzyme-linked immunosorbent assays will furnish results similar to those provided by the CHO and AGG assays in the evaluation of the immunogenicity of component vaccines. Antibodies to FIM seem to include the most important AGGs; however, there is evidence that agglutination by PRN antibody may be detected in the absence of antibody to FIM. Pediatrics 1995;96:595 600, antibody, assay, diphtheria-tetanus-pertussis, pertussis, vaccine., ABBREVIATIONS. ELISA, enzyme-linked immunosorbent assay; CHO, Chinese hamster ovary; PT, pertussis toxin; IgG, immunoglobulin G; FHA, filamentous hemagglutinin; PRN, pertactin; FIM, fimbrial protein; AGG, agglutinins; DTP, diphtheria and tetanus toxoids [...]

The assays used to determine immune response to pertussis vaccination appear to provide similar results at different laboratories and with repeated tests of the same sample. This means that research data measuring such responses is reliable. Antibody response to four protein components of the pertussis-causing bacterium was evaluated in a large, multicenter trial of the effectiveness of 13 new types of pertussis vaccine versus two types in standard use. During that trial, 10% of blood samples were retested at another laboratory using the same techniques. Analysis of the reagents found that assays were accurately measuring antibody response to those four specific proteins. Repeated assays of the same sample gave results similar enough to be within the bounds of tolerance for the study., Objective. To describe and evaluate the assays used to measure the antibody responses in infants to 13 experimental acellular pertussis vaccines and 2 licensed whole-cell pertussis vaccines. Methods. During a 53-week period, preimmunization and postimmunization sera were assayed for immunoglobulin G antibodies to pertussis toxin, filamentous hemagglutinin, pertactin, and a mixture of type 2 and type 3 fimbriae by enzyme-linked immunosorbent assay (ELISA), for whole-cell agglutinins (AGG), and for pertussis toxin-neutralizing antibodies by the Chinese hamster ovary cell assay. All ELISA reagents were characterized to assure antigen and isotype specificity of the assays. Intralaboratory reproducibility and temporal stability were evaluated by analysis of results of control sera and by assessment of the response to the control whole-cell vaccine. Interlaboratory reproducibility was assessed by repeating the assays on preimmunization and postimmunization sera for 10% of the infants in a second laboratory. Results. For control sera having antibody concentrations at least four times the minimum level of detection, the coefficients of variation within and between the ELISAs consistently were less than 20%. Trend analysis indicated that none of the assays drifted by more than 20% during the study period, and no significant drift was seen in the response to the control whole-cell vaccine. Results from the two laboratories correlated well; correlation coefficients were .93 or greater for the four ELISAs, .79 for the Chinese hamster ovary cell assay, and .82 for the AGG assay. For four of the six assays, there was either no difference or a modest (, ABBREVIATIONS. Ig, immunoglobulin; PT, pertussis toxin; FHA, filamentous hemagglutinin; PRN, pertactin; FIM, fimbrial protein; ELISA, enzyme-linked immunosorbent assay; AGG, agglutinin(s); CHO, Chinese hamster ovary; EU, ELISA unit; MLD, minimum level [...]

Giving a vaccination against Haemophilus influenzae Type b (Hib) at the same time as a new type of pertussis vaccine does not appear to interfere with the effectiveness of the pertussis vaccine or increase its side effects. Partway through a large, multicenter trial comparing 13 new types of pertussis vaccine with two standard types, the Hib vaccine was introduced. Therefore, some children received the Hib vaccine at the same visit as one of their diphtheria-pertussis-tetanus (DPT) immunizations. This allowed a comparison of effects between children receiving Hib and children who did not. The Hib vaccine had no consistent effect on antibody levels to protein components of the pertussis-causing bacterium., Objective. To evaluate the effect of simultaneous Haemophilus influenzae type b conjugate (Hib) vaccination on the safety and immunogenicity of selected acellular (DTaP) and whole-cell (DTP) pertussis vaccines with diphtheria and tetanus toxoids combined. Methods. Enrollment of infants into a large multicenter study of the safety and immunogenicity of 13 DTaP and 2 DTP vaccines was partially completed when the first Hib vaccine, HbOC (Haemophilus bioligosaccharide conjugate vaccine), was licensed for use in infants. Thereafter, at each immunization most infants received HbOC simultaneously with DTaP (or DTP), administered in opposite thighs. Postvaccination geometric mean titers or concentrations (GMTs) of pertussis antibodies as measured by six different assays were compared pairwise among groups of infants receiving 0, 1, 2, or 3 simultaneous HbOC immunizations. The incidence of reactions was compared between infants who received only DTaP or DTP and those who received HbOC simultaneously. Results. Comparison of postvaccination GMTs was possible among groups of infants receiving different numbers of simultaneous immunizations for 10 of the 13 DTaP and both DTP vaccines. Increased HbOC exposure had no consistent dose-response effect on antibody titers for DTaP or DTP vaccines in any assay. Significant differences between groups in postvaccination GMTs were observed with 4 DTaP vaccines in 1 to 2 assays each; the GMTs were higher with increasing HbOC exposure for 2 DTaP vaccines and lower for 2 others. There was no significant increase in reactions with simultaneous HbOC and DTaP immunization. Conclusions. Based on these retrospective analyses, there did not seem to be an interference in pertussis immunogenicity or alteration in reactogenicity associated with the simultaneous administration of HbOC and DTaP. These findings are encouraging with respect to the development of DTaP-Hib combination vaccines. Pediatrics 1995;96:576-579; acellular, antibody, diphtheria-tetanus-pertussis, Haemophilus influenzae, pertussis, vaccine, whole-cell, whooping cough., ABBREVIATIONS. DTaP, diphtheria and tetanus toxoids combined with acellular pertussis vaccine; DTP, diphtheria and tetanus toxoids combined with whole-cell pertussis vaccine; Hib, Haemophilus influenzae type b; GMT, geometric mean titer [...]

The new acellular pertussis vaccines do not appear to produce as many side effects as the conventional whole-cell vaccine. Acellular vaccines induce immunity to protein components of Bordetella pertussis, the bacterium that causes whooping cough. A group of 2,189 infants were randomly assigned to receive their regular series of three diphtheria-pertussis-tetanus immunizations with one of 13 varieties of acellular pertussis vaccine or the conventional whole cell vaccine. Parents kept track of the infant's temperature and other adverse symptoms after each vaccination. Fever and redness, swelling, or pain around the injection site were all less common and less severe after vaccination with the acellular vaccines compared with the whole-cell vaccine. The incidence of vomiting was similar. More serious adverse reactions were rarer as well. Overall, 2.5%. of the infants receiving the conventional vaccine were withdrawn from the trial mostly for prolonged, inconsolable, or high-pitched crying compared with 0.8% of infants receiving an acellular vaccine., Objective. To compare the reactogenicity of a licensed conventional whole-cell (WCL) and 13 acellular pertussis vaccines that differed in the source, manufacture, and quantity of included antigens; all vaccines included diphtheria and tetanus toxoids. Methods. Healthy infants were enrolled through six university-based vaccine and treatment evaluation units and were randomized to receive one of the study vaccines at 2, 4, and 6 months of age. Parents recorded the occurrence of fever, redness, swelling, pain, fussiness, drowsiness, anorexia, and use of antipyretics for 2 weeks after each inoculation; nurses interviewed parents on the third day and at each succeeding visit; long-term follow-up information was collected from parents and medical records 1 year after the third immunization. Results. Of 2200 vaccinated infants, 2189 contributed reaction data after 6375 vaccinations. For every acellular vaccine, every monitored reaction except vomiting occurred at a significantly lower frequency and severity than was seen with WCL. The groups receiving acellular pertussis vaccines differed significantly with respect to redness, swelling, pain, and vomiting, but not with respect to fussiness, antipyretic use, drowsiness, or anorexia. Conclusion. Although there were differences among the acellular vaccines, none was consistently the most or least reactogenic; all were associated with substantially fewer and less severe adverse reactions than a standard commercial whole-cell vaccine. Selection of acellular vaccines for further development and for introduction into efficacy trials can give priority to assessments of immunogenicity and purity, with comparative reactogenicity a secondary consideration. Pediatrics 1995;96:557-566; acellular, adverse reactions, diphtheria-tetanus-pertussis vaccine, pertussis vaccine, whole cell, whooping cough., ABBREVIATIONS. DTP, diphtheria and tetanus toxoids combined with whole-cell pertussis vaccine; DTaP, diphtheria and tetanus toxoids combined with acellular pertussis vaccine; SIDS, sudden infant death syndrome. For the abbreviations used [...]

Antibody response and frequency of side effects may vary between different brands of whole-cell pertussis vaccines. Whole-cell pertussis vaccines are the vaccines in current use to immunize against whooping cough. Ninety-four infants received their diphtheria-pertussis-tetanus immunization series at two, four, and six months with pertussis vaccine supplied by one manufacturer and 309 received vaccine from another manufacturer. One month after the series was completed, blood samples were tested for antigen response to four protein components of the pertussis-causing bacterium. The two vaccines varied in the immune responses they stimulated to these proteins. Infants receiving one type of vaccine were also less likely to have fevers of 101 degrees or more, pain or swelling at the injection site, or inconsolable crying., Objective. To compare prospectively the reactogenicity and immunogenicity of two licensed whole-cell pertussis vaccines. Methods. We conducted a prospective, randomized, double-blinded assessment of two licensed whole-cell pertussis vaccines with diphtheria and tetanus toxoids that were included in a multicenter trial evaluating 13 acellular pertussis vaccines. Infants were immunized at 2, 4, and 6 months of age with a single lot of Lederle (309 infants) or Massachusetts Public Health Biologic Laboratories (MPHBL; 94 infants) vaccine. Results. The group receiving the Lederle vaccine demonstrated significantly higher antibody titers to pertussis toxin by enzyme-linked immunosorbent assay (ELISA) and by the Chinese hamster ovary cell pertussis toxin neutralization assay, and to fimbrial antigens by ELISA, as well as higher mean agglutinin titers. In contrast, the group receiving the MPHBL vaccine demonstrated higher ELISA antibody levels to filamentous hemagglutinin and pertactin. Similar differences were observed in the proportions of vaccinees seroconverting to these antigens. Rates of systemic and local reactions were relatively low for both vaccines. Although the Lederle product had substantially lower reactogenicity in this study than previously reported for that vaccine, the MPHBL vaccine was significantly less reactogenic in nearly all clinical categories. Conclusion. The two whole-cell vaccines demonstrated statistically significant differences in postimmunization antibody levels to all six evaluated pertussis antigens. Whether these statistically significant differences in antibody levels have clinical relevance is not clear. Rates of nearly all local and systemic reactions were significantly lower among the MPHBL group than the Lederle group. Licensed whole-cell diphtheria-tetanus-pertussis vaccines produced by different manufacturers cannot be assumed to be similar in reactogenicity or immunogenicity. Pediatrics 1995;96:567-570; pertussis vaccine, infants, immune response, antibody, controlled trial., ABBREVIATIONS. DTP, diphtheria and tetanus toxoids combined with whole-cell pertussis vaccine; MPHBL, Massachusetts Public Health Biologic Laboratories; ELISA, enzyme-linked immunosorbent assay; PT, pertussis toxin; FHA, filamentous hemagglutinin; PRN, pertactin; FIM, [...]