Clinical trials in the United States and Japan with the Lederle-Takeda and Takeda acellular pertussis-diphtheria-tetanus (APDT) vaccines. The Multicenter APDT Vaccine Study Groups. Antibody response and reactions to completion of a four-dose series with a two- or three-component acellular pertussis vaccine compared to whole cell pertussis vaccine. Acellular and whole-cell pertussis vaccines as booster doses: a multicenter study. 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. A new DTPw-HB/Hib combination vaccine for primary and booster vaccination of infants in Latin America. DTPw-HB and Hib primary and booster vaccination: combined versus separate administration to Latin American children. Controlled study of a new five-component acellular pertussis vaccine in adults and young children. Multidose, live attenuated, cold-recombinant, trivalent influenza vaccine in infants and young children. Evaluation of the immunogenicity and reactogenicity of a DTPa-HBV-IPV Combination vaccine co-administered with a Hib conjugate vaccine either as a single injection of a hexavalent combination or as two separate injections at 3, 5 and 11 months of age.
The results of the following studies are reported: a longitudinal double blind trial comparing Lederle-Takeda APDT vaccine with Lederle DTP vaccine in two, four and six month old infants; two double blind similar APDT vs DTP trials in 18 month old and four to six year old children; a large longitudinal open trial with APDT in two, four and six month old infants and a household contact efficacy trial with Takeda APDT in Japan. APDT vaccine recipients had a lesser frequency and less severe reactions than whole cell vaccine recipients. Antibody responses to lymphocytosis-promoting factor and agglutinogens were higher in DTP recipients; APDT recipients had a better serologic response to filamentous hemagglutinin. Equivalent 69K protein antibody responses were seen. Vaccine efficacy in the household contact study was 98% (95% CI = 84% to 99%) against classical pertussis and 81% (95 CI = 64% to 90%) if all respiratory illnesses are considered. We compared the reactions and immunogenicity of DT acellular pertussis (DTaP) vaccines containing pertussis toxoid (PT) and filamentous haemagglutinin (FHA) (2-component DTaP) or PT, FHA and pertactin (PRN) (3-component DTaP vaccine) with a whole cell (DTwP) vaccine as a fourth-dose booster in 158 children (15-20 months old) who had received 3 primary vaccine doses with the same vaccines at 2, 4 and 6 months of age. Randomization was 3:1 for DTaP:DTwP and all children received concomitant oral polio vaccine (OPV). Fever (> 38 degrees C), irritability, local injection site erythema (> 10 mm), swelling (> 10 mm), and pain (moderate or more) were assessed for 72 h after booster vaccination. DTwP vaccinees had a higher incidence of fever (29.4%) and injection-site pain (45.7%) than 3-component DTaP vaccinees (fever, 9.6%, p < 0.02; injection-site pain, 3.8%, p < 0.01); 2-component DTaP vaccinees had less injection-site pain (8.3%, p < 0.01). Pre- and post-vaccination immunoglobulin G (IgG) antibody was measured by enzyme-linked immunosorbent assay (ELISA). Pre- and post anti-PT levels were similar for all 3 vaccine groups. Anti-FHA antibody was higher pre- and post-vaccination for both DTaP vaccine groups compared with the DTwP vaccinees (p < 0.01 for all comparisons). For 3-component DTaP vaccinees, anti-PRN antibody was higher pre- and post-vaccination compared to DTwP vaccinees (p < 0.01 for both comparisons). Tetanus antibody was higher pre- and post-vaccination for DTwP versus both DTaP vaccine groups, and diphtheria antibody was similar pre- and post-vaccination for all 3 groups. These 2- and 3-component DTaP vaccines produce less common reactions and comparable or higher antibody to the components they contain (except tetanus) than DTwP vaccine when given as a booster to 15- to 20-month-old children previously primed with the same vaccine. To compare the safety and immunogenicity of a variety of acellular (AC) and whole-cell (WC) pertussis vaccines combined with diphtheria and tetanus toxoids.
                Standard enrollment and reaction forms were used at five sites, and serologic evaluation was performed at a single site. Nine AC (Massachusetts Public Health Laboratories, Biocine Sclavo recombinant pertussis toxoid [PT], Connaught/BIKEN, Lederle three-component, Biocine Sclavo recombinant three-component, SmithKline Beecham three-component, Porton three-component, Takeda-Wyeth, and Connaught multicomponent), and three WC (Connaught Laboratories, Lederle Laboratories, and Massachusetts Public Health Laboratories) were studied. All AC contained varying concentrations of PT; some vaccines also contained filamentous hemagglutinin (FHA), pertactin, and/or agglutinogens.
                Two hundred forty children, aged 16 to 21 months and 4 to 6 years, were enrolled at five sites. Significantly less fever, redness, swelling, pain, limp, and use of pain medication were noted following AC compared with WC. Significant increases in antibody to PT were seen following all vaccines. Significant rises in FHA antibody were seen following all WC and the seven AC that contained FHA. Postbooster PT antibody levels were similar among the AC groups, regardless of the amount of PT administered (between 3.5 and 25 micrograms per dose). The dose of FHA did not affect PT antibody response. Infants primed with WC who were boosted with a monocomponent PT vaccine did not manifest a significant antibody response to FHA.
                The rate of adverse reactions was not a function of the number of antigens or the antigen quantity in the acellular vaccines, and antibody responses following AC were similar or better than antibody responses following WC. These results support the further evaluation of these vaccines in a larger National Institute of Allergy and Infectious Diseases-sponsored study in infants. 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.
                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.
                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.
                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. In 1998 the World Health Organization (WHO) recommended the inclusion of Haemophilus influenza type B (Hib) conjugate vaccines in infant immunization programs, whenever in accordance with national priorities. GlaxoSmithKline Biologicals has developed a new pentavalent combined diphtheria-tetanus-whole cell pertussis-hepatitis B/Hib (DTPw-HB/Hib) vaccine containing 5 microg of polyribosylribitol phosphate (PRP), and we assessed the immunogenicity and reactogenicity of primary and booster vaccination of healthy children with this new vaccine compared with a reference regimen consisting of the licensed DTPw-HB (Tritanrix) and Hib (Hiberix) vaccines given as simultaneous concomitant injections.
                We performed a randomized, double-blind study from September 1998 to August 1999 to establish the immunogenicity and reactogenicity of primary and booster vaccination of healthy children with the new pentavalent combined DTPw-HB/Hib vaccine given as a single injection, compared with the reference regimen.
                Both vaccination regimens elicited excellent immune responses, with all subjects in both groups achieving seroprotective anti-PRP antibody concentrations of > or = 0.15 microg/mL one month after primary vaccination. The combined DTPw-HB/Hib vaccine was non-inferior to the licensed vaccines in terms of seroprotection/seropositivity/vaccine response rates for all antigen components. Persistence of antibodies against all study vaccine antigens up to the time of booster vaccination was comparable between groups, and a marked increase of all antibody concentrations was observed after the booster dose. Both vaccine regimens were similar in terms of their overall reactogenicity profiles.
                Our results indicate that the new DTPw-HB/Hib pentavalent combination vaccine provides an efficient and reliable way of implementing WHO recommendations for controlling hepatitis B and Hib infections on a worldwide basis. This multicentre study was designed to establish the reactogenicity and immunogenicity profiles of primary and booster vaccination with diphtheria, tetanus, and pertussis whole-cell-hepatitis B/Haemophilus influenzae type-b (DTPw-HB/Hib) administered as either a syringe mix or as separate injections in 400 Latin American children. Both vaccine regimens were equally well tolerated and elicited post-primary excellent seropositivity rates at or close to 100% for all five component antigens. With regard to HB, 100% of subjects in the combined vaccination group, and 98.8% subjects in the separate injection vaccination group reached seroprotective antibody concentrations (>or=10 mIU/ml) 1 month after the primary vaccination course. Equally high anti-PRP antibody concentrations were reached 1 month after vaccination, with 100% of seroprotected subjects in the combined vaccination group (antibody concentrations >or=0.15 microg/ml), against 99.4% in the separate injection vaccination group. Seroprotective anti-HBs and anti-PRP antibody concentration levels persisted approximately 1 year after the primary vaccination course, just prior to booster vaccination. Finally, a significant increase of all antibody concentrations could be observed after the booster vaccination, since all but one subject in the separate injection vaccination group had protective levels of anti-HBs and anti-PRP antibodies 1 month after the booster dose. These results suggest that the combination of DTPw-HB and Hib vaccines provides an effective means for increasing vaccine coverage in childhood vaccination programmes. A new five-component acellular pertussis (AP) vaccine containing 10 micrograms of pertussis toxoid, 5 micrograms of filamentous hemagglutinin, 5 micrograms of combined agglutinogens 2 and 3, and 3 micrograms of pertactin was evaluated in adults and young children. AP vaccine was compared with saline placebo in 31 adults, and AP vaccine combined with diphtheria and tetanus toxoids (ADTP) was compared with whole cell DTP in 41 children, ages 16-20 months, who had received whole cell DTP during infancy. AP was mildly to moderately reactogenic in adults, with pain noted within 72 h and 5-8 days after immunization. ADTP was less reactogenic than DTP in children, with significantly decreased pain, redness, irritability, and fever and less use of acetaminophen reported. No late reactions were observed in any child. The multicomponent ADTP was immunogenic, with four-fold or greater antibody rises to at least four pertussis antibody assays in all 15 immunized adults. Pertussis-specific antibody responses in children who received ADTP and DTP were similar. The multicomponent ADTP vaccine is currently being studied in a National Institute of Allergy and Infectious Diseases-sponsored efficacy study in Sweden. Twenty-two healthy infants and children received either cold-recombinant, trivalent influenza vaccine or placebo in a three-dose vaccine trial. Most (82%) who received vaccine were seronegative to all three vaccine strains (10(6) TCID50/dose each): A/Kawasaki/9/86 (H1N1), A/Los Angeles/2/87 (H3N2), and B/Yamagata/16/88. Vaccine was administered intranasally at time 0 and 2 and 4 months later. The vaccine was well tolerated and immunogenic when administered in a multidose regimen. The first dose stimulated antibody to H1, H3, and B in 59%, 94%, and 35% of vaccinees, respectively, by hemagglutination inhibition (HAI) or ELISA. After two doses of vaccine, 93%, 93%, and 80% had antibody by HAI or ELISA to H1, H3, and B, respectively. Most vaccinees (67%) responded to all three viruses after two doses of vaccine. The third dose contributed little to the vaccine's immunogenicity. Multidose trivalent influenza vaccine is safe and induces an immune response in most vaccinees after two doses. A combined DTPa-HBV-IPV/Hib vaccine containing diphtheria (D), tetanus (T), acellular pertussis (Pa), hepatitis B (HBV) and types 1, 2 and 3 inactivated polioviruses (IPV) extemporaneously mixed with a conjugated Haemophilus influenzae type b (Hib) vaccine (Group 1) was compared to the DTPa-HBV-IPV and Hib vaccines (Group 2) administered separately at 3, 5 and 11 months of age (n = 440). A microneutralization assay was used to detect antibodies against the 3 polio virus types (cut-off 1:8 dil), RIA for anti-HBs antibodies (cut-off 10 mIU/ml) and ELISA for antibodies against all other vaccine antigens (cut-off: 0.1 IU/ml for anti-tetanus and anti-diphtheria antibodies; 5 El.U/ml for antibodies against each of the 3 acellular pertussis antigens and 0.15 microg/ml for anti-PRP antibodies). Similar immune responses were observed in both groups 1 month after dose 2 as well as after dose 3. Six months after dose 2 however, the proportion of subjects maintaining an anti-tetanus antibody concentration > or = 0.1 IU/ml was lower in Group 2 and a slight group difference in favour of Group 1 was also observed for anti-PRP, anti-diphtheria and anti-polio type 1 antibody persistence prior to the third dose. The overall incidence of local and general solicited symptoms was similar in both groups. One subject discontinued study vaccination following an SAE considered to be related to vaccination. The DTPa-HBV-IPV/Hib combined vaccine is immunogenic and well tolerated when administered according to a 3, 5 and 11 month vaccination schedule and can therefore be considered as a feasible alternative to the separate administration of the pentavalent DTPa-HBV-IPV and the monovalent Hib vaccines.
Multi-component (≥ three) aP vaccines are effective and show less adverse effects than wP vaccines for the primary series as well as for booster doses.