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. Efficacy of sequential annual vaccination with inactivated influenza virus vaccine. Primary and booster immunization with a diphtheria, tetanus, acellular pertussis, hepatitis B (DTPa-HBV) and Haemophilus influenzae type b (Hib) vaccine administered separately or together is safe and immunogenic. Comparison of acellular and whole-cell pertussis-component diphtheria-tetanus-pertussis vaccines in infants. The APDT Vaccine Study Group. Immunogenicity and Reactogenicity following Primary Immunisation with a Combined DTaP-HBV Vaccine and a Haemophilus influenzae Type B Vaccine Administered by Separate or Mixed Injection. Primary vaccination of infants with diphtheria-tetanus-acellular pertussis-hepatitis B virus- inactivated polio virus and Haemophilus influenzae type b vaccines given as either separate or mixed injections. A combined liquid Hib (PRP-OMPC), hepatitis B, diphtheria, tetanus and whole-cell pertussis vaccine: controlled studies of immunogenicity and reactogenicity. Immune response to simultaneous administration of a recombinant DNA hepatitis B vaccine and multiple compulsory vaccines in infancy. Comparison of an acellular pertussis-component diphtheria-tetanus-pertussis (DTP) vaccine with a whole-cell pertussis-component DTP vaccine in 17- to 24-month-old children, with measurement of 69-kilodalton outer membrane protein antibody. Comparison of a diphtheria and tetanus toxoids and bicomponent acellular pertussis vaccine with diphtheria and tetanus toxoids and whole-cell pertussis vaccine in infants. Simultaneous administration of a diphtheria and tetanus toxoids and acellular pertussis vaccine with measles-mumps-rubella and oral poliovirus vaccines. Effects of the potency and composition of the multivalent human-bovine (WC3) reassortant rotavirus vaccine on efficacy, safety and immunogenicity in healthy infants. Acellular pertussis vaccination of 2-month-old infants in the United States. Immunogenicity and reactogenicity of a novel hexavalent DTPa-HBV-IPV/Hib vaccine compared to separate concomitant injections of DTPa-IPV/Hib and HBV vaccines, when administered according to a 3, 5 and 11 month vaccination schedule. Newborn universal immunisation against hepatitis B: immunogenicity and reactogenicity of simultaneous administration of diphtheria/tetanus/pertussis (DTP) and oral polio vaccines with hepatitis B vaccine at 0, 2 and 6 months of age. Comparison of a three-component acellular pertussis vaccine with whole cell pertussis vaccine in two-month-old children. Administration of combined diphtheria and tetanus toxoids and pertussis vaccine, hepatitis B vaccine, and Haemophilus influenzae type b (Hib) vaccine to infants and response to a booster dose of Hib conjugate vaccine. Primary immunization series for infants: comparison of two-component acellular and standard whole-cell pertussis vaccines combined with diphtheria-tetanus toxoids. Differences in reactogenicity and antigenicity of acellular and standard pertussis vaccines combined with diphtheria and tetanus in infants. 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. Safety and immunogenicity of six acellular pertussis vaccines and one whole-cell pertussis vaccine given as a fifth dose in four- to six-year-old children. An evaluation of influenza immunization: influence of route of administration and vaccine strain. Primary and booster vaccination with DTPw-HB/Hib pentavalent vaccine in Costa Rican children who had received a birth dose of hepatitis B vaccine. Safety and immunogenicty of RTS,S/AS02A candidate malaria vaccine in Gambian children. Protective efficacy of a second pneumococcal conjugate vaccine against pneumococcal acute otitis media in infants and children: randomized, controlled trial of a 7-valent pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine in 1666 children. Immunization of infants and young children with live attenuated trivalent cold-recombinant influenza A H1N1, H3N2, and B vaccine. Comparison of the reactogenicity and immunogenicity of a combined diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated polio (DTPa-HBV-IPV) vaccine, mixed with the Haemophilus influenzae type b (Hib) conjugate vaccine and administered as a single injection, with the DTPa-IPV/Hib and hepatitis B vaccines administered in two simultaneous injections to infants at 2, 4 and 6 months of age. Immunogenicity of a Haemophilus influenzae type b-tetanus toxoid conjugate vaccine when mixed with a diphtheria-tetanus-acellular pertussis-hepatitis B combination vaccine. Safety and immunogenicity of Chiron/Biocine recombinant acellular pertussis-diphtheria-tetanus vaccine in infants and toddlers. A controlled trial of a formalin-inactivated hepatitis A vaccine in healthy children. Concomitant use of the 3-dose oral pentavalent rotavirus vaccine with a 3-dose primary vaccination course of a diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio-Haemophilus influenzae type b vaccine: immunogenicity and reactogenicity. Secondary efficacy endpoints of the pentavalent rotavirus vaccine against gastroenteritis in sub-Saharan Africa. [Characteristics of the clinical and immunologic safety of inactivated influenza vaccines in children undergoing multiple immunizations]. Vitamin a supplementation does not affect infants' immune responses to polio and tetanus vaccines.
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. Inactivated influenza virus vaccine efficacy after annual revaccination has been reported to be less than that after first vaccination in boarding school children. We prospectively examined the immunogenicity and efficacy of this vaccine in healthy 30- to 60-year-old volunteers in Houston, Texas, over two epidemic seasons (1983-1985) encompassing outbreaks due to influenza A (H3N2 and H1N1) and influenza B viruses. A placebo group that had never (or not in recent years) received inactivated influenza virus vaccine, a group that received the vaccine for the first time (first vac), and a group given two or more recent vaccinations (multivac) were evaluated in a double-blind fashion each year. Vaccination induced higher frequencies of rise in serum antibody titer to vaccine components in first vac than in multivac volunteers, but mean postvaccination titers were similar. Clinical and virologic evaluations of illnesses during both epidemics and of influenza infections diagnosed serologically over the epidemic seasons revealed no overall reduction in illness from that in the placebo group for either vaccine group; modest reductions in influenza infection-related illness that were significant only for the multivac group against A/H3N2-related illness (55%; p less than 0.04); reduction in moderate-to-severe lower respiratory and/or systemic illness due to influenza for multivac (73%, p less than 0.025) but not first vac (15%, p greater than 0.10) volunteers during the A/H3N2 epidemic; reduction in influenza virus shedding in the multivac (54%, p less than 0.05) but not the first vac (16%, p greater than 0.10) group when compared with the placebo group for both years; and overall 63-81% reductions in documented infections with each influenza virus for both vaccine groups with the exception of A/H1N1 for the first vac group (24%, p greater than 0.10) and type B for the multivac group (58%, p = 0.067). Vaccine efficacy was only modest in these studies, but in contrast to the earlier report in boarding school children, efficacy appeared to be somewhat greater after repeated annual vaccination than after first administration. The aim of this study was to evaluate the safety and immunogenicity of DTPa-HBV and Hib vaccines given mixed or separately to 360 healthy infants at 2, 4, and 6 months of age.
                Immune memory was assessed in lower responders (post-primary anti-PRP <0.545 microg/ml), through administration of plain polyribosylribitol phosphate (PRP) at 12-15 months. All subjects received a DTPa-HBV/Hib booster at 18-19 months.
                One month after primary vaccination, 98% had seroprotective antibody levels against HBV and 94-97% against Hib (anti-PRP> or =0.15microg/ml). A statistically significant difference between groups was observed in the proportion of subjects who achieved anti-PRP antibodies > or =1.0microg/ml post-primary vaccination; 68.1% for DTPa-HBV/Hib and 84.5% for DTPa-HBV and Hib. PRP administered to lower responders produced a 7-fold increase in anti-PRP antibodies, indicative of immunological memory. After DTPa-HBV/Hib booster vaccination, 96-100% of subjects had seroprotective antibody concentrations against Hib, hepatitis B, tetanus, and diphtheria and high vaccine response rates against pertussis toxoid, filamentous hemagglutinin, and pertactin.
                A robust and protective Hib response was demonstrated following plain PRP and/or a booster conjugate Hib vaccine in both lower and higher Hib responders.
                Copyright 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. In a multicenter, double-blind, randomized, longitudinal study, 252 children received licensed Lederle diphtheria-tetanus toxoids and pertussis vaccine adsorbed (DTP) at 2, 4, and 6 months of age, and 245 children received a DTP vaccine with the Lederle/Takeda acellular pertussis component (APDT) at the same ages. Both groups of children received APDT vaccine at 18 months of age. After each of the first three immunizations, APDT vaccine recipients had fewer local and systemic reactions than did DTP vaccinees. Reactions after the 18-month APDT vaccination were minimal in severity regardless of the vaccine previously received. Antibody responses to lymphocytosis-promoting factor and agglutinogens were more pronounced in DTP recipients; however, APDT recipients had a better serologic response to filamentous hemagglutinin, and responses to the 69K protein were equivalent. This APDT vaccine produces fewer reactions than the standard whole-cell DTP vaccine. The protective significance of the serologic responses to the APDT vaccine is unknown, but the greater response to filamentous hemagglutinin and equivalent response to the 69K protein compared with those to DTP vaccine seem promising. The aim of this open, randomised, multicentre trial was to evaluate the immunogenicity and reactogenicity of the tetravalent diphtheria-tetanus-acellular pertussis-hepatitis B (DTaP-HBV) vaccine when given either as a mixed or as a separate concomitant injection with the Haemophilus influenzae type b (Hib) vaccine at 3, 5 and 11 months of age.
                Antibody against diphtheria, tetanus, pertussis (ELISA), hepatitis B (radioimmunoassay) and Hib polyribosylribitol phosphate (PRP) [radiolabeled antigen binding assay] was determined. Solicited local and systemic adverse events were evaluated on the day of each vaccination and for three subsequent days. Follow-up of unsolicited and serious adverse events was conducted for 30 days following each vaccination.
                A total of 360 subjects were enrolled in the study. After completion of the three-dose vaccination course, seroprotective antibody concentrations against diphtheria, tetanus and hepatitis B, together with a pertussis vaccine response, were seen in almost all subjects with immunogenicity results (n = 336). All subjects had post-vaccination Hib anti-PRP antibody concentrations of at least 0.15 mug/mL, and 97.0% and 99.4%, respectively, of the subjects receiving a single or separate injections had Hib anti-PRP antibody concentrations >/=1.0 mug/mL. Addition of the Hib vaccine to the tetravalent DTaP-HBV vaccine did not increase the incidence of local or systemic reactions.
                Combination of DTaP-HBV and Hib vaccines in a single injection is safe, immunogenic and well tolerated, and thus has the potential to simplify the childhood immunisation schedule in Italy. The aim of this open, multicenter, randomized trial was to evaluate the immunogenicity and reactogenicity of a candidate combined diphtheria-tetanus-acellular pertussis-hepatitis B virus-inactivated polio virus (DTaP-HBV-IPV) vaccine when given as either a mixed or as separate concomitant injections with Haemophilus influenzae type b (Hib) vaccine.
                A total of 359 subjects were randomized to receive either DTaP-HBV-IPV/Hib (mixed administration - 180 subjects) or DTaP-HBV-IPV + Hib (separate administration in opposite limbs - 179 subjects) at 2, 3, and 4 months of age.
                After vaccination, seroprotective antibody concentrations against diphtheria, tetanus, hepatitis B, and polio viruses and a high (> or = 97%) pertussis vaccine response were seen in almost all study participants. All subjects except one in the mixed administration group had postvaccination Hib anti-PRP antibody concentrations > or = 0.15 microg/mL. Of subjects in the mixed and separate group, 77.2% (geometric mean antibody concentration, 2. 62 microg/mL) and 88.6% (geometric mean antibody concentration, 4.45 microg/mL) had Hib anti-PRP concentrations > or = 1 microg/mL, respectively. The addition of the Hib component to the 5-component vaccine did not increase the incidence of local or general reactions.
                Both administrations of the candidate vaccine were found to be safe, immunogenic, and well tolerated. Although anti-PRP geometric mean antibody concentrations and the percent of subjects achieving the 1 microg/mL seroprotective level were lower after the mixed administration, they were in the range seen with monovalent Hib vaccines or with other DTaP-based/Hib combinations licensed in some European countries. Therefore both administrations have the potential to simplify childhood immunization. We evaluated the immunogenicity and reactogenicity of a new liquid pentavalent combination vaccine, which incorporates a diphtheria, tetanus and whole-cell pertussis vaccine (DTP) with Hib (PRP-OMPC) and hepatitis B vaccine (HB), in a series of three studies involving 2156 infants. The vaccination schedule was 2, 4, 6 and 18 months for all studies. In addition, subjects in the third study also received a dose of monovalent hepatitis B vaccine at birth. The principal study was a randomised double blind trial of two separate, but concurrently administered vaccines in each of three groups: pentavalent vaccine [DTP-Hib-HB] plus placebo (Group A, n=619); quadrivalent vaccine [DTP-HB] plus Hib vaccine (Group B, n=620); and bivalent vaccine [Hib-HB] plus DTP (Group C, n=226). The second study (Group D, n=231) was an open trial of three separate, but concurrently administered licensed control vaccines (DTP, Hib and HB). The third study (Group E, n=460) administered a dose of monovalent hepatitis B vaccine at birth followed by pentavalent vaccine as for Group A. Subjects were bled prior to the 2- and 18-month vaccinations, and a month after the 6- and 18-month vaccinations. A diary card was used to record subject temperatures and other systemic and local clinical signs for 7 days after each vaccination. The pentavalent vaccine, whether or not preceded by a birth dose of hepatitis B vaccine, was generally well tolerated at all administration times, and had a reactogenicity profile similar to that observed for licensed vaccine controls. Diphtheria and tetanus antibody levels were substantially above protective levels in all study groups. The anti-HBs responses (% > or = 10 mIU/ml) following the 6-month dose of vaccines were, respectively, for Groups A-E: 83.2, 91.7, 96.5, 98.8 and 93.9%, and following the 18-month doses: 87.9, 97.5, 98.8, 98.8 and 92.8%. Anti-PRP responses (% > or = 1.0 microg/ml) following the 6-month dose for Groups A-D were 86.0, 90.5, 91.2, and 74.4%, and after the 18-month dose for Groups A-E were 97.3, 98.3, 98.1, 97.0, and 99.5%. Consistently higher geometric mean titres (GMTs) for pertussis antibodies to agglutinogens (Agg2, Agg3) and pertactin were recorded for the pentavalent vaccine compared to the licensed control vaccine, though they were somewhat lower for pertussigen (PT). Except for the hepatitis B response, antibody responses induced by the pentavalent vaccine to all antigens with a schedule commencing at 2 months of age and completed at 18 months were equivalent to responses to the same antigens induced by the separate, but concurrently administered licensed control vaccines. A regimen of a birth dose of hepatitis B vaccine followed by pentavalent vaccine at 2, 4, 6 and 18 months was not countered by any clinically significant decrease in seroresponses. The reactogenicity and immunogenicity of simultaneous administration of recombinant DNA hepatitis B vaccine with diphtheria and tetanus toxoids (DT) and oral poliovirus vaccine (OPV) in 111 infants were compared with those of DT and OPV alone in a control group of 21 infants. All subjects received three doses of the vaccine according to one of three different schedules of vaccination. Reactions following simultaneous administration of vaccines were all but absent, with mild pain reported for four out of 111 subjects, compared with one of 21 in the control group. Seroconversion rates of 98-100% and high anti-HBs geometric mean titres (GMTs) were observed in all study groups after three doses of hepatitis B vaccine. Significantly higher anti-HBs were seen in Group III, where six months is allowed between the second and the third hepatitis B vaccine doses, compared with Group I and II, where only 1-2 months separate the second and third doses. A fourth dose of vaccine was needed in both these groups to obtain anti-HBs levels as high as seen in Group III after three vaccine doses at 3, 4 and 10 months of age. The immune response to DT and OPV was similar in the study groups and the control group. It is concluded that a course of 10 micrograms doses of recombinant hepatitis B vaccine given simultaneously with DT and OPV elicits a strong anti-HBs response and does not interfere with the immune response to the other antigens. Healthy 17- to 24-month-old children, previously immunized with three doses of whole-cell diphtheria-tetanus-pertussis (DTP) vaccine, were enrolled in a multi-center double-blind, randomized study comparing a DTP vaccine with an acellular pertussis-component (APDT) and a conventional whole-cell pertussis-component DTP vaccine. Thirty-eight children received APDT vaccine, and 37 children received DTP vaccine. APDT vaccine recipients had significantly less local pain and warmth than DTP vaccine recipients. Antibody responses to lymphocytosis-promoting factor were similar in the two groups. The APDT vaccine recipients had a higher IgG antibody response to filamentous hemagglutinin than the DTP vaccinees had. Equivalent agglutinin responses were seen in the two groups. The APDT vaccine recipients had a significantly better antibody re-enzyme-linked immunosorbent assay, than DTP vaccinees had 1 month and 1 year after immunization. This APDT vaccine was immunogenic and caused fewer local reactions than conventional DTP vaccine when administered as a fourth dose to 17- to 24-month-old children. To compare the reactogenicity and immunogenicity of a diphtheria and tetanus toxoids and two-component acellular pertussis (ADTP) vaccine with a US-licensed whole-cell (WDTP) vaccine.
                General pediatric practice in suburban Rochester, NY.
                Prospective, double-blind, randomized study.
                One hundred ten infants were studied; 88 (80%) received ADTP and 22 (20%) received WDTP at ages 2, 4, and 6 months.
                Vaccination.
                Temperature of 38.3 degrees C or higher (P = .03) and moderate or severe injection-site pain (P = .02) occurred less frequently in infants receiving ADTP than those receiving WDTP for the combined three doses. Following the third dose, ADTP vaccination produced higher antibody responses than WDTP to pertussis toxin (geometric mean enzyme-linked immunosorbent assay IgG was 52.2 vs 12.5; P < .001) and to filamentous hemagglutinin (geometric mean IgG was 182.8 vs 3.5; P < .001). No interference in the diphtheria or tetanus antibody responses was observed in recipients of the ADTP vaccine.
                This two-component ADTP vaccine, when given as a primary infant series, produces fewer adverse effects and greater immunogenicity to the two pertussis components that it contains than US-licensed WDTP vaccine. To compare the safety and immunogenicity of Lederle Laboratories' (Pearl River, NY) diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine with diphtheria and tetanus toxoids and whole-cell pertussis (DTwP) vaccine when administered simultaneously with measles-mumps-rubella (MMR) vaccine and trivalent oral poliovirus (OPV) vaccine at 15 to 16 months of age.
                Randomized and double-blind.
                Two general pediatric practices.
                Ninety-seven infants, aged 15 to 16 months, who had received three previous DTwP immunizations. SELECTION PROCEDURES AND INTERVENTIONS: Healthy children received the DTaP or DTwP vaccine. Infants received the MMR vaccine at a separate site and the OPV vaccine concurrently. Blood was obtained on day 0 and at 6 weeks. Adverse events were recorded by parents at specified times after immunization.
                Within 3 days of immunization, DTaP vaccine recipients had less fever, drowsiness, and irritability (P = .01, .04, .01, respectively). They also experienced less tenderness, erythema, and induration (.001, .001, and .002, respectively). There was no difference in the frequency of adverse reactions 6 to 14 days after immunization. Enzyme-linked immunosorbent assays were used to determine all antibody values. Antibody responses to filamentous hemagglutinin and pertussis toxoid were significantly greater in the DTaP group (P = .0001 and .02, respectively). Immune responses to the other measured antigens were similar.
                Simultaneous administration of the Lederle DTaP with MMR and OPV vaccines did not interfere with antibody response to pertussis antigens measured or measles, mumps, or rubella viruses and was associated with fewer local and systemic adverse events during the first 3 days following immunization when compared with the simultaneous administration of the DTwP, OPV, and MMR vaccines. We conclude that the DTaP vaccine can be administered at 15 months of age concurrently with the MMR and OPV vaccines. Rotavirus gastroenteritis, which causes substantial infant mortality and morbidity worldwide, is a vaccine-preventable disease. The purpose of this study was to evaluate different compositions and potencies (vaccine virus titers) of a live multivalent human-bovine (WC3) reassortant rotavirus vaccine in order to select the potency and composition of the vaccine for further development.
                The efficacy, safety, and immunogenicity of a G1, G2, G3, G4, and P1A pentavalent composition at three different potencies, a G1, G2, G3, G4 quadrivalent composition, and a P1A monovalent composition of an oral human-bovine (WC3) reassortant rotavirus vaccine were compared in a blinded, placebo-controlled trial conducted between 1998 and 2001 enrolling 1,946 healthy Finnish infants 2-8 months of age.
                All potencies of the pentavalent and quadrivalent vaccines were efficacious (58-74%) against wild-type rotavirus gastroenteritis of any severity and 100% protective against severe rotavirus disease caused by vaccine G-serotypes through the first rotavirus season post-vaccination. The monovalent P1A vaccine was 53% efficacious against moderate-and-severe rotavirus gastroenteritis. Protection against rotavirus gastroenteritis of any severity was demonstrated through two and three rotavirus seasons for all vaccine compositions. After the third dose, the percentage of infants with >or=3-fold rise in baseline serum neutralizing antibody titers against G1 ranged from 62% to 86% for recipients of the pentavalent vaccine, depending on the potency. The incidence of fever, irritability, vomiting, and diarrhea did not significantly differ between vaccine and placebo groups. A 7-month-old male developed intussusception 9 days after the first dose of the low-potency pentavalent vaccine.
                Based on the results of this trial, a pentavalent composition (G1, G2, G3, G4, and P1A) of human-bovine (WC3) reassortant rotavirus vaccine with a potency similar to that of the middle-potency pentavalent vaccine ( approximately 8 x 10(6) plaque-forming units/dose) was selected for further development. This is the first study in children from the United States that evaluates the immunogenicity of and adverse reactions to the Connaught/Biken two-component acellular pertussis vaccine compared with whole-cell pertussis vaccine when given as a primary immunization series at 2, 4, and 6 months of age. Three hundred eighty infants were studied; 285 received acellular diphtheria-tetanus toxoids-pertussis (DTP (ADTP)) and 95 received whole-cell DTP (WDTP). Following the third dose, ADTP vaccination produced higher antibody responses than WDTP to lymphocytosis-promoting factor (enzyme-linked immunosorbent assay IgG geometric mean titer (GMT) = 131 vs 9 and Chinese hamster ovary cell assay GMT = 273 vs 16) and to filamentous hemagglutinin (IgG GMT = 73 vs 10) (all P less than .0001). Agglutinin responses were higher in WDTP compared with ADTP recipients (GMT = 50 vs 37; P = .02). Local reactions were fewer for all three doses following ADTP vaccination. Fever, irritability, drowsiness, anorexia, vomiting, and unusual crying all occurred less frequently in ADTP compared with WDTP recipients for one or more of the three doses. We conclude that this two-component ADTP vaccine when given as a primary series produces greater immunogenicity and fewer adverse effects than the currently licensed WDTP vaccine. In an open randomised trial, 312 eligible infants were enrolled to receive either a single injection of the hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B virus-inactivated polio/ Haemophilus influenzae b (DTPa-HBV-IPV/Hib) vaccine, or concomitant injections of commercial DTPa-IPV/Hib and HBV vaccines (comparator). Vaccines were administered at 3, 5 and 11 months of age. The statistical approach for non-inferiority showed that the DTPa-HBV-IPV/Hib vaccine was at least as immunogenic as the comparator vaccines in terms of immunogenicity of all antigens 1 month after the 2nd dose. Non-inferiority criteria were also met immediately before and 1 month after the 3rd dose for all antigens except poliovirus type 3 prior to the 3rd dose. The majority of subjects were seroprotected against diphtheria, tetanus, polyribosyl-ribitol-phosphate, hepatitis B and poliovirus after the 2nd dose and maintained seroprotective antibody levels until the 3rd dose. A marked difference was observed in anti-HBs antibody geometric mean antibody concentrations (GMCs) at 1 month after the 2nd dose (higher GMCs in DTPa-HBV-IPV/Hib group). Reactogenicity (incidence of solicited local and general symptoms) was similar between the two study groups and no vaccine-related serious adverse events occurred.
                the new diphtheria-tetanus-acellular pertussis-hepatitis B virus-inactivated polio/ Haemophilus influenzae b vaccine administered at 3, 5 and 11 months of age was safe and at least as immunogenic as the comparator vaccines thus providing an effective and more comfortable option for this infant vaccination schedule. The reactogenicity and immunogenicity of the administration of recombinant vaccine against hepatitis B simultaneously (but at separate sites) with diphtheria/tetanus/pertussis (DTP) and oral polio vaccines were examined. Six hundred and twenty-six children (group I) were given hepatitis B vaccine at 0, 2 and 6 months of age; the other vaccines were administered at 2, 4 and 6 months of age. A control group of 731 children (group II) received only DTP and oral polio vaccines. The results showed that 93% of the infants in group I had anti-HBs titres above the protective level ( > or = 10 mIU ml-1) after vaccination. There were no differences in the immune responses for DTP and polio between the two study groups. The vaccine efficacy against poliomyelitis was 96% for serotype I, 100% for serotype II and 97-98% for serotype III. Of the infants in both groups, 97% had antibodies against B. pertussis; all children were positive for tetanus and diphtheria. There were no differences in the incidences of general reactions between groups. Local swelling and redness were reported following 4.2 and 4.4%, respectively, of all injections of hepatitis B vaccine. These reactions were reported following 31 and 33%, respectively, of all doses of DTP vaccine. It can be concluded that the simultaneous administration of hepatitis B vaccine with the DTP and polio vaccines is well-tolerated; hepatitis B vaccine remained highly immunogenic and did not interfere with the immune response to the other antigens. An acellular pertussis vaccine (DTaP) containing pertussis toxoid, filamentous hemagglutinin and the 69-kDa outer membrane protein (pertactin) was compared with United States-licensed whole cell pertussis vaccine (DTwP) as a three dose sequence at 2, 4 and 6 months of age. Eighty infants were enrolled; 62 received DTaP and 18 received DTwP. Sixty-two infants had preimmunization and 1 month postimmunization sera available for pertussis antibodies. No infant experienced a serious adverse reaction. Significantly fewer infants in the DTaP group experienced irritability (P < 0.001) and moderate to severe injection site pain and redness (P < 0.001, and P = 0.03, respectively). The DTaP group also had significantly greater increases in geometric mean titers of antibodies against filamentous hemagglutinin (P < 0.001) and pertactin (P = 0.006). This three-component DTaP vaccine induced an antibody response to pertussis toxin, filamentous hemagglutinin and pertactin but caused fewer adverse reactions than DTwP when administered as a primary series of immunization to 2-month-old infants. We compared antibody levels following separate but simultaneous administration of diphtheria and tetanus toxoids with acellular pertussis vaccine (DTaP) containing pertussis toxoid, filamentous hemagglutinin, and pertactin (PRN); hepatitis B vaccine; and Haemophilus influenzae type b polysaccharide (polyribosylribitol phosphate; PRP) vaccine conjugated to tetanus toxoid (PRP-T) with those following administration of a combination of a DTaP-hepatitis B vaccine-PRP-T to infants at 2, 4, and 6 months of age. The antibody response to a booster dose of PRP conjugate vaccine (CRM197-OS) in infants with low (< 1 microgram/mL) or undetectable (< 0.10 microgram/mL) postpriming levels of antibody to PRP was also studied. Antibody levels were quantitated before and after dose 3 by enzyme-linked immunosorbent assay, radioimmunoassay, or neutralization assay. Seroresponse rates were not different between the two vaccine groups except for rates of response to PRP. There was a trend that levels of antibody to all the antigens included in the combination vaccine were lower than those of antibody to antigens in separate vaccines; for levels of antibody to diphtheria toxoid (P = .001), PRN (P < .0001), and PRP (P < .0001), the differences were significant. Despite low or undetectable postpriming levels of antibody to PRP, high-titered (geometric mean concentration, 9.02 micrograms/mL; range, 1.0-81.5 micrograms/mL), immunoglobulin G-predominant antibody to PRP was produced following a booster dose of CRM197-OS, a finding consistent with a memory response. At 2 months of age, 145 infants were randomized to receive either a two-component acellular pertussis vaccine [lymphocytosis-promoting factor (LPF)/filamentous hemagglutinin (FHA)] or standard whole-cell pertussis vaccine, each combined with diphtheria-tetanus toxoids, as their primary immunization series. Of the 132 subjects (91%) who completed the study, those receiving the acellular vaccine had significantly fewer adverse reactions: 5% vs 30% (local) and 17% vs 30% (systemic, including fever). During the first 24 hours acetaminophen usage, a general measure of adverse reactions, was lower in the test group. Overall, 35% of the acellular vaccine doses were reaction free vs 12% of the whole-cell doses. No serious reactions occurred in either group. Antibody responses to LPF and to FHA were significantly increased after the second and third immunizations with the test vaccine and were consistently higher than levels achieved with the standard vaccine. Thus the two-component acellular pertussis vaccine was associated with fewer adverse reactions and improved serologic responses to LPF and FHA as compared with the currently recommended whole-cell vaccine. Clinical and serological responses of infants to primary immunization with diphtheria-tetanus-pertussis (DTP) vaccine containing components of acellular pertussis vaccine (DTP-AC) were compared in a double-blind study with responses of infants receiving whole-cell DTP vaccine (DTP-WC). Three doses of either DTP-AC containing lymphocytosis-promoting factor (LPF) and filamentous hemagglutinin (FHA) or DTP-WC vaccine were given to infants at two, four, and six months of age. Nineteen infants received DTP-AC vaccine, and 20 infants received DTP-WC vaccine. Significantly more infants who received DTP-WC vaccine manifested fever, swelling, and/or total reactions than did infants who received DTP-AC vaccine. Infants who received DTP-AC vaccine had comparable antibody titers to LPF and significantly higher titers to FHA after three immunizations, as compared with the infants who received DTP-WC vaccine (P less than or equal to .001). The DTP-WC vaccine stimulated higher pertussis agglutination titers (P = .04) than did DTP-AC. The DTP-AC vaccine was immunogenic and significantly less reactogenic in infants than was the currently used DTP-WC vaccine. We compared an acellular (B type) pertussis-component diphtheria-tetanus-pertussis (DTP-Ac) vaccine containing equal amounts of filamentous hemagglutinin and lymphocytosis-promoting factor with a conventional whole-cell vaccine as the first booster immunization in 162 healthy children 15 to 24 months of age. Fewer local reactions (e.g., erythema, swelling, and tenderness at the injection site) were seen in DTP-Ac vaccine recipients during the first 48 hours of observation. This group also had fewer episodes of fever (> or = 38 degrees C) and other systemic reactions (e.g., irritability, drowsiness, and anorexia). Overall, 57% of the DTP-Ac vaccine recipients had no obvious adverse reactions, in contrast to 5% in the comparison group. At 4 to 8 weeks after vaccination, serum antibody responses to filamentous hemagglutinin and lymphocytosis-promoting factor were greater in recipients of the acellular vaccine as determined by an enzyme-linked immunosorbent assay. We conclude that this B-type acellular vaccine is both immunogenic and much less likely to cause an adverse reaction than a currently licensed whole-cell vaccine, and is suitable for routine booster immunizing doses to protect against pertussis. To evaluate the safety and immunogenicity of 6 different acellular pertussis vaccines combined with diphtheria and tetanus toxoids (DTaP) and with 1 licensed whole-cell pertussis vaccine (DTwP) as a fifth dose in children who had previously received the same DTaP, a different DTaP, or DTwP as primary and fourth-dose vaccinations.
                Healthy 4- to 6-year-old children were enrolled at 5 National Institute of Allergy and Infectious Diseases Vaccine Treatment and Evaluation Units to receive a fifth dose of a DTaP or DTwP vaccine. All had been randomly assigned to receive 3 primary doses of DTaP or DTwP at 2, 4, and 6 months and a fourth-dose booster at 15 to 20 months of age as part of earlier National Institutes of Health multicenter acellular pertussis vaccine trials. 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 by enzyme-linked immunosorbent assay for antibody to pertussis toxin, filamentous hemagglutinin, fimbriae, pertactin, and diphtheria and tetanus toxoid. Safety and/or immunogenicity data are reported for 317 children who received DTaP and 10 children who received DTwP.
                Fever and moderate or severe irritability were uncommon following the fifth dose of DTaP vaccine and were generally less frequent than following the fourth dose. However, for the DTaP vaccine groups, redness, swelling, and pain increased in prevalence compared with the fourth dose. The time course and frequency of reactions following DTaP vaccination were generally similar in children who received the same DTaP, a different DTaP, or DTwP for previous doses in the 5- dose series. No significant differences among the DTaP vaccines were detected in the occurrence of reactions, but the statistical power to detect differences was limited by sample size. Significant increases in antibodies directed against the included antigens were observed for all DTaP vaccines in paired pre- and post-fifth dose sera. Post-fifth dose antibody concentrations differed significantly among the DTaP vaccines. Some children in the study showed an antibody response to an antigen not reported to be in the DTaP vaccine.
                All the studied DTaP vaccines performed similarly with regard to reactions, whether given as a fifth sequential dose of the same vaccine, a mix of different DTaP vaccines in the 5-dose sequence, or after 3 DTwP and 1 DTaP vaccinations. Large injection site reactions occurred more frequently after the fifth dose of DTaP than after the previous 4 doses. A fifth dose of all DTaP vaccines induced an antibody response to those antigens contained in the vaccine. No DTaP was consistently most or least reactogenic or immunogenic. A field study was undertaken in Tampa, Fla., to assess the efficacy of subcutaneous and aerosol methods of administering vaccine, and to compare the protection afforded by bivalent (A2 and B) influenza virus vaccine and by A2/Hong Kong/68 virus vaccine. Further objectives of the study included a comparison of the effectiveness of single-dose and 2-dose immunization. Approximately 2100 volunteers received, in a double-blind manner, both an injection and an aerosol administration on 2 occasions 3 weeks apart. The results showed that aerosol administration gave a lower over-all protection rate, although the booster dose seemed to have a marked effect. The protection afforded by A2/Hong Kong/68 virus vaccine was considerably greater than that afforded by the bivalent vaccine, particularly when administration was subcutaneous. Results are also given on the occurrence of side-effects and on the correlation between cigarette smoking and the occurrence of influenza-like illness. The DTPw-HB/Hib pentavalent combination vaccine has been developed following recommendations of the World Health Organization for the introduction of hepatitis B (HB) and Haemophilus influenzae type b (Hib) vaccines into routine childhood vaccination programs. The objectives of this study were to: 1) analyze the immunogenicity and the reactogenicity of the DTPw-HB/Hib pentavalent combination vaccine in comparison to separate injections of DTPw-HB and Hib vaccines as primary vaccination in a group of children who had received a dose of HB vaccine at birth and 2) in the second year of life to assess the antibody persistence as well as the response to a DTPw-HB/Hib or DTPw/Hib booster.
                In the first part of the study (primary-vaccination stage), conducted in 1998-1999, we analyzed the immunogenicity and reactogenicity of the DTPw-HB/Hib combination vaccine in comparison to separate injections of DTPw-HB and Hib vaccines as primary vaccination at 2, 4, and 6 months of age in 207 Costa Rican children who had received a dose of HB vaccine at birth. Later, in the booster-vaccination stage of the study, in 1999-2000, in a subset of the children (69 toddlers, now 15-18 months old), antibody persistence was measured, and response to a DTPw-HB/Hib or DTPw/Hib booster was also assessed.
                In both primary-vaccination groups, at least 97.5% of the infants reached protective levels of antibodies (seropositivity) against the antigens employed in the vaccines. The DTPw-HB/Hib pentavalent combination vaccine did not result in more local reactions than did the DTPw-HB vaccine alone, and, in terms of general reactions, there was no clinically significant difference between the combination or separate injections, and with the pentavalent vaccine having the benefit of needing one less injection. Nine months after the third dose of the primary-vaccination course, antibody persistence was similar in both groups, with over 93% of children still having protective/seropositive titers for Hib, HB, and tetanus and about 50% for diphtheria and Bordetella pertussis. At 15 months of age, virtually all the toddlers responded with a strong boost response to all the vaccine antigens, whether they received the DTPw-HB/Hib pentavalent vaccine or the DTPw/Hib vaccine as a booster. Both booster regimens were equally well tolerated, indicating that up to five doses of the HB vaccine can be given without impact on safety.
                Our study confirms that the DTPw-HB/Hib pentavalent vaccine is highly immunogenic as a primary vaccination in children who received an HB vaccine at birth, with the pentavalent combination inducing both persisting immunity and boostable memory. The pentavalent vaccine was safe both for primary and booster vaccinations. Thus, this study in Costa Rican infants supports the routine use of the pentavalent DTPw-HB/Hib vaccine as part of childhood vaccination programs in Latin America and the Caribbean. RTS,S/AS02A is a pre-erythrocytic malaria vaccine candidate in which a portion of the circumsporozoite surface protein (CSP) of Plasmodium falciparum is genetically linked to hepatitis B surface antigen (HBsAg) coexpressed in yeast with unfused HBsAg. The resulting particulate antigen is formulated with the adjuvant system AS02A. We have initiated the paediatric clinical development of this vaccine by conducting two sequential Phase I studies in children: a study in older children (6--11 years), followed by a second study in younger children (1--5 years). In each study, a double-blind, randomised controlled, staggered, dose-escalation design was used to evaluate 10 microg RTS,S dose (10 microg RTS,S in 0.1mL AS02A), 25 microg dose (25 microg RTS,S in 0.25mL AS02A) and finally a 50 microg dose (50 microg RTS,S in 0.5mL AS02A) of the RTS,S/AS02A candidate malaria vaccine administered according to a 0-, 1- and 3-month vaccination schedule. Safety and reactogenicity were evaluated before moving to a higher dose level. The RTS,S/AS02A vaccine was safe at all dose levels, in both age groups. No serious adverse events related to vaccination were reported. The frequency of local Grade 3 symptoms was low but tended to increase with increasing dose level. Grade 3 general adverse events in the RTS,S/AS02A groups were infrequent and of short duration. The majority of local and general Grade 3 symptoms resolved or decreased in intensity within 48h. The pattern and intensity of reactogenicity seen in these studies are similar to those of previous studies with RTS,S/AS02A. All doses were highly immunogenic for anti-CSP and anti-HBsAg antibodies. The pooled anti-CSP antibody data from the two studies showed that the 25 microg dose and 50 microg dose anti-CSP antibody response were similar at both dose levels. However, the immunogenicity of the 10 microg dose anti-CSP response was significantly lower than that of either the 50 microg or 25 microg dose. The 25 microg dose was selected for future studies of RTS,S/AS02A in paediatric populations. To assess the efficacy of a 7-valent pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine (PncOMPC) against acute otitis media (AOM), 1666 infants were randomly assigned to receive either PncOMPC or control vaccine (hepatitis B vaccine) at 2, 4, 6, and 12 months of age. Of the 835 children assigned to receive PncOMPC, 187 received a 23-valent pneumococcal polysaccharide vaccine (PncPS) at 12 months of age instead. Whenever AOM was diagnosed, middle ear fluid was aspirated for bacterial culture. In the PncOMPC and control groups, there were 110 and 250 AOM episodes, respectively, in children between 6.5 and 24 months of age that could be attributed to vaccine serotypes, which indicates a vaccine efficacy of 56% (95% confidence interval, 44%-66%). The serotype-specific efficacy ranged from 37% for 19F to 82% for 9V. The 2 boosters seemed to provide equal protection against AOM, but PncPS induced markedly higher antibody concentrations. The efficacy of PncOMPC was comparable to that of the recently licensed pneumococcal conjugate vaccine. Seventeen triply seronegative infants and young children, and 15 infants and young children seropositive to all three influenza virus strains were vaccinated intranasally with 10(5) TCID50 of each of three (H1N1, H3N2, and B) live attenuated, cold-adapted influenza vaccine strains. Seventeen controls were given placebo. Vaccination with trivalent influenza vaccine was not associated with adverse reactions in triply seronegative or seropositive children. Overall, 12 (71%), 13 (76%), and 13 (76%) of seronegative children were infected by H1N1, H3N2, or B vaccine viruses, respectively, as indicated by viral shedding or by hemagglutination inhibition assay or ELISA antibody response. Of the triply seronegative children, 47% shed all three viruses; 7 children had an antibody rise to all three vaccine viruses and 4 shed all three viruses. A dose of 10(4.4) - 10(5.0) TCID50 of each of three intranasally administered vaccine viruses was safe, immunogenic and antigenic; however, strategies to increase the proportion of children infected by each of the vaccine viruses should be studied, including higher doses and multiple doses of live trivalent vaccine. An open, randomised, multicentre trial was performed to compare the reactogenicity and safety profile of the administration of a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio (DTPa-HBV-IPV) vaccine administered in one injection mixed with Haemophilus influenzae type b (Hib) conjugate vaccine (Group 1) with that of a pentavalent DTPa-IPV vaccine mixed with a Hib vaccine (DTPa-IPV/Hib), simultaneously administered with HBV (Group 2) in two injections in opposite thighs, as a primary vaccination course, to healthy infants at 2, 4 and 6 months of age. A total of 235 completed the study, 120 from Group 1 and 115 from Group 2. Blood samples (pre-vaccination and 1 month after the third dose) were obtained from a subset of infants (Group 1: 40; Group 2: 31) to assess the immune response to vaccination. Local and general solicited symptoms were recorded by parents on diary cards. Seven hundred and five diary cards (Group 1: 360; Group 2: 345) were collected. The clinically relevant and most commonly reported local reaction was pain (infant cried when the limb was moved) in 2.5% (Group 1) and 1.2% (Group 2) of diary cards. Fever was more frequently reported in Group 1 (21% of diary cards) than in Group 2 (12% of diary cards). However only 3 and 2% of doses in Groups 1 and 2, respectively, were responsible for a rectal temperature between 38.6 and 39.5 degrees C and only one case (Group 2) had > or =39.5 degrees C. Other clinically relevant general symptoms were rarely recorded: irritability (2-2.8%), loss of appetite (0.3-0.6%) and drowsiness (0.3-0.3%). All subjects included in the immunogenicity analysis had seroprotective titres to diphtheria, tetanus, polio virus types 1 and 3, Hib. Almost all subjects were seroprotected for anti-polio type 2 and hepatitis B (with the exception of 1 subject in Group 1 for each antigen). The vaccines response rates to pertussis antigens were over 97 and 90% in Groups 1 and 2, respectively. This study shows that, from a clinical perspective, the DTPa-HBV-IPV/Hib vaccine given in a single injection has a similar reactogenicity and safety profile to that of two licensed vaccines (DTPa-IPV/Hib, HBV) given in two simultaneous injections to infants at 2, 4 and 6 months of age. This is a valuable advantage, since in some countries, such as Spain and the UK, an additional injection (for the administration of meningococcal C conjugate vaccine) has been recently included in the infants' vaccination calendars. Combination vaccines are urgently needed to reduce the number of injections given to young children. The aim of the study was to evaluate the safety and immunogenicity of a combination vaccine that contains diphtheria and tetanus toxoids and acellular pertussis antigens (DTaP), recombinant hepatitis B surface antigen (HepB) and Haemophilus influenzae type b (Hib) polysaccharide conjugated to tetanus toxoid (PRP-T).
                Four hundred five infants were randomized equally to three groups and immunized at 2, 4 and 6 months of age with: (1) DTaP/HepB vaccine used to reconstitute lyophilized PRP-T vaccine and administered as a single injection; (2) DTaP/HepB vaccine and PRP-T vaccine administered as two separate injections; or (3) DTaP, HepB and PRP-T vaccines administered as three separate injections. Safety was closely monitored, and blood specimens were obtained to assess antibody responses to each vaccine antigen.
                All study vaccines were well-tolerated, and the rates of systemic and injection site reactions were similar between groups. After the third dose the geometric mean antibody concentrations to Hib were significantly lower in subjects in Group 1 (1.63 microg/ml) compared with subjects in Groups 2 and 3 (6.26 and 6.15 microg/ml, respectively; P < 0.0001). Subjects with antibody concentrations <1.0 microg/ml after the third dose responded well to a booster dose of Hib conjugate vaccine given at 11 to 15 months of age (41 of 44 with anti-PRP > or = 1.0 microg/ml). Differences between groups for antibody responses to the other vaccine components were not clinically significant.
                Infants given a combined DTaP/ HepB/PRP-T vaccine experienced a significantly lower antibody response to the PRP-T component than infants given PRP-T vaccine as a separate injection. However, the immune response to a booster dose of Hib conjugate vaccine indicated the presence of immunologic memory. To evaluate the safety and immunogenicity of the recombinant acellular pertussis-diphtheria-tetanus (aPDT) vaccine (C-aPDT, Chiron/Biocine).
                This is a randomized blinded trial evaluating the safety and immunogenicity of the recombinant aPDT vaccine (C-aPDT, Chiron/Biocine) in 2000 infant recipients compared with 498 controls who received whole cell diphtheria-pertussis-tetanus (wDPT; Connaught) vaccine at 2, 4 and 6 months of age. In addition the safety and immunogenicity of the same C-aPDT vaccine were evaluated as a booster dose in a subset of the same population when given at 15 to 18 months of age and compared with licensed Lederle aPDT vaccine.
                The C-aPDT vaccine was associated with very few local or systemic reactions when compared with wDPT. In toddlers the local and systemic side effects observed were similar after either acellular vaccine. When the immunogenicity of the C-aPDT vaccine was compared with the wDPT (Connaught) in infancy, the vaccines were equivalent for anti-diphtheria response, the wDPT developed higher anti-tetanus response and the C-aPDT vaccine was significantly more immunogenic for all other antigens tested. In toddlers the C-aPDT acellular vaccine exhibited equal or improved immunogenicity for antigens tested as compared with Lederle aPDT except for a higher anti-filamentous hemagglutinin response with the Lederle aPDT vaccine.
                The Chiron/Biocine aPDT vaccine offers an improved safety profile as well as improved immunogenicity when compared with a licensed wDPT product. Although inactivated hepatitis A vaccine is known to be well tolerated and immunogenic in healthy children and adults, its efficacy has yet to be established.
                To evaluate the efficacy of the hepatitis A vaccine in protecting against clinically apparent disease, we conducted a double-blind, placebo-controlled trial in an Hasidic Jewish community in upstate New York that has had recurrent outbreaks of hepatitis A. At the beginning of a summer outbreak, 1037 healthy seronegative children 2 to 16 years of age were randomly assigned to receive one intramuscular injection of a highly purified, formalin-inactivated hepatitis A vaccine or placebo. A case was defined by the presence of typical signs and symptoms, a diagnostic increase in IgM antibody to hepatitis A, and a serum concentration of alanine aminotransferase at least twice the upper limit of normal. Cases occurring greater than or equal to 50 days after the injection were included in the evaluation of efficacy. The children were followed for a mean of 103 days.
                A total of 519 children received vaccine, and 518 received placebo. The vaccine was well tolerated, with no serious adverse reactions. From day 50 after the injection, 25 cases of clinically apparent hepatitis A occurred in the placebo group and none in the vaccine group (P less than 0.001), confirming that the vaccine had 100 percent protective efficacy. Before day 21, seven cases occurred in the vaccine group and three cases in the placebo group. After that time, there were no cases among vaccine recipients and 34 cases among placebo recipients.
                The inactivated purified hepatitis A vaccine that we tested is well tolerated, and a single dose is highly protective against clinically apparent hepatitis A. The pentavalent rotavirus vaccine (PRV), RotaTeq, can be concomitantly administered with most routine childhood vaccines. This study evaluated the immunogenicity and reactogenicity of PRV when used concomitantly with a hexavalent vaccine containing diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus, and Haemophilus influenzae type b.
                Healthy infants (N = 403) received hexavalent vaccine concomitantly with either PRV or placebo at 2, 3, and 4 months of age. Antibody responses were measured immediately before and 42 +/- 3 days after vaccination. Parents/legal guardians recorded all adverse events for 14 days after vaccination.
                Seroprotective titers for hepatitis B (hepatitis B surface antigen > or =10 mIU/mL) were achieved by 97.8% of subjects in both vaccine treatment groups. Seroprotective titers to H. influenzae type b (polyribosylribitol phosphate > or =0.15 microg/mL) were achieved by 91.4% of subjects receiving both vaccines and 95.1% of subjects receiving only hexavalent vaccine. Seroprotective titers to diphtheria, tetanus, and poliovirus were also comparable between the vaccine treatment groups, as were geometric mean antibody titers to the pertussis antigens. Among PRV recipients, 92% had a > or =3-fold rise in serum antirotavirus immunoglobulin A levels. Concomitant administration was well tolerated. The incidence of adverse events was similar for both groups, with no statistically significant increases in fever, vomiting, diarrhea, or irritability.
                In this study, concomitant administration of PRV with hexavalent vaccine was well tolerated and the immune responses to the antigens of the hexavalent vaccine were noninferior when compared with those of the control group. In addition, PRV was immunogenic when administered concomitantly with hexavalent vaccine. The efficacy of the pentavalent rotavirus vaccine (PRV), RotaTeq(®), was evaluated in a double-blind, placebo-controlled, multicenter Phase III clinical trial conducted (April 2007-March 2009) in 3 low-income countries in Africa: Ghana, Kenya, and Mali. In total, 5468 infants were randomized 1:1 to receive 3 doses of PRV/placebo at approximately 6, 10, and 14 weeks of age; concomitant administration with routine EPI vaccines, including OPV, was allowed. HIV-infected infants were not excluded. The primary endpoint, vaccine efficacy (VE) against severe-rotavirus gastroenteritis (RVGE), as measured by Vesikari scoring system (VSS, score ≥11), from ≥14 days following Dose 3 through a follow-up period of nearly 2 years in the combined 3 African countries, and secondary endpoints by total follow-up period have been previously reported. In this study, we report post hoc subgroup analyses on secondary endpoints of public health importance. VE against RVGE of any severity was 49.2% (95%CI: 29.9, 63.5) through the first year of life and 30.5% (95%CI: 16.7, 42.2) through the complete follow-up period. VE against severe-gastroenteritis of any etiology was 21.5% (95%CI: <0, 38.4) through the first year of life and 10.6% (95%CI: <0, 24.9) through the complete follow-up period. Through the complete follow-up period, VE against severe-RVGE caused by (i) vaccine-contained G and P types (G1-G4, P1A[8]), (ii) non-vaccine G types (G8, G9, G10), and (iii) non-vaccine P types (P1B[4], P2A[6]) was 34.0% (95%CI:11.2, 51.2), 81.8% (95%CI:16.5, 98.0) and 40.7% (95%CI:8.4, 62.1), respectively. There was a trend towards higher VE with higher disease severity, although in some cases the numbers were small. In African countries with high under-5 mortality rates, PRV significantly reduced RVGE through nearly 2 years of follow-up; more modest reductions were observed against gastroenteritis of any etiology. PRV provides protection against severe-RVGE caused by diverse rotavirus genotypes, including those not contained in the vaccine.
                Copyright © 2012 Elsevier Ltd. All rights reserved. In a strictly controlled epidemiological trial on 12,643 school children aged 11-14 years the reactogenic properties and safety of killed influenza chromatographic vaccine under the conditions of multiple immunization were studied. A single immunization dose of the vaccine (0.2 ml) contained the hemagglutinins of influenza viruses A/Philippines/82 (H3N3) and A/Kiev/59/79 (H1N1), 3.5 micrograms each. The preparation was introduced by means of a jet injector. The vaccine was shown to be clinically and immunologically safe under the conditions of the regular multiple immunization of children over the period of 4 years. It has been suggested that administering vitamin A with the measles vaccine may reduce the vaccine's immunogenicity. This trial examined the effect of supplementing vitamin A during the early months of life on infants' immune responses to tetanus and polio vaccines. Young infants (n = 1085) were enrolled and individually randomized into 1 of 4 groups in a factorial, double-blind, placebo-controlled trial. Three vitamin A supplementation strategies were investigated: 1) supplementation of breast-feeding mothers with 60 mg retinol equivalent (RE) vitamin A within 4 wk of delivery; 2) Expanded Program on Immunization (EPI)-linked supplementation of infants with 7.5 mg RE vitamin A at 6, 10, and 14 wk; and 3) combined mother and child supplementations. A 4th group in which mother and child were given placebos served as controls. Blood samples were collected from each child at 6 wk and 6 mo of age to measure antipolio antibody titer, antitetanus toxoid antibodies, and avidity of antibodies to tetanus. Of the infants randomized into the 4 arms of the study, 767 (71%) completed follow-up at 6 mo of age. Follow-up rates were similar in all 4 arms (69-72%, P = 0.8). Antibody titers were relatively high in all 4 groups at both 6 wk and 6 mo of age, with no differences among the groups. We found no evidence that vitamin A supplementation affects infants' antibody responses to tetanus toxoid or oral polio vaccine delivered at EPI contacts.
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.