中国婴幼儿接种吸附无细胞百白破灭活脊髓灰质炎和b型流感嗜血杆菌(结合)联合疫苗的安全性和免疫原性研究

目的 比较吸附无细胞百白破灭活脊髓灰质炎和b型流感嗜血杆菌(结合)联合疫苗(DTaP-IPV//PRP～T联合疫苗)与吸附无细胞百白破联合疫苗(DTaP)、b型流感嗜血杆菌结合疫苗(Hib结合疫苗)、注射用灭活脊髓灰质炎疫苗(IPV)的免疫原性和安全性.方法 受试者随机分为三组.试验组(A组和B组)分别于2、3、4月龄...     

Associated or combined vaccination of Brazilian infants with a conjugate Haemophilus influenzae type b (Hib) vaccine, a diphtheria-tetanus-whole-cell pertussis vaccine and IPV or OPV elicits protective levels of antibodies against Hib

This study investigated the immunogenicity and safety of including a Haemophilus influenzae type b vaccine (polyribosylribitol phosphate conjugated to tetanus toxoid, PRP-T) in three different vaccination schemes: (1) PRP-T reconstituted with a combined diphtheria-tetanus-pertussis-inactivated poliovirus vaccine (DTP-IPV//PRP-T); (2) PRP-T reconstituted with DTP and administered concomitantly with an oral poliovirus vaccine (DTP//PRP-T+OPV); and (3) PRP-T administered concomitantly with DTP at a different injection site and OPV (DTP+PRP-T+OPV). Vaccines were given at 2, 4, and 6 months of age. A total of 252 infants were enrolled, and randomly assigned to one of the three vaccination groups (84 infants in each group); 241 infants were followed until the end of the study. Antibody production against PRP, diphtheria, tetanus and pertussis antigens was satisfactory for each vaccination scheme used. A good response to Hib vaccine was elicited in each group, and 3 months after the third vaccine dose, at least 97% of children in each group had levels of PRP antibody considered to be seroprotective (>0.15 microg/ml), and over 90% of children in each group had levels over 1. 0 microg/ml. The solicited local and systemic adverse events following vaccination were mild in all groups and resolved within 4 days without medical intervention. With the exception of fever, which was more common after the second dose in children who received DTP-IPV//PRP-T, local and systemic reactions did not differ between the vaccination groups. Due to the practical advantages of combined vaccines, their use in routine immunization programs in developing countries is highly desirable. Our results show that Hib conjugate vaccine can be included in routine immunization programs that include either OPV or IPV with satisfactory immunogenicity and safety profiles. This flexible approach should facilitate the inclusion of the Hib conjugate vaccine in routine immunization programs on a world-wide scale.     

Immunogenicity and safety of four different doses of Haemophilus influenzae type b-tetanus toxoid conjugated vaccine, combined with diphtheria-tetanus-pertussis vaccine (DTP-Hib), in Indonesian infants

Widespread use of Haemophilus influenzae type b (Hib) conjugated vaccine in industrialized countries has resulted in a dramatic decline in the incidence of invasive Hib diseases, but the vaccine's cost has prevented its inclusion in basic immunization programs in developing countries. To overcome this problem, combination with diphtheria-tetanus-pertussis (DTP) vaccine or reduction in the dose of Hib vaccine has been proposed. To evaluate the immunogenicity and adverse reactions from lower doses of Hib-polyribosylphosphate (PRP) conjugated with tetanus toxoid (PRP-T), a double-blind study was conducted in Jakarta, Indonesia, and its suburbs. A total of 1048 infants 6 weeks to 6 months of age received three doses of DTP vaccine combined with the usual 10 microg dose or with a reduced dose of 5, 2.5 or 1.25 microg of PRP-T at two-monthly intervals. Antibodies were measured prior to the first dose and 4-6 weeks following the third dose. Adverse reactions were similar among all four groups. The only significant difference was a higher rate of irritability (p<0.02) and of temperature elevation >38 degrees C (p<0.009) after doses 1 and 2 in the lowest dose group (1.25 microg PRP-T) compared to the other groups. All participants tested had a 4-fold increase in antibodies against all DTP antigens. In addition, after a fourth booster dose of Hib, 99.6% of infants produced >or=0.15 microg/ml of antibody to Hib-PRP, and 96.4% showed levels >or=1.0 microg/ml after primary immunization, level that correlate with short- and long-term immunity, respectively. Antibody titers to the PRP antigen showed no significant differences among dosage groups with the exception of the 5.0 microg group, which had a significantly higher GMC than the 1.25 microg group (p<0.012). This study demonstrates that primary vaccination with half, one-fourth, or one-eighth of the usual dose of PRP-T, combined with DTP vaccine, produces protective immune responses, and has side effects that are comparable to DTP vaccination alone. In these lower dosages, PRP-T conjugate vaccine can lower vaccine costs to a level that is affordable for infant immunization programs in developing countries.     

The effect of reconstitution of an Haemophilus influenzae type b-tentanus toxoid conjugate (PRP-T) vaccine on the immune responses to a diphtheria-tetanus-whole cell pertussis (DTwP) vaccine: a five-year follow-up.

Controversial results have been obtained from previous studies on the combined administration of Haemophilus influenzae type b-tetanus toxoid conjugate (PRP-T) and diphtheria-tetanus-whole-cell pertussis (DTwP) combination vaccines, with regard to possible reciprocal interference between the constituent antigens. To document the priming effect and possible long-term immunogenic interference of PRP-T and DTwP combination vaccines, a randomized, double-blind, controlled study was conducted in Belgium. A total of 168 healthy infants received, at 3, 4 and 5 months of age, DTwP vaccine mixed just prior to injection either with PRP-T vaccine (group A, DTwP//PRP-T, N = 85) or with placebo (group B, DTwP//Placebo, N = 83). At the age of 14 months, children of both groups were randomized to receive either a dose of DTwP//PRP-T vaccine (subgroups A1 and B1) or a dose of Hib polysaccharide (PRP) vaccine (subgroups A2 and B2). Those children in subgroups A1 and B1 had an additional serum sample taken at the age of 5 years (at the time of a DT booster). The immune response to Hib polysaccharide at the age of 4, 5 and 6 months confirmed the excellent immunogenicity profile of PRP-T in infants. In addition, the vigorous anamnestic response (i.e. a 20-fold increase of GMT) to a booster dose of the plain capsular polysaccharide (PRP) reflected the efficient Hib-priming induced by the combined DTwP//PRP-T vaccine. Reconstitution of PRP-T with DTwP did not affect the immune response to diphtheria toxoid or pertussis agglutinins. Nevertheless, at almost any time point during the five-year follow-up, the tetanus antitoxin GMT values were significantly lower in the DTwP//PRP-T group (A and A1) than in the DTwP//Placebo group (B and B1). Despite the suppressive effect on GMT values, intergroup differences in rates of seroprotection were never significant, except after doses 2 and 3 for which there were lower percentages of children in group A with antitoxin titers > 0.05 IU/mL and > 1.0 IU/mL. In the group primed with the combined DTwP//PRP-T vaccine, (1) a DT booster dose at the age of 5 years provoked a 150-fold increase in tetanus antitoxin GMT, (2) a high tetanus antitoxin GMT value was attained (GMT = 19.3 IU/mL) and (3) all children in this group had tetanus antitoxin titers > 1.0 IU/mL, so it may be concluded that all these children will still be protected against tetanus until at least the age of the next recommended booster dose (i.e. the age of 15 years). No differences in the occurrence of adverse events were observed between the groups who received the DTwP//PRP-T vaccine or the DTwP//Placebo vaccine, both vaccines being associated with events customarily attributable to DTwP (data not shown). Our results indicate (1) that the combination vaccine, DTwP//PRP-T, represents a safe and effective alternative for the existing uncombined vaccines and (2) that the long-term effect of interference between the components of future combination vaccines should be studied with subsequent booster doses, followed by the evaluation of persistence of antibodies over several years.     

Safety and immunogenicity of combined diphtheria-tetanus-pertussis (whole cell and acellular)-Haemophilus influenzae-b conjugate vaccines administered to Indonesian children

A randomized double-blind trial was conducted to evaluate the safety and immunogenicity of vaccines comprised of diphtheria (D) and tetanus (T) toxoids combined with either a whole cell (P) or an acellular (aP) pertussis component and Haemophilus influenzae type b polyribosylphosphate (PRP) tetanus toxoid conjugate (PRP-T) in Indonesian infants. Three doses of either DTaP, DTaP-PRP-T, or DTP-PRP-T were administered to 930 infants approximately 2-3 months of age and at 2 month intervals thereafter. A booster dose of either DTP-PRP-T or DTaP-PRP-T was administered at 15-18 months of age. Both local and systemic reactions occurred at a significantly (p < 0.001-0.026) higher rate in the group that received whole cell pertussis vaccine versus groups which were immunized with aP containing vaccines. There was no significant difference (p > 0.05) in the rate of adverse events between groups immunized with DTaP or DTaP PRP T. One month after the third dose of vaccine, 99% of subjects had achieved > or =0.1 IU of anti-D and anti-T antibody per ml of serum. The geometric mean titer (GMT) to D was significantly (p < 0.001) higher in the group immunized with DTaP versus the other two groups whereas the anti-T GMT was significantly (p < 0.006) higher for the group immunized with DTP-PRP-T. Both the anti-pertussis toxin (PT) and anti-filamentous hemagglutinin (FHA) antibody levels were significantly (p < 0.001) higher in recipients of acellular versus whole cell pertussis vaccine. In contrast, the anti-B. pertussis agglutinating antibody response was significantly (p < 0.0001) higher in the group immunized with whole cell pertussis vaccine. The anti-PRP GMTs (microg antibody/ml) at 7 months were 0.096, 3.35 and 6.11 for groups immunized with DTaP, DTaP-PRP-T and DTP-PRP-T, respectively. The GMT for those immunized with DTP-PRP-T was significantly (p < 0.001) higher compared to recipients of DTaP-PRP-T. The percent of children who attained > or =0.15 or > or =1 microg/ml after immunization was 18 and 2% for the DTaP group, 93 and 76% for the DTaP-PRP-T group and 97 and 88% for the DTP-PRP-T group. At the > or =1 microg/ml level the difference between the DTaP-PRP0-T and DTP-PRP-T groups was significant (p < 0.01). Children immunized with either DTaP, DTaP-PRP-T, or DTP-PRP-T were reimmunized with DTaP-PRP-T whereas a portion of children immunized with DTP PRP T where also boosted with this vaccine at 15-18 months of age. There was a vigorous anamnestic response to the D and T components with all children possessing > or =0.1 IU/ml. There was also a substantial increase in anti-PT, anti-FHA and B. pertussis agglutinating antibodies. The poorest anti-PT response was seen among children receiving DTP-PRP-T for both primary and reimmunization while the highest agglutinating antibody response followed receipt of 4 doses of DTP-PRP-T. Greater than 80% of children immunized with either DTP PRP T or DTaP-PRP-T possessed > or =0.15 microg/ml before boosting versus 38% for those vaccinated with DTaP (p < 0.001). Primary immunization with DTP-PRP-T resulted in a significantly (p < 0.05) higher percentage (72%) maintaining > or =1 microg/ml compared to those immunized with DTaP-PRP-T (46%). Prior to reimmunization, the anti-PRP GMT was significantly (p < 0.005) higher for children immunized with 3 doses of DTP-PRP-T versus DTaP-PRP-T. Subsequent to reimmunization, > or =95% of subjects attained > or =1 microg/ml.     

Immunogenicity and safety of a fully liquid aluminum phosphate adjuvanted Haemophilus influenzae type b PRP-CRM197-conjugate vaccine in healthy Japanese children: A phase III,randomized, observer-blind,multicenter, parallel-group study

BackgroundBroad use of monovalent Haemophilus influenzae type b (Hib) conjugate vaccines based on the capsular polysaccharide polyribosyl-ribitol phosphate (PRP), has significantly reduced invasive Hib disease burden in children worldwide, particularly in children aged <1 year. In Japan, PRP conjugated to tetanus toxoid (PRP-T) vaccine has been widely used since the initiation of public funding programs followed by a routine vaccination designation in 2013.MethodsWe compared the immunogenicity and safety of PRP conjugated to a non-toxic diphtheria toxin mutant (PRP-CRM₁₉₇) vaccine with the PRP-T vaccine when administered subcutaneously to healthy Japanese children in a phase III study. Additionally, we evaluated the immunogenicity and safety profiles of a diphtheria–tetanus acellular pertussis (DTaP) combination vaccine when concomitantly administered with either PRP-CRM₁₉₇ or PRP-T vaccines. The primary endpoint was the “long-term seroprotection rate”, defined as the group proportion with anti-PRP antibody titers ⩾1.0 μg/mL, after the primary series.ResultsLong-term seroprotection rates were 99.3% in the PRP-CRM₁₉₇ group and 95.6% in the PRP-T group. The intergroup difference (PRP-CRM₁₉₇ group – PRP-T group) was 3.7% (95% confidence interval: 0.099–7.336), demonstrating that PRP-CRM₁₉₇ vaccine was non-inferior to PRP-T vaccine (p < 0.0001). Furthermore, the “short-term seroprotection rate” (anti-PRP antibody titer ⩾0.15 μg/mL) before booster vaccination was higher in the PRP-CRM₁₉₇ group than in PRP-T. Concomitant administration of PRP-CRM₁₉₇ vaccine with DTaP vaccine showed no differences in terms of immunogenicity compared with concomitant vaccination with PRP-T vaccine and DTaP vaccine. Although CRM₁₉₇ vaccine had higher local reactogenicity, overall, both Hib vaccines had acceptable safety and tolerability profiles.ConclusionThe immunogenicity of PRP-CRM₁₉₇ vaccine administered subcutaneously as a three-dose primary series in children followed by a booster vaccination 1 year after the primary series induced protective levels of Hib antibodies with no safety or tolerability concerns.Clinical trial registry: Registered on ClinicalTrials.gov: NCT01379846     

A clinical trial examining the effect of increased total CRM(197) carrier protein dose on the antibody response to Haemophilus influenzae type b CRM(197) conjugate vaccine

CRM(197) is a carrier protein in certain conjugate vaccines. When multiple conjugate vaccines with the same carrier protein are administered simultaneously, reduced response to vaccines and/or antigens related to the carrier protein may occur. This study examined responses of infants who, in addition to diphtheria toxoid/tetanus toxoid/acellular pertussis vaccine (DTaP) received either diphtheria CRM(197)-based Haemophilus influenzae type b conjugate vaccine (HbOC) or HbOC and a diphtheria CRM(197)-based combination 9-valent pneumococcal conjugate vaccine/meningococcal group C conjugate vaccine. Administration of conjugate vaccines with CRM(197) carrier protein load >50 microg did not reduce response to CRM(197) conjugate vaccines or immunogenicity to immunologically cross-reactive diphtheria toxoid.     

以吸附无细胞百日咳-白喉-破伤风疫苗为基础的联合疫苗研究进展

吸附无细胞百日咳疫苗、白喉和破伤风类毒素联合疫苗（Adsorbed Acellular Pertussis Vaccine,Diphtheria Toxoid＆Tetanus Toxoid Combined Vaccine,DTaP）已有30多年的使用历史。将DTaP与乙型肝炎疫苗（Hepatitis B Vaccine,HepB）、脊髓灰质炎灭活疫苗（Inactivated Poliovirus Vaccine,IPV）和b型流行性感冒嗜血杆菌结合疫苗（Haemophilus Influenzae Type b Conjugate Vaccine,Hib）等制备成为联合疫苗使用,可以减少接种剂次,提高受种者的依从性,从而提高疫苗接种率。但是,联合疫苗不是几种疫苗简单地混合,在将DTaP与其他疫苗联合的过程中面临许多技术挑战,如DTaP与Hib联合存在Hib免疫原性降低的问题,DTaP与HepB联合存在免疫程序不统一和HepB免疫持久性的问题,DTaP与IPV联合时,其中的防腐剂柳硫汞会降低IPV的免疫原性的问题等。现就DTaP与这些疫苗联合时所面临的技术挑战、目前的研究进展和未来发展方向作一综述。     

A comparative study of PENTA vaccine booster doses given at 12, 15, or 18 months of age

For infants immunized with Haemophilus influenzae type b conjugate vaccines, booster immunization is usually recommended in the second year of life, typically between 12 and 18 months. This study assessed the effect of age at booster immunization on pre-immunization antibody trough levels and on subsequent responses, for a PRP-T conjugate vaccine. Subjects were healthy children who had received PENTA vaccine (DPT-IPV/PRP-T combination) as infants. They were enrolled and given measles-mumps-rubella vaccine (MMR) at 12 months of age, then randomly assigned to receive PENTA vaccine concurrently with MMR or at 15 or 18 months of age. Parents were asked to note any adverse effects after PENTA vaccination. Blood samples were obtained prior to PENTA vaccination and 4 weeks later, and tested for antibodies to each antigen. In total 253 children received PENTA vaccine: 86 at 12 months, 85 at 15 months and 82 at 18 months. Injection site redness and swelling were least extensive in the youngest group (p < 0.001) but their rates of occurrence did not differ with age. Anti-PRP levels were similar in each age group prior to immunization; post-booster geometric mean concentrations (GMCs) ranged from 13.0 microg/ml in the youngest to 33.9 microg/ml in the oldest subjects (p < 0.0001). For each of the other antigens examined, booster responses were strongest at 18 months. We conclude that anti-PRP levels are stable between 12 and 18 months in children previously given PRP-T vaccine. PENTA boosters given at 12 months appear to cause milder injection site morbidity whereas those given at 18 months result in stronger responses to virtually every constituent antigen, although each age group responded satisfactorily.     

Response and persistence of antibodies to PRP-T and DTwP vaccines with concomitant administration of conjugate vaccines

We first studied the immunogenicity of PRP-T and DTwP vaccines in Filipino infants given at 6, 10 and 14 weeks concomitantly with either an aluminum adjuvanted eleven-valent pneumococcal conjugate vaccine (11PncTD) or a meningococcal diphtheria-conjugated vaccine as compared to a control group that received only DTwP/PRP-T. The GMCs and proportions of infants achieving protective antibody concentrations to DTwP and PRP-T vaccine antigens were similar among the groups. In the second phase, the control group received 11PncTD at 18 weeks and the antibody concentrations were measured at 9 months in all children; 11PncTD induced a booster response to diphtheria in the control group. There was no negative interference from concomitant administration of new conjugate vaccines. In contrast, 11PncTD can boost the antibody response to the carrier proteins.     

Immunogenicity and reactogenicity of diphtheria, tetanus and pertussis toxoids combined with inactivated polio vaccine, when administered concomitantly with or as a diluent for a Hib conjugate vaccine

In an open trial, 400 infants were randomized to vaccination with a combined diphtheria-tetanus-pertussis-inactivated polio vaccine (DTaP-IPV) either mixed with a Haemophilus influenzae type b (Hib) tetanus toxoid conjugate immediately before injection (DTaP-IPV/Hib (mix)) or given concurrently with the Hib conjugate at separate injection sites (DTaP-IPV+Hib (sep)). The pertussis component consisted of pertussis toxoid alone. The vaccines were given intramuscularly at 3, 5 and 12 months of age. No vaccine-related serious adverse events occurred. Local reactions were evaluated from diary cards completed by the parents. Infants who received DTaP-IPV/Hib (mix) experienced fewer local reactions. Sera were obtained 28-45 days after the second and third vaccinations. Total Hib capsular antibodies were similar in the two groups after the second injection but lower in the group receiving DTaP-IPV/Hib (mix) than in the group receiving DTaP-IPV+Hib (sep) after the third injection (geometric mean 6.1 vs 10.4 microg/ml). Mixing of the vaccines also led to somewhat lower diphtheria toxin antibodies (5.9 vs. 7.7 IU/ml after the third injection) while tetanus antibodies were higher (3.9 vs. 2.5 IU/ml after the third injection). Antibodies against pertussis toxin and the three polio virus types were similar in the two groups. The moderate impairment of the Hib antibody response caused by mixing of the Hib conjugate with aluminium adsorbed DTaP may be due to physicochemical interference but is probably of little clinical importance because of the ability of the Hib conjugates to induce an immunologic memory.     

A Phase III randomized,double-blind,clinical trial of an investigational hexavalent vaccine given at 2, 4, and 11–12 months

BackgroundCombination vaccines simplify vaccination visits and improve coverage and timeliness. DTaP5-HB-IPV-Hib is a new investigational, fully-liquid, combination vaccine designed to protect against 6 infectious diseases, including 5 pertussis antigens and OMPC instead of PT as conjugated protein for Hib component.MethodsIn this multicenter, double-blind, comparator-controlled, Phase III study (NCT01480258) conducted in Sweden, Italy, and Finland, healthy infants were randomized 1:1 to receive one two immunization regimens. The DTaP5-HB-IPV-Hib Group received the investigational hexavalent vaccine (DTaP5-HB-IPV-Hib) and the Control Group received Infanrix-hexa (DTPa3-HBV-IPV/Hib) at 2, 4 and 11–12 months of age. Both groups received concomitantly Prevnar 13 (PCV13) and Rotateq (RV5) or Rotarix (RV1) at 2, 4 months of age and PCV13 at 11–12 months. Subjects administered RV5 received a 3rd dose at 5 months of age.ResultsA total of 656 subjects were randomized to the DTaP5-HB-IPV-Hib Group and 659 subjects to Control Group. Immune responses to all vaccine antigens post-toddler dose were non-inferior in the DTaP5-HB-IPV-Hib Group as compared to the Control Group. Additionally, the post-dose 2 and pre-toddler DTaP5-HB-IPV-Hib anti-PRP responses were superior. The DTaP5-HB-IPV-Hib Group responses to concomitant RV1 were non-inferior compared to the Control Group.Solicited adverse event rates after any dose were similar in both groups, except for higher rates of pyrexia (6.4% difference; 95% CI: 1.5, 11.3) and somnolence (5.8% difference; 95% CI: 1.7, 9.8) in the DTaP5-HB-IPV-Hib Group. Vaccine-related serious adverse events occurred infrequently in the DTaP5-HB-IPV-Hib Group (0.3%) and the Control Group (0.5%).ConclusionsThe safety and immunogenicity of DTaP5-HB-IPV-Hib is generally comparable to Control when administered in the 2, 4, 11–12 month schedule. Early Hib responses were superior versus Control. DTaP5-HB-IPV-Hib could provide a new hexavalent option for pediatric combination vaccines, aligned with recommended immunizations in Europe.Study identification: V419-008CLINICALTRIALS.GOV identifier: NCT01480258     

Immune interaction between components of acellular pertussis-diphtheria-tetanus (DTaP) vaccine and Haemophilus influenzae b (Hib) conjugate vaccine in a rat model

We have previously shown that, consistent with clinical trial results, the immune response to a Haemophilus influenzae b (Hib) conjugate vaccine in a rat model was compromised and modulated when given combined with a DTaP3 vaccine, as compared to both vaccines given separately. The present study extended our investigation to evaluate the immunogenicity of all DTaP3 components in combined versus separate administration of Hib with DTaP3 and investigated immune interactions between Hib and individual components of DTaP3. Rats were immunised with Hib and DTaP3 or with Hib and individual DTaP3 components. Cellular and humoral immune responses to Hib and DTaP3 components were evaluated. Our results indicate that the immunogenicity of DTaP3 components was similar or greater in combined versus separate administration of Hib and DTaP3. Moreover, combined administration of Hib and TT reduced immunogenicity of both Hib and TT. Hib immunogenicity was also significantly reduced when given combined with FHA and following adsorption to Al(OH)3.     

Safety and immunogenicity of a hexavalent diphtheria–tetanus–acellular pertussis–inactivated poliovirus–Haemophilus influenzae b conjugate–hepatitis B vaccine at 2, 3, 4, and 12–14 months of age

Combination vaccines improve parental and provider satisfaction and schedule compliance by decreasing the number of injections. In a Phase 2, randomized, double-blind, multicenter study, we compared four formulations of a liquid, hexavalent diphtheria–tetanus–acellular pertussis–inactivated poliovirus–Haemophilus influenzae b conjugate–hepatitis B virus (DTaP–IPV–Hib–HBV) vaccine in 708 infants immunized at 2, 3, 4, and 12–14 months of age. The formulations contained identical DTaP and IPV components, differing in the contents of Hib polyribosylribitol phosphate (PRP) conjugate component (tetanus-toxoid [PRP-T, 12 μg] or Neisseria meningitidis outer-membrane-protein-complex [PRP-OMPC, 3 μg or 6 μg]), and in hepatitis B surface antigen (HBsAg, 10 μg or 15 μg). A minimum acceptable postdose 3 antibody response rate was defined by the lower limit of the 95% confidence interval exceeding a prespecified target. Rates of adverse events (AEs) were similar among groups, with a trend for increased solicited injection-site reactions (pain, redness, swelling) with increasing PRP-OMPC and HBsAg concentration. Serious AEs reported by eight subjects were not considered to be vaccine related. All PRP-OMPC formulations met prespecified acceptability criteria for postdose 3 immunogenicity for all antigens: PRP, HBsAg, pertussis, diphtheria, tetanus and polio. Apart from the Hib response, the postdose 3 responses obtained with the PRP-T formulation met the acceptability criterion for each antigen. Postdose 4 responses were acceptable for all antigens in all formulations. All vaccine formulations were well tolerated. The three PRP-OMPC formulations met prespecified immunogenicity criteria, and the one with the lowest PRP-OMPC concentration was selected for further optimization of immunogenicity.     

Antibody persistence, PRP-specific immune memory, and booster responses in infants immunised with a combination DTPa-HBV-IPV/Hib vaccine

A new single-injection combination vaccine against six diseases has been developed to accommodate the growing number of recommended paediatric vaccines. A pentavalent liquid diphtheria, tetanus, acellular pertussis (3-component), hepatitis B, and inactivated polio (types 1-3) combined vaccine (DTPa-HBV-IPV) is extemporaneously mixed with a lyophilized Haemophilus influenza type B (Hib) conjugate vaccine (polyribosyl-ribitol phosphate (PRP)-T) and given as a single-injection. A cohort of 368 healthy infants was initially studied to evaluate the immunogenicity and reactogenicity of this hexavalent combination given as a primary course at 2, 4, and 6 months of age. At 15 months of age, from this cohort, 219 children received a booster dose of a licensed DTPa/Hib (PRP-T) vaccine to assess the booster response, while 70 received a challenge dose of unconjugated PRP (PRP) vaccine (to evaluate Hib-specific memory) plus a separate DTPa vaccine. Seven to 10 days following plain PRP challenge, anti-PRP geometric mean antibody concentrations (GMCs) had increased 13-fold to 5.67 microg/ml, and thirty days after conjugated PRP booster vaccination, anti-PRP antibody GMCs increased 102-fold. Both responses are indicative of immune memory. Vaccination was well tolerated following all primary and booster doses, although 10.5% of booster recipients experienced >50-mm local swelling at the site of DTPa vaccination. We conclude that DTPa-HBV-IPV/Hib is safe and immunogenic for primary vaccination, and that Hib-specific memory is induced by primary vaccination.     

Assessment of nine candidate DTP-vaccines with reduced amount of antigen and/or without adjuvant as a fourth (booster-) dose in the second year of life

BACKGROUND: The incidence of local reactions to diphtheria-, tetanus and acellular pertussis (DTaP-) vaccines in infants and toddlers increases with each subsequent dose, and entire thigh swellings (ETS) have been reported. Lowering the amount of antigen or of adjuvant may decrease the reactogenicity of DTaP while maintaining a protective immune response. OBJECTIVES: Following priming with three doses of a DTaP vaccine during infancy, the safety, reactogenicity and immunogenicity of nine different candidate DTaP-vaccines with reduced amounts of antigen and/or adjuvant given as fourth (booster) dose were evaluated. METHODS: Study participants were healthy infants aged 15-27 months at the time of booster vaccination. Each participant had received three doses of a DTaP vaccine (Infanrixtrade mark, GlaxoSmithKline, Rixensart, Belgium; "reference DTaP") at age 3, 4, and 5 months as part of a previous clinical trial. More than 20,000 children were eligible for participation in the current study protocol at the time. In a first phase at a University hospital-based vaccination study center, nine sequential cohorts of 63-119 study subjects received one of nine different candidate vaccines. Patients and study personal were blinded with regard to which vaccine was currently in use. Reactogenicity was solicited from parents using diary cards. Blood was drawn prior to and 4 weeks after vaccination and immediately centrifuged. The serum was stored at -20 degrees C until serology was performed by ELISA tests. As soon as the first candidate vaccine with adequate reactogenicity and immunogenicity profile was identified in the first study phase, a second study phase was initiated in parallel, to evaluate the safety and reactogenicity of the respective candidate vaccine in private practices in large cohorts (1613-2095 study subjects per group). RESULTS: In the first study phase, DTaP with no aluminum induced the highest frequency of ETS and fever. All other candidate vaccines caused lower rates of local and general reactions than the reference DTaP. As a general rule, vaccines with less antigen induced fewer reactions, although there was no strict dose-response effect and the difference, e.g. between a one-tenth and a one-fifth DTaP dose (DTaP 1/5; DTaP 1/10) was not clinically relevant. Separate injections of Td and aP caused fewer general reactions than the respective TdaP combination and local reactions were higher at the aP than at the Td injection site. Again, as a general rule, reduced amounts of antigen induced lower antibody concentrations, although all vaccines induced "protective" anti-tetanus and anti-diphtheria antibody responses. A total of 92-100% of children showed seroresponses to pertussis antigens even when vaccinated with reduced amounts of the respective pertussis antigen. Elimination of aluminum from DTaP vaccine induced higher anti-tetanus-antibody concentrations and so did a reduction of the amount of diphtheria antigen. Additional examples for antigen interaction were increased antibody concentrations, observed with injection of Td and aP into different limbs. In the second study phase, all three vaccines evaluated (one with a reduced amount of diphtheria antigen, TdaP; one with reduced amounts of all antigens, tdap; and one with a fifth dose of the reference vaccine (DTaP 1/5)) were safe and had an acceptable reactogenicity profile in a total of 4871 study subjects. CONCLUSIONS: Local reactions due to DTaP booster doses in the second year of life can be reduced by reducing the amount of antigen in the respective vaccine while an adequate immunogenicity is maintained. Aluminum-free vaccines induced ETS and fever most commonly. Any changes in vaccine composition should lead to a full evaluation of the new product.     

Immunogenicity of three Haemophilus influenzae type b protein conjugate vaccines in HIV seropositive adults and analysis of predictors of vaccine response.

HIV-seropositive adults may be at increased risk of infection due to Haemophilus influenzae type b (Hib) as compared with HIV-seronegative adults. Protein conjugate vaccines have been demonstrated to induce protective levels of antibodies against Hib in immunocompetent infants and also in HIV-seropositive infants. In this study we determined the immunogenicity of three protein conjugate Hib vaccines (PRP-D, HbOC, HbNOMP) in 135 HIV-seropositive adults who received one dose of Hib vaccine. Anti-polyribosylribitol phosphate (PRP) antibodies were measured at 0, 1, 3 and 12 months postimmunization by the Farr method. We demonstrate that all three vaccines are highly immunogenic and result in protective (> 1.0 microg/ml) levels of antibody. Overall the anti-PRP antibody level was > 1.0 microg/ml in 26% of patients preimmunization, 91% at both 1 and 3 months, and 79% at 12 months postvaccination. Comparison of responses to the three vaccines over time demonstrated differences in the mean geometric anti-PRP antibody level at 1 month (p=0.03) and the 12 month time points (p=0.03) with lower geometric mean levels in the HbNOMP group, though baseline differences in groups limit the interpretation of these findings. In a univariate analysis of baseline characteristics which predicted poor vaccine response, low total IgG2 levels preimmunization predicted a poor antibody response at 1 month (p < 0.01) and at 12 months (p=0.05), while low CD4 T-cell count predicted poor response at 12 months (p < 0.01). We conclude that all three US licensed protein conjugate Hib vaccines are immunogenic in HIV-seropositive adults, and that baseline CD4 T-cell count and IgG2 levels predict the likelihood of antibody response to vaccine.     

Safety and immunogenicity of a diphtheria,tetanus, acellular pertussis and Haemophilus influenzae Type b combination vaccine compared with separate administration of licensed equivalent vaccines in Chinese infants and toddlers for primary and booster immunization

To evaluate the safety and immunogenicity of a diphtheria, tetanus, acellular pertussis and Haemophilus infuenzae Type b (DTaP/Hib) combination vaccine first developed by a Chinese manufacturer, a randomized, two-stage, parallel controlled, single center clinical trial was conducted in Dafeng, Jiangsu Province of China. A total of 720 infants were enrolled and randomly assigned to two groups with a 2:1 allocation. In Stage I, 480 subjects in Group T were administered with 3 doses of the DTaP/Hib vaccine at 3, 4 and 5 months of age, respectively, while 240 subjects in Group C received separate licensed DTaP vaccine and Hib conjugate vaccine on the same schedule. In Stage II, 633 primed toddlers (431 of Group T and 202 of Group C) were given a booster dose at 18 months of age. Sera samples were collected at pre-dose 1, 4 weeks post-dose 3, pre-dose 4 and 4 weeks post-dose 4, respectively. Levels of protective antibodies were measured by Enzyme Linked Immunoadsorbent Assay (ELISA). Immunogenicity was evaluated with regard to geometric mean concentrations (GMCs), seroconversion rates and seroprotection rates of the antibodies. Solicited adverse reactions were recorded for 3 days after each dose; unsolicited adverse events and serious adverse events were monitored for 28 days after vaccination. Results showed that seroconversion rates of anti-pertussis toxoid (PT), anti-filamentous hemagglutinin (FHA), anti-diphtheria toxoid (DT), anti-tetanus toxid (TT) and anti-polyribosyl-ribitol-phosphate (PRP) in Group T (Stage I: 98.06%, 97.33%, 100%, 100%, 98.79%; Stage II: 99.18%, 83.42%, 99.18%, 63.32%, 85.05%) were comparable to that of Group C (Stage I: 95.26%, 93.16%, 100%, 100%, 98.42%; Stage II: 98.89%, 83.89%, 98.33%, 53.89%, 76.67%). Nearly 100% of the subjects in both groups achieved seroprotective levels of anti-DT (≥0.1 IU/ml), anti-TT (≥0.1 IU/ml) and anti-PRP (≥0.15 μg/ml) after primary and booster vaccination. The frequencies of local induration, swelling and redness as well as general reactions such as fever, diarrhea and anaphylaxis were low and acceptable in both groups. In conclusion, the DTaP/Hib vaccine was demonstrated to be non-inferior to the control vaccines on safety and immunogenicity. There could be a bright future for the DTaP/Hib vaccine to be widely used in the universal vaccination of Chinese children.     

A combined liquid Hib (PRP-OMPC), hepatitis B, diphtheria, tetanus and whole-cell pertussis vaccine: controlled studies of immunogenicity and reactogenicity

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.