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In the pivotal phase 3 efficacy trial (NCT02747927) of the TAK-003 dengue vaccine, 5 of 13,380 TAK-003 recipients and 13 of 6,687 placebo recipients experienced two episodes of symptomatic dengue between the first dose and the end of the study, ∼57 months later (patients received the second dose 3 months after the first dose). Two of these participants experienced repeat infection with the same serotype (i.e., homotypic reinfection). In comparison with placebo, the relative risk of a subsequent episode of symptomatic dengue was 0.19 (95% CI, 0.07–0.54) in TAK-003 recipients. Based on the small number of subsequent episodes, these data suggest a potential incremental effect of TAK-003 beyond prevention of the first episode of symptomatic dengue after vaccination.

Background Takeda’s dengue vaccine is under evaluation in an ongoing phase 3 efficacy study; we present a 2-year update. Methods Children (20 099, 4–16 years old) were randomized to receive 2 doses of TAK-003 or placebo 3 months apart and are under surveillance to detect dengue by serotype-specific RT-PCR. Results Cumulative efficacy against dengue approximately 27 months since first dose was 72.7% (95% confidence interval [CI], 67.1%–77.3%), including 67.0% (95% CI, 53.6%–76.5%) in dengue-naive and 89.2% (95% CI, 82.4%–93.3%) against hospitalized dengue. In the second year, decline in efficacy was observed (56.2%; 95% CI, 42.3%–66.8%) with the largest decline in 4–5 year olds (24.5%; 95% CI, −34.2% to 57.5%); efficacy was 60.6% (95% CI, 43.8%–72.4%) in 6–11 year and 71.2% (95% CI, 41.0%–85.9%) in 12–16 year age groups. As TAK-003 efficacy varies by serotype, changes in serotype dominance partially contributed to efficacy differences in year-by-year analysis. No related serious adverse events occurred during the second year. Conclusions TAK-003 demonstrated continued benefit independent of baseline serostatus in reducing dengue with some decline in efficacy during the second year. Three-year data will be important to see if efficacy stabilizes or declines further. Clinical Trials Registration. NCT02747927. Takeda’s tetravalent dengue vaccine (TAK-003) continued to demonstrate benefit in reducing dengue independent of baseline serostatus up to 2 years after completing vaccination with some decline in efficacy during the second year in 4–16 year olds in dengue-endemic countries.

A substantial unmet need remains for safe and effective vaccines against dengue virus disease, particularly for individuals who are dengue-naive and those younger than 9 years. We aimed to assess the efficacy, safety, and immunogenicity of a live attenuated tetravalent dengue vaccine (TAK-003) in healthy children aged 4-16 years.We present data up to 18 months post-vaccination from an ongoing phase 3, randomised, double-blind trial of TAK-003 in endemic regions of Asia and Latin America (26 medical and research centres across Brazil, Colombia, Dominican Republic, Nicaragua, Panama, Philippines, Sri Lanka, and Thailand). Healthy children aged 4-16 years were randomly assigned 2:1 (stratified by age and region) to receive two doses of TAK-003 or two doses of placebo, 3 months apart. Investigators, participants and their parents or guardians, and sponsor representatives advising on trial conduct were masked to trial group assignments. Participants presenting with febrile illness were tested for virologically confirmed dengue (VCD) by serotype-specific RT-PCR. In timeframes beginning 30 days post-second dose, the primary endpoint (overall vaccine efficacy) was assessed in the first 11 months, and the secondary endpoints (efficacy by baseline serostatus, serotype, hospitalised dengue, and severe dengue) in the first 17 months. This study is registered with ClinicalTrials.gov, NCT02747927.20 099 participants were randomly assigned and vaccinated between Sept 7, 2016, and Aug 18, 2017; 19 021 (94·6%) were included in the per protocol analysis, and 20 071 (99·9%) in the safety set. The primary endpoint was achieved with an overall vaccine efficacy of 80·2% (95% CI 73·3 to 85·3; 61 cases of VCD in the TAK-003 group vs 149 cases of VCD in the placebo group). In the secondary endpoint assessment timeframe, an overall vaccine efficacy of 73·3% (95% CI 66·5 to 78·8) was observed. Analysis of secondary endpoints showed efficacies of 76·1% (95% CI 68·5 to 81·9) in individuals who were seropositive at baseline, 66·2% (49·1 to 77·5) in individuals who were seronegative at baseline, 90·4% (82·6 to 94·7) against hospitalised dengue, and 85·9% (31·9 to 97·1) against dengue haemorrhagic fever. Efficacy varied by individual serotypes (DENV 1, 69·8% [95% CI 54·8 to 79·9]; DENV 2, 95·1% [89·9 to 97·6]; DENV 3, 48·9% [27·2 to 64·1]; DENV 4, 51·0% [-69·4 to 85·8]). Cumulative rates of serious adverse events were similar in TAK-003 (4·0%) and placebo (4·8%) recipients, and were consistent with expected medical disorders in the study population. Infection was the most frequent reason leading to serious adverse events. 20 participants (0·1% of the safety set) were withdrawn from the trial due to 21 adverse events by the end of part two; 14 of these participants received TAK-003 and six received placebo.TAK-003 was well tolerated and efficacious against symptomatic dengue in children regardless of serostatus before immunisation. Vaccine efficacy varied by serotype, warranting continued follow-up to assess longer-term vaccine performance.Takeda Vaccines.

Dengue, a mosquito-borne viral disease, was designated a World Health Organization top 10 threat to global health in 2019.We present primary efficacy data from part 1 of an ongoing phase 3 randomized trial of a tetravalent dengue vaccine candidate (TAK-003) in regions of Asia and Latin America in which the disease is endemic. Healthy children and adolescents 4 to 16 years of age were randomly assigned in a 2:1 ratio (stratified according to age category and region) to receive two doses of vaccine or placebo 3 months apart. Participants presenting with febrile illness were tested for virologically confirmed dengue by serotype-specific reverse-transcriptase polymerase chain reaction. The primary end point was overall vaccine efficacy in preventing virologically confirmed dengue caused by any dengue virus serotype.Of the 20,071 participants who were given at least one dose of vaccine or placebo (safety population), 19,021 (94.8%) received both injections and were included in the per-protocol analysis. The overall vaccine efficacy in the safety population was 80.9% (95% confidence interval [CI], 75.2 to 85.3; 78 cases per 13,380 [0.5 per 100 person-years] in the vaccine group vs. 199 cases per 6687 [2.5 per 100 person-years] in the placebo group). In the per-protocol analyses, vaccine efficacy was 80.2% (95% CI, 73.3 to 85.3; 61 cases of virologically confirmed dengue in the vaccine group vs. 149 cases in the placebo group), with 95.4% efficacy against dengue leading to hospitalization (95% CI, 88.4 to 98.2; 5 hospitalizations in the vaccine group vs. 53 hospitalizations in the placebo group). Planned exploratory analyses involving the 27.7% of the per-protocol population that was seronegative at baseline showed vaccine efficacy of 74.9% (95% CI, 57.0 to 85.4; 20 cases of virologically confirmed dengue in the vaccine group vs. 39 cases in the placebo group). Efficacy trends varied according to serotype. The incidence of serious adverse events was similar in the vaccine group and placebo group (3.1% and 3.8%, respectively).TAK-003 was efficacious against symptomatic dengue in countries in which the disease is endemic. (Funded by Takeda Vaccines; TIDES ClinicalTrials.gov number, NCT02747927.).

Background Takeda’s live attenuated tetravalent dengue vaccine candidate (TAK-003) is under evaluation in a long-term clinical trial across 8 dengue-endemic countries. Previously, we have reported its efficacy and safety in both seronegative and seropositive participants and that its performance varies by serotype, with some decline in efficacy from first to second year postvaccination. This exploratory analysis provides an update with cumulative and third-year data. Methods Healthy 4–16 year olds (n = 20099) were randomized 2:1 to receive TAK-003 or placebo (0, 3 month schedule). The protocol included baseline serostatus testing of all participants and detection of all symptomatic dengue throughout the trial with a serotype specific reverse transcriptase-polymerase chain reaction. Results Cumulative efficacy after 3 years was 62.0% (95% confidence interval, 56.6–66.7) against virologically confirmed dengue (VCD) and 83.6% (76.8–88.4) against hospitalized VCD. Efficacy was 54.3% (41.9–64.1) against VCD and 77.1% (58.6–87.3) against hospitalized VCD in baseline seronegatives, and 65.0% (58.9–70.1) against VCD and 86.0% (78.4–91.0) against hospitalized VCD in baseline seropositives. Efficacy against VCD during the third year declined to 44.7% (32.5–54.7), whereas efficacy against hospitalized VCD was sustained at 70.8% (49.6–83.0). Rates of serious adverse events were 2.9% in TAK-003 group and 3.5% in placebo group during the ongoing long-term follow-up (ie, second half of the 3 years following vaccination), but none were related. No important safety risks were identified. Conclusions TAK-003 was efficacious against symptomatic dengue over 3 years. Efficacy declined over time but remained robust against hospitalized dengue. A booster dose evaluation is planned.

Summary Background An unmet clinical need remains for an effective tetravalent dengue vaccine suitable for all age groups, regardless of serostatus. We assessed the immunogenicity and safety of three different dose schedules of a tetravalent dengue vaccine (TAK-003) over a 48-month period in children living in dengue-endemic countries. Methods We did a large, phase 2, double-blind, placebo-controlled trial at three sites in the Dominican Republic, Panama, and the Philippines. Healthy participants aged 2–17 years were randomly assigned 1:2:5:1 using an interactive web response system with stratification by age to receive either a two-dose primary series (days 1 and 91), one primary dose (day 1), one primary dose plus booster (days 1 and 365), or placebo. Participants and relevant study personnel were masked to the random assignment until completion of the study at month 48. To maintain masking, TAK-003 recipients were administered placebo doses when appropriate. The primary objective was assessment of neutralising geometric mean titres for each serotype to month 48 assessed in the per-protocol immunogenicity subset. Secondary safety endpoints included proportions of participants with serious adverse events and symptomatic virologically confirmed dengue. This study is registered with ClinicalTrials.gov , NCT02302066 . Findings Between Dec 5, 2014, and Feb 13, 2015, 1800 children were randomly assigned to the following groups: two-dose primary series (n=201), one primary dose (n=398), one primary dose plus 1-year booster (n=1002), and placebo (n=199). Of them, 1479 (82%) participants completed the 48-month study. Immunogenicity endpoints were assessed in 562 participants enrolled in the immunogenicity subset, of whom 509 were included in the per-protocol subset. At month 48, antibody titres remained elevated in all TAK-003 groups compared with placebo, irrespective of baseline serostatus. At month 48, geometric mean titres were 378 (95% CI 226–632) in two-dose, 421 (285–622) in one-dose, 719 (538–960) in one-dose plus 1-year booster, and 100 (50–201) in placebo recipients against DENV 1; 1052 (732–1511), 1319 (970–1794), 1200 (927–1553), and 208 (99–437) against DENV 2; 183 (113–298), 201 (135–298), 288 (211–392), and 71 (37–139) against DENV 3; and 152 (97–239), 164 (114–236), 219 (165–290), and 46 (26–82) against DENV 4; and tetravalent seropositivity rate was 89% (79–96), 86% (80–92), 97% (93–99), and 60% (47–72), respectively. Virologically confirmed dengue was recorded in 37 (2%) TAK-003 and 13 (7%) placebo participants, with a relative risk of 0·35 (0·19–0·65). No vaccine-related serious adverse events or severe dengue virus disease were reported. Interpretation TAK-003 elicited antibody responses against all four serotypes, which persisted to 48 months post-vaccination, regardless of baseline serostatus. No important safety risks were identified. We observed a long-term reduction in risk of symptomatic dengue virus disease in vaccinees. Results from this study provide a long-term safety database and support assessment of the vaccine in the ongoing phase 3 efficacy study. Funding Takeda Vaccines.

Background With the introduction of routine childhood rotavirus vaccination, norovirus is now becoming the major cause of medically-attended gastroenteritis in children. Takeda is developing a norovirus vaccine (NoV) that contains genotypes GI.1 and GII.4 consensus (GII.4c) sequence VLPs. We report the immunogenicity data of NoV administered to children from 6 months up to 4 years of age. Methods Two age cohorts (1 to < 4 years, and 6 to < 12 months, n = 120 per cohort) were enrolled in this ongoing double-blind, randomized, phase 2 dose-finding study conducted in Colombia and Panama. Children received one or two intramuscular doses of NoV formulations containing 15/15, 15/50, 50/50 or 50/150 μg of GI.1/GII.4c VLPs adjuvanted with 0.5 mg Al(OH)3. Vaccinations were on Days 1 and 29, with saline placebo as dose two to maintain blinding in one dose groups. Antibody responses to each VLP were measured on days 1, 29 and 57 as functional histo-blood group binding antigen blocking antibodies (HBGA), expressed as seroresponse rates (SRR), the proportions displaying ≥ 4-fold increases over baseline, and geometric mean titres (GMT). Results Each formulation induced dosage-dependent HBGA responses after a single dose, with a further increase after a second dose. In 1- to

Persistent immunity to hepatitis A and hepatitis B antibodies six years after vaccination of adolescents (aged 12-15 years) with a combined hepatitis A and B (HAB) vaccine following a 0, 6 month or a 0, 12 month schedule was assessed. Yearly (Year-2-6) serum samples were tested for anti-HAV and anti-HBs using EIA. Subjects with anti-HBs concentrations10 mIU/mL (14/23) at Year-5 or Year-6, received an additional HBV vaccine dose approximately 12 months after Year-6. Blood samples were collected pre-booster and 1 month post-booster to assess booster response. 240 subjects were vaccinated in the study; at Year-6, data were available from 88 subjects. At that time 84.8% (39/46; 0, 6 month) and 92.9% (39/42; 0, 12 month) of subjects had anti-HBs concentrationsor = 10 mIU/mL. All but one of the 14 boosted subjects responded to the additional HBV vaccine dose with anti-HBs concentrationsor = 100 mIU/mL. All seroconverted subjects who returned at Year-6 were seropositive for anti-HAV. Simplification, reduced number of doses and similar long-term persistence of immunity make the 0, 6 month and 0, 12 month schedule preferable for immunization against HAV/HBV in this population.

The response to booster vaccination at 15-18 months of age and the presence of immune memory in 10-month old children, primed with a new combined diphtheria-tetanus-hepatitis B-whole cell pertussis vaccine extemporaneously mixed with Haemophilus influenzae type b-tetanus toxoid conjugate (DTPw-HBV/Hib) from new antigen sources and containing 2.5 microg polyribosyl-ribitol-phosphate (PRP) was assessed. Primary vaccination with the new DTPw-HBV/Hib vaccine was immunogenic and of comparable tolerability to commercially available Tritanrix HepB/Hiberix. Children were boosted with DTPw-HBV, DTPw-HBV/Hib or separate DTPw-HBV+Hiberix. Immune memory was assessed through administration of 10 microg PRP polysaccharide. Anti-PRP antibody GMCs increased substantially after the challenge in DTPw-HBV/Hib-primed subjects indicating the presence of immune memory. One month after the booster dose, 100% of subjects had seroprotective antibody concentrations against PRP, diphtheria and tetanus, >95% were seroprotected against hepatitis B, > or =94.0% had a pertussis booster response. Substantial increases in antibody GMCs against all antigens were observed. Swelling >20 mm was the most common Grade 3 solicited symptom reported (up to 26.0% of subjects). Fever >39.5 degrees C was uncommon (>2.5%). Eleven large swelling reactions were reported; none involved an adjacent joint. One serious adverse event occurred that was considered unrelated to vaccination. This new DTPw-HBV/Hib vaccine with new vaccine components and 2.5 microg PRP induced effective priming against Hib evidenced by a vigorous anamnestic response on exposure to PRP polysaccharide. The booster dose was immunogenic and the safety profile was acceptable. Combined DTPw-HBV and DTPw-HBV/Hib vaccines using new vaccine antigen sources will promote continued supply of combined DTPw-based vaccines to global mass vaccination campaigns.

Background Diphtheria-tetanus-whole-cell pertussis (DTPw)-based combination vaccines are an attractive option to rapidly achieve high coverage and protection against other important pathogens, such as hepatitis B virus (HBV) and Haemophilus influenzae type B (Hib). To ensure adequate antigen supply, GlaxoSmithKline Biologicals has introduced a new DTPw antigen source and developed a new DTPw-HBV/Hib combination vaccine containing a reduced amount of Hib polyribosylribitol phosphate (PRP). This study was undertaken to compare the immunogenicity and reactogenicity of this new DTPw-HBV/Hib vaccine with a licensed DTPw-HBV/Hib vaccine (Tritanrix™-HBV/Hib). Methods This was a randomized, partially-blind, multicenter study in three countries in Latin America (Argentina, Chile and Nicaragua). Healthy children received either the new DTPw-HBV/Hib vaccine (1 of 3 lots; n = 439; double-blind) or Tritanrix™-HBV/Hib (n = 146; single-blind) co-administered with oral poliovirus vaccine (OPV) at 2, 4 and 6 months, with a booster dose at 18-24 months. Results One month after the end of the 3-dose primary vaccination course, the new DTPw-HBV/Hib vaccine was non-inferior to Tritanrix™-HBV/Hib in terms of seroprotection/vaccine response rates for all component antigens; ≥97.3% and ≥93.9% of subjects in the two groups, respectively, had seroprotective levels of antibodies against diphtheria, tetanus, hepatitis B and Hib and a vaccine response to the pertussis component. Persistence of antibodies against all vaccine antigens was comparable between groups, with marked increases in all antibody concentrations after booster administration in both groups. Both vaccines were generally well-tolerated as primary and booster doses. Conclusions Results confirm the suitability of this new DTPw-HBV/Hib vaccine comprising antigens from a new source and a reduced PRP content for inclusion into routine childhood vaccination programs. Trial registration http://www.clinicaltrials.gov NCT00332566

To evaluate the immunogenicity, reactogenicity and safety of primary and booster vaccination with DTPw-HBVLT/Hib2.5 vaccine containing low thiomersal and reduced quantities of Hib polysaccharide (PRP).Combined DTP vaccines have high global coverage. Thus, the addition of new antigens to existing DTP vaccines is the most effective way to ensure high coverage.192 healthy infants were randomized to receive the investigational DTPw-HBVLT/Hib2.5 vaccine or licensed DTPw-HBV/Hib10 at 6, 10, 14 weeks. Immune memory to the Hib antigen was assessed through administration of plain PRP challenge at 10 months in 50% of subjects. Challenged and unchallenged subjects respectively received a DTP-HBV or DTPa-HBV/Hib booster at 15-18 months of age. Antibody responses were measured using enzyme-linked immunosorbent assay (ELISA) and reactogenicity was assessed using diary cards.One month post-primary vaccination, 100% and ≥ 93.7% of subjects in both groups had anti-PRP antibody concentrations ≥ 0.15 μg/mL and ≥ 1.0 μg/mL, respectively. Robust responses to PRP were observed after the 10 month plain PRP challenge and booster responses were observed in unchallenged subjects after the booster dose at 15-18 months of age. Post-primary and post-booster responses to the other vaccine antigens were at least as high in the DTPw-HBVLT/Hib2.5 group versus the DTPw-HBV/Hib10 group. The reactogenicity profile of the DTPw-HBVLT/Hib2.5 vaccine was acceptable.The DTPw-HBVLT/Hib2.5 combination vaccine with reduced thiomersal and Hib content had equivalent immunogenicity and tolerability versus the full standard DTPw-HBV/Hib10 vaccine. DTPw-HBVLT/Hib2.5 or DTPw-HBV/Hib10 vaccines can contribute to reducing childhood diseases through ensuring high vaccine coverage in mass vaccination programs. ClinicalTrials.gov identifiers: NCT 01061541, NCT00158808.

Vaccination with recombinant hepatitis B vaccines is highly effective in preventing hepatitis B infection. Recently, a preservative-free (PF) formulation of hepatitis B vaccine [GlaxoSmithKline (GSK) Biologicals, Rixensart, Belgium] has been licensed. The immunogenicity of the PF hepatitis B vaccine and antibody persistence 6 years later was assessed in this study. This formulation was compared with the preservative- containing (PC) formulation of the vaccine and a low-preservative (LP) content formulation. Five hundred forty-one healthy adult subjects were evaluated in the primary study. Over 94% of the subjects in the three study groups had seroprotective anti-HBs antibody concentrations (10 mIU/ml) 1 month after completing primary vaccination. Antibody measurements in 242 healthy adults who returned for the follow-up study and who had received primary vaccination 6 years earlier showed that over 81% of subjects in the three study groups still had anti-HBs antibody concentrations 10 mIU/ml. No apparent differences in antibody decline or distribution between the study groups were observed. These results indicate that the removal of preservatives from the hepatitis B vaccine does not affect adversely its immunogenicity both in the short and in the longer term.

Malaysian infants would have to receive nine injections during the first few months of life in order to be protected against disease caused by hepatitis B (HBV), diphtheria, tetanus, pertussis and Haemophilus influenzae type b (Hib) if single HBV and Hib vaccines were used. We evaluated a combined DTPw-HBV/Hib vaccine administered at 1.5, 3 and 5 months after a birth dose of hepatitis B vaccine (HBV). One month after completion of the primary vaccination, 99% of subjects had seroprotective anti-HBV antibody levels, and at least 98% had seroprotective antibodies against diphtheria, tetanus, and Hib, and were seropositive for pertussis antibodies. The immune response to the combined vaccine was comparable to that induced by separate injections with DTPw, HBV and Hib vaccines. Overall, the DTPw-HBV/Hib vaccine was as well tolerated as separate administration of DTPw, HBV and Hib vaccines. The combined DTPw-HBV/Hib vaccine induces protection against five diseases as recommended in the Malaysian routine vaccination schedule. Use of the combined DTPw-HBV/Hib vaccine can reduce the required number of injections from nine to four in the first few months of life.

This paper presents 7- and 10-year follow-up immunogenicity data from two studies, which explored long-term persistence induced by combined tetravalent DTPw-HBV vaccines. The 10-year follow-up study compared two identical antigen-content, but different formulations of DTPw-HBV vaccine (adsorbed on either Al(OH)(3) or Al(PO(4)), whilst the 7-year follow-up study compared two different formulations of DTPw-HBV vaccines containing 5 and 10 microg of hepatitis B surface antigen (HBsAg), following a birth dose of HBV. Primary vaccination took place at 2, 4, 6 months and booster dosing at 18 months. A booster dose of local DTPw vaccine was given at 4 years of age to all returning subjects. At the end of the 7-year study, 90.9% subjects receiving 10 microg HBsAg had anti-HBs antibody concentrationsor =10mIU/ml; the majority of subjects remained seroprotected against diphtheria and tetanus (or =90.9 and 100%, respectively) and 100% had seropositive levels for pertussis antigens. At the end of the 10-year follow-up study,or =60.9% subjects had seroprotective concentrations of anti-HBs antibodies;or =95.2 and 100% subjects were seroprotected against diphtheria and tetanus, respectively;or =78.3% subjects were seropositive for pertussis. The results demonstrate long-term antibody persistence induced by combined DTPw-HBV vaccine.

The immunogenicity and reactogenicity of primary vaccination at 3, 4 and 5 months and boosting at 12-18 months with a new DTPw-HBV vaccine was compared with either licensed DTPw and HBV vaccines given separately or a licensed DTPw-HBV combination (Tritanrix-HepB) in this randomized, partially double-blind primary vaccination and single-blind booster vaccination study in healthy infants (n = 239; Trial DTPw-HBV-001/004). One month after primary vaccination with the new DTPw-HBV vaccine, seroprotection against diphtheria, tetanus, hepatitis B and vaccine response to B. pertussis was seen in 100%, 98.7%, 94.9% and 98.7% of subjects, respectively, compared to 100%,or =98.5%, 89.2% and 92.2% of subjects in the comparator groups, respectively. One month after the booster dose, a marked response to all vaccine antigens was observed, resulting in seroprotection against diphtheria, tetanus, hepatitis B in all DTPw-HBV recipients and response to B. pertussis in over 98.6%. After primary vaccination, there was evidence that feveror =38.0 degrees C (rectal route) occurred more frequently after the new vaccine (following 41.6% of doses, compared with 32.2% and 29.3% in the comparator groups, p0.05) and that pain and drowsiness occurred more frequently than after licensed DTPw-HBV (45.3% versus 35.1% and 37.1% versus 24.9%, respectively). However after primary and booster doses Grade 3 symptoms occurred at similar frequencies in the three groups suggesting these possible differences are of minimal clinical significance. In conclusion, within the framework of this study the immunogenicity and safety profiles of GSK Biologicals' new DTPw-HBV vaccine when used for primary and booster vaccination were acceptable.

New combination vaccines and reliable sources of vaccine components are essential to ensure the success of mass immunisation programmes in the 21st century. We evaluated a new combined diphtheria-tetanus-whole-cell-pertussis-hepatitis B vaccine, extemporaneously mixed with a Haemophilus influenzae type b conjugate vaccine (DTPw-HBV/Hib) containing 2.5 microg PRP in 913 Philippino infants, administered according to the EPI schedule at 6, 10 and 14 weeks of age after a birth dose of hepatitis B vaccine (HBV; trial DTPw-HBV/Hib-001). One month after the third dose of DTPw-HBV/Hib (N = 182), 99.4% and 94.2% of subjects had anti-PRP antibody levels > or =0.15 microg/mL and > or =1.0 microg/mL, respectively. In addition, 95.9%, 100.0% and 87.6% of subjects had seroprotective antibody concentrations against diphtheria, tetanus and hepatitis B, respectively. The seroprotection rate to hepatitis B increased significantly to 94.3% in subjects who received a dose of HBV at birth. The pertussis vaccine response rate was > or =95%. Seroprotection/vaccine response rates to all antigens after DTPw-HBV/Hib were at least as good as those observed after vaccination with GSK Biologicals' licensed Tritanrix HepB/Hiberix (containing 10 microg PRP) which was used as comparator. Although redness >20 mm in diameter and fever > or = 37.5 degrees C (axillary route) occurred more often after the new DTPw-HBV/Hib vaccine (p < 0.05), other Grade 3 adverse events occurred similarly between the groups. The new DTPw-HBV/Hib vaccine was as immunogenic and well tolerated as the licensed control vaccine when administered according to the immunologically challenging EPI schedule. A birth dose of HBV is important to maximize protection against hepatitis B in endemic regions where the EPI schedule is in place.

This paper presents the results of four separate phase III trials, which assessed the immunogenicity and reactogenicity of DTPw-HBV/Hib 2.5 in comparison with licensed Tritanrix-Hep B (GlaxoSmithKline Biologicals) and Hiberix (10 microg PRP), given as separate or mixed injections (3 trials) or with or without hepatitis B vaccine at birth (1 trial). The immunogenicity of DTPw-HBV/Hib 2.5 was non-inferior to the reference vaccine regimen in terms of seropositivity rates. The overall reactogenicity profile of DTPw-HBV/Hib 2.5 was also similar to that of the reference vaccine regimen. These results confirm the previously established immunogenicity and safety of reduced dose PRP conjugated vaccine regimens.