Antibody persistence and booster response 68 months after vaccination at 2-10 years of age with one dose of MenACWY-TT conjugate vaccine.

BACKGROUND: We evaluated antibody persistence up to 68 months (M) post-vaccination with a quadrivalent meningococcal serogroups A, C, W and Y tetanus toxoid conjugate vaccine (MenACWY-TT) or a licensed monovalent MenC conjugate vaccine (MenC-CRM197) and subsequent booster responses to MenACWY-TT in healthy European children. METHODS: In the initial study (NCT00674583), healthy children, 2-10 years of age, were randomized to receive a single dose of either MenACWY-TT or MenC-CRM197. In the follow-up study, we present the persistence at 32, 44, 56, and 68 M post-vaccination, overall and stratified by age (2-5 and 6-10 years), and the immunogenicity and safety of MenACWY-TT administered to all study participants at M68 post-primary vaccination. RESULTS: At M68, 33.3% (age group 2-5 years) and 47.1% (age group 6-10 years) of the children vaccinated with MenACWY-TT, and 50.0% (age group 2-5 years) and 75.9% (age group 6-10 years) vaccinated with MenC-CRM197 retained titers ≥1:8 for MenC, as assessed by a serum bactericidal assay using rabbit complement (rSBA). In the MenACWY-TT recipients, the percentages of children retaining rSBA titers ≥1:8 for MenA, MenW, and MenY were 81.7%, 47.3% and 66.7% in age group 2-5 years and 91.8%, 58,8% and 76.5% in age group 6-10 years, respectively. The booster dose induced robust responses (100% for all serogroups) and was well-tolerated. CONCLUSIONS: Antibody persistence (rSBA titers ≥ 1:8) for serogroups A, W and Y was observed in more than 50.0% of the children 68 M after receiving one dose of MenACWY-TT; for MenC, antibody persistence was observed in more than one third of MenACWY-TT and more than half of MenC-CRM197 recipients. Vaccination with a booster dose of MenACWY-TT induced robust immune responses for all serogroups.

Immunogenicity and Reactogenicity of DTPa-HBV-IPV/Hib and PHiD-CV When Coadministered With MenACWY-TT in Infants: Results of an Open, Randomized Trial.

BACKGROUND: This study evaluated the immunogenicity and reactogenicity of a combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus virus-Haemophilus influenzae type b vaccine (DTPa-HBV-IPV/Hib) and a 10-valent pneumococcal conjugate vaccine (PHiD-CV) coadministered with a quadrivalent meningococcal conjugate vaccine (MenACWY-TT) in infants/toddlers. METHODS: In this open, controlled, phase III study (NCT01144663), 2095 healthy infants were randomized (1:1:1:1) into 4 groups to receive MenACWY-TT at 2, 3, 4 and 12 months of age or MenACWY-TT, MenC-CRM197, or MenC-TT at 2, 4 and 12 months of age. All participants received PHiD-CV and DTPa-HBV-IPV/Hib at 2, 3, 4 and 12 months of age. Immunogenicity of DTPa-HBV-IPV/Hib was evaluated in exclusive randomized subsets of 25% of participants from each group postprimary, prebooster and postbooster vaccination, whereas immunogenicity of PHiD-CV was evaluated at all time points. Reactogenicity was evaluated on the total vaccinated cohorts during 8 days after each vaccination. RESULTS: For each DTPa-HBV-IPV/Hib antigen, ≥97.2%, ≥76.5% and ≥97.9% of participants had seropositive/seroprotective levels 1 month postprimary vaccination, before the booster dose and 1 month postbooster, respectively. For each vaccine pneumococcal serotype, ≥74.0% of infants had antibody concentrations ≥0.35 µg/mL at 1 month postprimary vaccination, and robust increases in antibody geometric mean concentrations were observed from prebooster to postbooster. Redness was the most frequent solicited local symptom at the DTPa-HBV-IPV/Hib and PHiD-CV injection sites, reported after up to 47.7% and 57.0% of doses postprimary and postbooster vaccination, respectively. CONCLUSIONS: Primary and booster vaccinations of infants/toddlers with DTPa-HBV-IPV/Hib and PHiD-CV coadministered with MenACWY-TT were immunogenic with clinically acceptable reactogenicity profiles. These results support the coadministration of MenACWY-TT with routine childhood vaccines.

Immunogenicity and safety of one or two doses of the quadrivalent meningococcal vaccine MenACWY-TT given alone or with the 13-valent pneumococcal conjugate vaccine in toddlers: A phase III, open-label, randomised study.

BACKGROUND: We evaluated the immunogenicity and safety of 1 and 2 doses of quadrivalent meningococcal serogroup A, C, W and Y tetanus toxoid-conjugate vaccine (MenACWY-TT) given alone or co-administered with 13-valent pneumococcal conjugate vaccine (PCV13) in toddlers. METHODS: In this phase III, open-label, controlled, multicentre study (NCT01939158), healthy toddlers aged 12-14 months were randomised into 4 groups to receive 1 dose of MenACWY-TT at month (M) 0 (ACWY_1), 2 doses of MenACWY-TT at M0 and M2 (ACWY_2), MenACWY-TT and PCV13 at M0 (Co-ad), or PCV13 at M0 and MenACWY-TT at M2 (PCV13/ACWY). Immune responses were assessed 1 month post-each vaccination. Solicited and unsolicited symptoms were recorded for 4 and 31 days post-each vaccination, respectively; serious adverse events (SAEs) and new onset of chronic illnesses (NOCIs) up to M9 from first vaccination. RESULTS: 802 toddlers were vaccinated. Post-dose 1 of MenACWY-TT, ≥92.8% of toddlers had rSBA titres ≥1:8, and ≥62.5% had hSBA titres ≥1:4 for each meningococcal serogroup. Post-dose 2 of MenACWY-TT, rSBA titres ≥1:8 were observed in ≥98.0% and hSBA titres ≥1:4 in ≥95.3% of toddlers. Percentages of toddlers with hSBA titres ≥1:4 were higher after 2 doses versus 1 dose of MenACWY-TT for MenW (97.1% versus 62.5-68.9%) and MenY (95.3% versus 64.3-67.6%). Non-inferiority of immune responses to co-administered MenACWY-TT and PCV13 over their separate administration was demonstrated. AEs incidence was comparable among groups. SAEs were reported for 4.9%, 5.1%, 5.5% and 7.5%, and NOCIs for 2.0%, 3.0%, 0.5% and 3.5% of toddlers in the ACWY_1, ACWY_2, Co-ad and PCV13/ACWY groups, respectively; 4 SAEs reported in 3 toddlers were vaccine-related. Two fatal vaccine-unrelated SAEs were reported. CONCLUSION: MenACWY-TT was immunogenic when administered as a single dose at 12-14 months of age. A second dose in toddlers increased hSBA responses against MenW and MenY. MenACWY-TT and PCV13 can be co-administered without impairing the immunogenicity or safety profile of either vaccine.

Immunogenicity and safety of the quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine (MenACWY-TT) in splenectomized or hyposplenic children and adolescents: Results of a phase III, open, non-randomized study.

BACKGROUND: Individuals with functional or anatomic asplenia are at high risk for meningococcal disease. We evaluated the immunogenicity and safety of 1 and 2 doses of the quadrivalent meningococcal serogroups A, C, W, Y tetanus toxoid-conjugate vaccine (MenACWY-TT) in this high-risk population. METHODS: This phase III, open-label, controlled, non-randomized study (NCT01641042) enrolled 1-17-year-olds with impaired splenic activity (high-risk group) and age-matched healthy controls (control group). We measured immune responses to MenACWY-TT by serum bactericidal activity assays using rabbit (rSBA) and human (hSBA) complement and in terms of antibodies against polysaccharides of the 4 vaccine serogroups. We evaluated vaccine response rates (VRRs) as 4-fold increases from pre-vaccination levels or titers ≥1:32 (rSBA)/≥1:8 (hSBA). We recorded solicited and unsolicited adverse events (AEs) during 4 and 31 days post-vaccination, and serious AEs (SAEs) and new onset of chronic illnesses (NOCIs) throughout the study. RESULTS: The according-to-protocol cohort for immunogenicity included 40 participants per group. In both groups, the first MenACWY-TT dose induced rSBA VRRs of 92.5-100% and hSBA VRRs of 55.6-77.1% across vaccine serogroups. Following the second MenACWY-TT dose, all participants had high responses, with rSBA and hSBA VRRs of 73.0-100% across vaccine serogroups. rSBA and hSBA geometric mean titers for each serogroup increased in both groups (with different magnitudes, but ≥13.1-fold) compared with baseline levels. Polysaccharide antibody concentrations ≥2.0 µg/ml were detected in ≥84.4% of participants and were similar between groups. Incidences of solicited and unsolicited AEs were comparable between groups. We recorded SAEs in 4/43 participants in the high-risk group and 1/43 participants in the control group (none vaccine-related). No NOCIs were reported. CONCLUSION: In this descriptive study, MenACWY-TT induced similar functional and humoral immune responses and had a clinically acceptable safety profile in children and adolescents with impaired splenic activity and in healthy controls.

Antibody persistence up to 5 y after vaccination with a quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine in adolescents.

Long-term protection against meningococcal disease relies on antibody persistence after vaccination. We report antibody persistence up to 5 y after vaccination in adolescents who received a single dose of either meningococcal serogroups A, C, W, Y tetanus toxoid conjugate vaccine (MenACWY-TT, Pfizer) or MenACWY polysaccharide vaccine (MenPS, GSK Vaccines) at the age of 11-17 y in the randomized controlled primary study NCT00464815. In this phase III, open, controlled, multi-center persistence follow-up study conducted in India and the Philippines (NCT00974363), antibody persistence was evaluated by a serum bactericidal antibody assay using rabbit complement (rSBA) yearly, up to year 5 after vaccination. Serious adverse events (SAEs) related to study participation were recorded. Five years after a single dose of MenACWY-TT, the percentage of participants (N = 236) with rSBA titers ≥1:8 was 97.5% for serogroup A, 88.6% for serogroup C, 86.0% for serogroup W and 96.6% for serogroup Y. The percentages in the MenPS group (N = 86) were 93.0%, 87.1%, 34.9% and 66.3%, respectively. Exploratory analysis indicated a higher percentage of subjects with rSBA titers ≥1:8 for serogroups W and Y, and higher rSBA geometric mean antibody titers for serogroups A, W and Y in the MenACWY-TT group than the MenPS group at each time point (years 3, 4 and 5). No differences between groups were observed for serogroup C. No SAEs related to study participation were reported. In conclusion, the results of this follow-up study indicate that antibodies persisted up to 5 y after a single dose of MenACWY-TT in adolescents.

Etiology of acute otitis media and serotype distribution of Streptococcus pneumoniae and Haemophilus influenzae in Chilean children <5 years of age.

The impact of bacterial conjugate vaccines on acute otitis media (AOM) is affected by several factors including population characteristics, bacterial etiology and vaccine conjugation method, carrier, and coverage. This study estimated the baseline etiology, distribution, and antibiotic susceptibility of bacterial serotypes that causes AOM in children aged <5 years in a public setting in Santiago, Chile.Children aged ≥3 months and <5 years referred to the physician for treatment of AOM episodes (with an onset of symptoms <72 h) were enrolled between September 2009 and September 2010. Middle ear fluid (MEF) was collected by tympanocentesis or by otorrhea for identification and serotyping of bacteria. Antibacterial susceptibility was tested using E-test (etrack: 112671).Of 160 children (mean age 27.10 ±â€Š15.83 months) with AOM episodes, 164 MEF samples (1 episode each from 156 children; 2 episodes each from 4 children) were collected. Nearly 30% of AOM episodes occurred in children aged 12 to 23 months. Streptococcus pneumoniae (41.7% [58/139]) and Haemophilus influenzae (40.3% [56/139]) were predominant among the cultures that showed bacterial growth (85% [139/164]). All Streptococcus pneumoniae positive episodes were serotyped, 19F (21%) and 14 (17%) were the predominant serotypes; all Haemophilus influenzae strains were nontypeable. Streptococcus pneumoniae were resistant to penicillin (5%) and erythromycin (33%); Haemophilus influenzae were resistant to ampicillin (14%) and cefuroxime and cefotaxime (2% each).AOM in Chilean children is predominantly caused by Streptococcus pneumoniae and nontypeable Haemophilus influenzae. Use of a broad spectrum vaccine against these pathogens might aid the reduction of AOM in Chile.

Antibody persistence and immunologic memory in children vaccinated with 4 doses of pneumococcal conjugate vaccines: Results from 2 long-term follow-up studies.

To investigate long-term antibody persistence following the administration of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV), we present results of 2 follow-up studies assessing antibody persistence following 2 3+1 schedules up to 4 (NCT00624819 - Study A) and 5 years (NCT00891176 - Study B) post-booster vaccination. In Study A, antibody persistence was measured one, 2 and 4 years post-booster in children previously primed and boosted with PHiD-CV, or primed with the 7-valent pneumococcal conjugate vaccine (7vCRM) and boosted with either PHiD-CV or 7vCRM. In Study B, PHiD-CV was co-administered with meningococcal vaccines, and pneumococcal antibody persistence was measured 2, 3 and 5 years post-booster. An age-matched control group, unvaccinated against Streptococcus pneumoniae, was enrolled in Study A, allowing assessment of immunologic memory by administration of one dose of PHiD-CV to both primed (4 years post-booster) and unprimed 6-year-old children. Four years post-booster (Study A), antibody concentrations and opsonophagocytic activity (OPA) titers remained higher compared to the pre-booster timepoint, with no major differences between the 3 primed groups. Antibody persistence was also observed in Study B, with minimal differences between groups. The additional PHiD-CV dose administered 4 years post-booster in Study A elicited more robust immune responses in primed children than in unprimed children. Long-term serotype-specific antibody persistence and robust immunologic memory responses observed in these 2 studies suggest induction of long-term protection against pneumococcal disease after PHiD-CV vaccination.

Safety and Immunogenicity of the Quadrivalent Meningococcal Serogroups A, C, W and Y Tetanus Toxoid Conjugate Vaccine Coadministered With Routine Childhood Vaccines in European Infants: An Open, Randomized Trial.

BACKGROUND: This was the first study evaluating the immunogenicity and safety of the quadrivalent meningococcal tetanus toxoid conjugate vaccine (MenACWY-TT) coadministered with routine childhood vaccines in young infants. METHODS: In this open, randomized, controlled, phase III study (NCT01144663), 2095 infants (ages 6-12 weeks) were randomized (1:1:1:1) into 4 groups to receive MenACWY-TT at 2, 3, 4 and 12 months of age, or MenACWY-TT, MenC-cross-reactive material (CRM197) or MenC-TT at 2, 4 and 12 months of age. All participants received PHiD-CV and DTPa-HBV-IPV/Hib at 2, 3, 4 and 12 months of age. Immune responses were measured by serum bactericidal activity assays using rabbit (rSBA) and human (hSBA) complement. Solicited and unsolicited symptoms were recorded during 8 and 31 days post-vaccination, respectively, and serious adverse events throughout the study. RESULTS: Noninferiority of immune responses to MenC induced by 2 or 3 doses of MenACWY-TT versus 2 doses of MenC-TT or MenC-CRM197 was demonstrated. Predefined criteria for the immunogenicity of MenACWY-TT to MenA, MenW and MenY were met. One month after 2 or 3 primary MenACWY-TT doses, ≥93.1% and ≥88.5% of infants had rSBA and hSBA titers ≥1:8 for all serogroups. The robust increases in rSBA and hSBA titers observed for all vaccine serogroups postbooster vaccination suggested that MenACWY-TT induced immune memory. MenACWY-TT coadministered with childhood vaccines had a clinically acceptable safety profile. CONCLUSIONS: This study supports the coadministration of MenACWY-TT with routine childhood vaccines as 2 or 3 primary doses during infancy followed by a booster dose in the second year of life.

Persistence of the immune response two years after vaccination with quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine (MenACWY-TT) in Asian adolescents.

Invasive meningococcal disease is a serious infection that is most often vaccine-preventable. Long-term protection relies on antibody persistence. Here we report the persistence of the immune response 2 y post-vaccination with a quadrivalent meningococcal serogroups A, C, W, Y tetanus toxoid conjugate vaccine (MenACWY-TT) compared with a MenACWY polysaccharide vaccine (Men-PS), in Asian adolescents aged 11-17 y. We also report a re-analysis of data from the primary vaccination study. This persistence study (NCT00974363) conducted in India and the Philippines included subjects who previously (study NCT00464815) received a single dose of MenACWY-TT or Men-PS. Persistence of functional antibodies was measured in 407 MenACWY-TT recipients and 132 Men-PS recipients (according-to-protocol cohort) using a rabbit complement serum bactericidal assay (rSBA, cut-off 1:8). Vaccine-related serious adverse events (SAEs) occurring since the end of the initial vaccination study were retrospectively recorded. Two y post-vaccination ≥99.3% of adolescents who received MenACWY-TT had persisting antibody titers ≥1:8 against each vaccine serogroup. Antibody persistence was higher (exploratory analysis) in the MenACWY-TT group than the Men-PS group in terms of rSBA titers ≥1:8 for serogroups W and Y; rSBA titers ≥1:128 for serogroups A, W and Y; and rSBA GMTs for serogroups A, W and Y; and was lower in the MenACWY-TT group for rSBA GMTs for serogroup C. No vaccine-related SAEs were reported. The results of this study indicated that antibodies persisted for at least 2 y in the majority of adolescents after vaccination with a single dose of MenACWY-TT.

Antibody Persistence in Young Children 5 Years after Vaccination with a Combined Haemophilus influenzae Type b-Neisseria meningitidis Serogroup C Conjugate Vaccine Coadministered with Diphtheria-Tetanus-Acellular Pertussis-Based and Pneumococcal Conjugate Vaccines.

We evaluated antibody persistence in children up to 5 years after administration of a combined Haemophilus influenzae type b (Hib)-Neisseria meningitidis serogroup C (MenC)-tetanus toxoid (TT) conjugate vaccine coadministered with a pneumococcal conjugate vaccine. This is the follow-up study of a randomized trial (ClinicalTrials.gov registration no. NCT00334334/00463437) in which healthy children were vaccinated (primary vaccinations at 2, 4, and 6 months of age and booster vaccination at 11 to 18 months of age) with Hib-MenC-TT or a control MenC conjugate vaccine, coadministered with diphtheria-tetanus-acellular pertussis (DTPa)-based combination vaccines (DTPa/Hib for control groups) and a pneumococcal conjugate vaccine (10-valent pneumococcal nontypeable H. influenzae protein D conjugate vaccine [PHiD-CV] or 7-valent cross-reacting material 197 [CRM197] conjugate vaccine [7vCRM]). MenC antibody titers were measured with a serum bactericidal antibody (SBA) assay using rabbit complement (i.e., rabbit SBA [rSBA]), and antibodies against Hib polyribosylribitol phosphate (PRP) were measured with an enzyme-linked immunosorbent assay. Antibody persistence up to 5 years after booster vaccination is reported for 530 children ∼6 years of age. The percentages of children with seroprotective rSBA-MenC titers were between 24.2% and 40.1% in all groups approximately 5 years after booster vaccination. More than 98.5% of children in each group retained seroprotective anti-PRP concentrations. No vaccine-related serious adverse events and no events related to a lack of vaccine efficacy were reported. Approximately 5 years after booster vaccination, the majority of children retained seroprotective anti-PRP antibody concentrations. The percentage of children retaining seroprotective rSBA-MenC titers was low (≤40%), suggesting that a significant proportion of children may be unprotected against MenC disease. (This study has been registered at ClinicalTrials.gov under registration no. NCT00891176.).

Five-year Antibody Persistence and Booster Response After 1 or 2 Doses of Meningococcal A, C, W and Y Tetanus Toxoid Conjugate Vaccine in Healthy Children.

BACKGROUND: We evaluated antibody persistence up to 5 years postvaccination with a quadrivalent meningococcal serogroups A, C, W and Y tetanus toxoid conjugate vaccine (MenACWY-TT), and subsequent booster responses to MenACWY-TT in healthy US children. METHODS: In the initial phase II, open, multicenter study (NCT00471081), 349 infants were randomized (1:1) to receive MenACWY-TT (1 or 2 doses). In the follow-up study (NCT00718666), we evaluated antibody persistence at years 1, 3 and 5 by serum bactericidal assay using human complement (hSBA). At year 5, children received a booster dose of MenACWY-TT. We compared their immune responses at 1 month postbooster with those from 100 age-matched, meningococcal naive children, who received a primary MenACWY-TT dose. We recorded solicited adverse events for 4 days and unsolicited adverse events for 31 days, followed by an additional 5-month extended safety follow-up. RESULTS: At year 5, ≥64.0% of 1-dose and ≥74.6% of 2-dose recipients had hSBA titers ≥8 for MenC, MenW and MenY. For MenA, 31.7% of 1-dose and 38.0% of 2-dose recipients had hSBA titers ≥8. One month postvaccination, all booster dose recipients and ≥78.5% of primary dose recipients exhibited hSBA titers ≥8 for all serogroups. Geometric mean titers were higher in primed than in naive children. MenACWY-TT had a clinically acceptable safety profile. CONCLUSIONS: With the exception of serogroup W, antibody persistence 5 years after MenACWY-TT vaccination did not differ substantially between children who received 1 or 2 doses in infancy. A booster dose of MenACWY-TT elicited robust anamnestic responses and was well tolerated.

Long-term immunogenicity and safety after a single dose of the quadrivalent meningococcal serogroups A, C, W, and Y tetanus toxoid conjugate vaccine in adolescents and adults: 5-year follow-up of an open, randomized trial.

BACKGROUND: Long-term protection against meningococcal disease is associated with persistence of post-vaccination antibodies at protective levels. We evaluated the bactericidal antibody persistence and safety of the quadrivalent meningococcal serogroups A, C, W and Y tetanus-toxoid conjugate vaccine (MenACWY-TT) and the meningococcal polysaccharide serogroups A, C, W, and Y vaccine (MenACWY-PS) up to 5 years post-vaccination. METHODS: This phase IIb, open, randomized, controlled study conducted in the Philippines and Saudi Arabia consisted of a vaccination phase and a long-term persistence phase. Healthy adolescents and adults aged 11-55 years were randomized (3:1) to receive a single dose of MenACWY-TT (ACWY-TT group) or MenACWY-PS (Men-PS group). Primary and persistence results up to 3 years post-vaccination have been previously reported. Antibody responses against meningococcal serogroups A, C, W, and Y were assessed by a serum bactericidal antibody assay using rabbit complement (rSBA, cut-off titers 1:8 and 1:128) at Year 4 and Year 5 post-vaccination. Vaccine-related serious adverse events (SAEs) and cases of meningococcal disease were assessed up to Year 5. RESULTS: Of the 500 vaccinated participants, 404 returned for the Year 5 study visit (Total Cohort Year 5). For the Total Cohort Year 5, 71.6-90.0 and 64.9-86.3 % of MenACWY-TT recipients had rSBA titers ≥1:8 and ≥1:128, respectively, compared to 24.8-74.3 and 21.0-68.6 % of MenACWY-PS recipients. The rSBA geometric mean titers (GMTs) remained above the pre-vaccination levels in both treatment groups. Exploratory analyses suggested that both rSBA GMTs as well as the percentages of participants with rSBA titers above the cut-offs were higher in the ACWY-TT than in the Men-PS group for serogroups A, W and Y, with no apparent difference for MenC. No SAEs related to vaccination or cases of meningococcal disease were reported up to Year 5. CONCLUSION: These results suggest that a single dose of MenACWY-TT could protect at least 72 % of vaccinated adolescents and adults against meningococcal disease at least 5 years post-vaccination. TRIAL REGISTRATION: ClinicalTrials.gov NCT00356369.

Five-year Antibody Persistence and Safety After a Single Dose of Combined Haemophilus influenzae Type B Neisseria meningitidis Serogroup C-Tetanus Toxoid Conjugate Vaccine in Haemophilus influenzae Type B-primed Toddlers.

BACKGROUND: Antibody persistence is evaluated in healthy Australian children 4 and 5 years postvaccination with a single dose of combined Haemophilus influenzae type b-Neisseria meningitidis serogroup C tetanus toxoid conjugate vaccine (Hib-MenC-TT) compared with separately administered Hib-TT and MenC-CRM197 vaccines (Hib + MCC). METHODS: This is another follow-up of a phase III, open, randomized, controlled study (NCT00326118), in which 433 Hib-primed but MenC naïve toddlers aged 12-18 months were randomized 3:1 to receive Hib-MenC-TT or Hib + MCC vaccines. Protection against (1) MenC was measured by serum bactericidal antibody assay using rabbit complement (rSBA) and (2) Hib was measured by enzyme-linked immunosorbent assay of antibodies to polyribosylribitol phosphate (anti-PRP). Study children were assessed for any potentially vaccine-related serious adverse events at each persistence study visit. RESULTS: The according-to-protocol cohorts for persistence at years 4 and 5 included 282 and 263 children, respectively. The percentages of children with rSBA-MenC titers ≥1:8 at years 4 and 5 were 12.5% and 19.0%, respectively, in the Hib-MenC group; and 12.3% and 25.0% in the Hib + MCC group. All children in each group had anti-PRP concentrations ≥0.15 µg/mL at year 5. Exploratory analyses suggested no potential differences between groups in rSBA-MenC or anti-PRP antibody persistence. No vaccine-related serious adverse events were reported. CONCLUSIONS: Antibody persistence was similar for years 4 and 5 after Hib-MenC-TT or Hib + MCC vaccination, with the majority of children retaining anti-PRP antibody concentrations ≥0.15 µg/mL at both timepoints. The percentage of children retaining rSBA-MenC titers ≥1:8 was low (≤25%), suggesting that a MenC booster dose may be warranted before adolescence.

Five-year Antibody Persistence and Booster Response to a Single Dose of Meningococcal A, C, W and Y Tetanus Toxoid Conjugate Vaccine in Adolescents and Young Adults: An Open, Randomized Trial.

BACKGROUND: We evaluated antibody persistence after 1 dose of meningococcal serogroups ACWY tetanus toxoid (MenACWY-TT) or diphtheria toxoid (MenACWY-DT) conjugate vaccines and subsequent booster responses to MenACWY-TT. METHODS: In the initial phase II, open, multicenter study (NCT00454909), 872 participants aged 10-25 years received 1 MenACWY-TT or MenACWY-DT dose. In this study (NCT00715910), antibody persistence was evaluated at years 1, 3 and 5 by serum bactericidal activity assays using human complement (hSBA). At year 5, all participants received a MenACWY-TT booster dose. Immune responses at 1-month postbooster were compared with a control group including 101 participants aged 15-30 years who received a primary MenACWY-TT dose. Solicited and unsolicited adverse events were recorded for 4 and 31 days, respectively, followed by a 6-month extended safety follow-up. RESULTS: At year 5, ≥79.5% of MenACWY-TT-primed (n = 170) and MenACWY-DT-primed (n = 45) participants had hSBA titers ≥1:8 for MenC, MenW and MenY, and ≥37.5% for MenA. For all serogroups, ≥85.7% and ≥67.1% of MenACWY-TT booster and primary dose recipients exhibited vaccine responses 1-month postmvaccination, respectively. Geometric mean titers were potentially higher in primed versus naive participants, with no potential difference between MenACWY-TT-primed and MenACWY-DT-primed participants (exploratory analyses). MenACWY-TT had a clinically acceptable safety profile. CONCLUSIONS: Before the booster dose administration at year 5, hSBA-MenC, -MenW and -MenY antibody persistence was observed in most participants. However, only ≥37.5% of MenACWY-TT and 44.4% of MenACWY-DT recipients retained hSBA-MenA titers ≥1:8. MenACWY-TT booster doses elicited robust anamnestic responses, irrespective of the priming vaccine, and were well tolerated.

A randomized, dose-ranging assessment of the immunogenicity and safety of a booster dose of a combined diphtheria-tetanus-whole cell pertussis-hepatitis B-inactivated poliovirus-Hemophilus influenzae type b (DTPw-HBV-IPV/Hib) vaccine vs. co-administration of DTPw-HBV/Hib and IPV vaccines in 12 to 24 months old Filipino toddlers.

As progress toward global poliovirus eradication continues, more and more countries are moving away from use of oral poliovirus vaccines (OPV) to inactivated poliovirus vaccines (IPV) in national vaccination schedules. Reduction of antigen dose in IPV could increase manufacturing capacity and facilitate the change from OPV to IPV. Combination vaccines reduce the number of injections required to complete vaccination, thus playing an important role in maintaining high vaccine coverage with good public acceptability. Three formulations of a combined, candidate hexavalent diphtheria-tetanus-whole cell pertussis-hepatitis B-inactivated poliovirus-Hemophilus influenzae type b conjugate vaccine (DTPw-HBV-IPV/Hib, GlaxoSmithKline Biologicals) differing only in IPV antigen content (full-dose, half-dose and one-third dose as compared with available stand-alone IPV vaccines), were evaluated when administered to healthy toddlers. Controls received separately administered licensed DTPw-HBV/Hib and IPV vaccines. Immunogenicity was assessed before and one month after vaccination. Safety and reactogenicity data were assessed for 30 d after vaccination. A total of 312 Filipino children were vaccinated in their second year of life. Each DTPw-HBV-IPV/Hib formulation was non-inferior to control in terms of pre-defined criteria for IPV immunogenicity. Post-vaccination GMTs against each poliovirus type were increased between 4.2- and 37.9-fold over pre-vaccination titers. Non-inferiority to other vaccine antigens was also demonstrated. The safety profile of the 3 DTPw-HBV-IPV/Hib formulations resembled licensed DTPw-HBV/Hib Kft and IPV in terms of the frequency and intensity of adverse reactions after vaccination. Further investigation of DTPw-HBV-IPV/Hib containing reduced quantity of IPV antigen for primary vaccination in infants is warranted. This study is registered at www.clinicaltrials.gov NCT number: NCT01106092.

Immunogenicity of Infanrix™ hexa administered at 3, 5 and 11 months of age.

A pooled analysis of data from four vaccination studies conducted in Europe was undertaken to assess the immunogenicity of Infanrix™ hexa (DTPa-HBV-IPV/Hib, GlaxoSmithKline Biologicals) when administered in a total of 702 healthy infants at 3, 5 and 11-12 months of age. One month after dose 2, between 96.3% and 100% of subjects had seroprotective antibodies against diphtheria, tetanus, hepatitis B and poliovirus types 1, 2 and 3; 91.7% against Hib and ≥99.0% were seropositive for each pertussis antigen. One month after the third dose, 98.9-100% of subjects were seroprotected/seropositive for all vaccine antigens. Geometric mean antibody concentrations/titres for each vaccine antigen increased by 6.7-52.9 fold after the third vaccine dose. No serious adverse events in DTPa-HBV-IPV/Hib recipients were vaccine related. Infanrix™ hexa induces an adequate immune response after 2-dose primary plus booster doses when administered according to a 3, 5 and 11 months schedule.

An open-label, randomized, multi-center study of the immunogenicity and safety of DTaP-IPV (Kinrix™) co-administered with MMR vaccine with or without varicella vaccine in healthy pre-school age children.

BACKGROUND: In the US, it is recommended that 4-6 year old children receive diphtheria-tetanus-acellular pertussis (DTaP), inactivated poliovirus (IPV), measles-mumps-rubella (MMR), varicella (V), and influenza vaccines. Data relating to the concomitant administration of combination DTaP-IPV vaccine (Kinrix™; GlaxoSmithKline Biologicals) and influenza or V vaccines are currently limited. This study was undertaken to evaluate the immunogenicity and reactogenicity of Kinrix™ when co-administered with MMR (M-M-RII(®), Merck & Co.) and Varivax™ (Merck & Co.) in 4-6 year old children. METHODS: Phase IIIb, open-label, non-inferiority study (NCT00871117). We randomized (1:1) healthy 4-6 year olds to receive Kinrix™+MMR+V on day 0 (Group 1), or Kinrix™+MMR on day 0, followed by V at month 1 (Group 2). We measured DTaP-IPV immunogenicity before and 1 month post-vaccination (prior to V vaccination in Group 2). We collected local and general solicited symptoms within 4 days after vaccination and serious adverse events (SAEs) through 6 months post-vaccination. RESULTS: We enrolled 478 subjects. One month post-vaccination, >95% of subjects in both groups had booster responses to diphtheria, tetanus and pertussis antigens and all subjects had seroprotective anti-poliovirus antibody titers. Immune responses in Group 1 were non-inferior to Group 2 for responses to DTaP-IPV antigens according to pre-specified criteria. Reporting of solicited local events at the DTaP-IPV site appeared to be similar between the two vaccine groups, as was reporting of solicited general adverse events within 4 days of vaccination; no vaccine related SAEs were reported. CONCLUSION: Concomitant administration of varicella vaccine with Kinrix™ and MMR did not impact the immunogenicity of diphtheria, tetanus, pertussis or poliovirus antigens. Both vaccine regimens were well tolerated. These results support the co-administration of DTaP-IPV, MMR, and V vaccines in 4-6-year-old children, providing protection against multiple diseases in a timely and efficient manner.

Impact of rotavirus vaccination on childhood deaths from diarrhea in Brazil.

OBJECTIVES: Rotavirus vaccination was introduced in Brazil in March 2006, targeting an annual birth cohort of approximately 3.5 million. We analyzed trends in all-cause gastroenteritis-related deaths in children <5 years of age during the pre- and post-vaccination periods. METHODS: Data from the National Immunization Program and the Mortality Information System were used to calculate vaccine coverage and mortality rates related to gastroenteritis in children <1 year and 1-4 years of age, using population estimates from the census as the denominator. Relative reductions in mortality rates were calculated for 2007 and 2008, using the 2004-2005 mean as baseline before vaccine introduction. RESULTS: Coverage of two doses of human rotavirus vaccine was 39% in 2006, increasing to 72% in 2007 and 77% in 2008. During 2004-2005, the gastroenteritis mortality rate in children <1 year of age was 56.9 per 100 000, decreasing by 30% (95% confidence interval (CI) 19-41) in 2007 and by 39% (95% CI 29-49) in 2008. In children 1-4 years of age, the mortality rate was 4.5 per 100 000 during 2004-2005, decreasing by 29% (95% CI 10-49) in 2007 and by 33% (95% CI 15-52) in 2008. CONCLUSIONS: The decreased rates of childhood gastroenteritis-related deaths in Brazil following rotavirus vaccine introduction, particularly among children <1 year of age, suggest the potential benefit of vaccination.