Jacqueline M. Miller

Tetravalent meningococcal serogroups A, C, W-135 and Y conjugate vaccine is well tolerated and immunogenic when co-administered with measles–mumps–rubella–varicella vaccine during the second year of life: An open, randomized controlled trial

Co-administration of meningococcal ACWY-tetanus toxoid conjugate vaccine (ACWY-TT) with MMRV vaccine was investigated in 1000 12-23-month old children randomized (3:3:1:1) to receive co-administered ACWY-TT+MMRV, or a single dose of ACWY-TT, MMRV or MenC-CRM(197). Non-inferiority of ACWY-TT to MenC-CRM(197) and non-inferiority of ACWY-TT+MMRV to ACWY-TT and MMRV alone, and the immunogenicity of serogroups AWY were demonstrated according to pre-defined criteria. Fever reactions in ACWY+MMRV and MMRV groups were comparable. ACWY-TT can be co-administered with MMRV without affecting immunogenicity or safety profiles of either vaccine. This study has been registered at www.clinicaltrials.gov NCT00474266.

An investigational tetravalent meningococcal serogroups A, C, W-135 and Y-tetanus toxoid conjugate vaccine co-administered with Infanrix™ hexa is immunogenic, with an acceptable safety profile in 12-23-month-old children.

Tetravalent meningococcal serogroups ACWY conjugate vaccines will provide an advantage to those at most risk of invasive meningococcal disease; namely young children. Co-administration of ACWY-TT with DTaP-HBV-IPV/Hib was assessed in a randomized trial in 793 children aged 12-23 months. Pre-specified criteria for non-inferiority of immunogenicity following co-administration versus separate ACWY-TT and DTaP-HBV-IPV/Hib administration were reached. One month post-vaccination, ≥ 97.3% of ACWY-TT vaccinees had rSBA titres ≥ 1:8 (all serogroups). Seroprotection/seropositivity rates against DTaP-HBV-IPV/Hib antigens were ≥ 98.2%. The safety profile of co-administration was similar to that of DTaP-HBV-IPV/Hib alone. ACWY-TT and DTaP-HBV-IPV/Hib co-administration during the second year would facilitate introduction of ACWY-TT into routine toddler vaccination schedules.

Safety and immunogenicity of a tetravalent meningococcal serogroups A, C, W-135 and Y conjugate vaccine in adolescents and adults

The highest incidence of invasive meningococcal disease is in young children, with a second peak in adolescents/young adults. All five major disease-causing serogroups (A, B, C, W-135 and Y) have been described in Asia. Immunogenicity and safety of the investigational meningococcal ACWY-tetanus toxoid conjugate vaccine (ACWY-TT, GlaxoSmithKline Biologicals) was evaluated in healthy, meningococcal conjugate vaccine-naïve adolescents in the Philippines, India and Taiwan. 1025 adolescents were randomized (3:1) to receive one dose of ACWY-TT or tetravalent ACWY polysaccharide vaccine (Mencevax™, Men-PS). Serum bactericidal activity using rabbit complement (rSBA) was measured. Local and systemic adverse reactions were recorded for 4 days. Safety data were pooled with results from a second, similarly designed study in adults for evaluation of grade 3 systemic events. The pre-specified immunogenicity criterion for non-inferiority to Men-PS was met. One month post-vaccination, ≥85.4%-97.1% had a vaccine response (post-titre ≥1:8 in initially seronegative and ≥4-fold increase in seropositive), versus 78.0%-96.6% after Men-PS, against each vaccine serogroup. Exploratory comparisons showed statistically significantly higher post-vaccination rSBA geometric mean titres against all serogroups following ACWY-TT versus Men-PS. Exploratory analysis showed no statistically significant differences between groups in grade 3 general symptoms; however, the statistical criterion for non-inferiority between pooled treatment groups in terms of the ratio of incidences of grade 3 general symptoms was not demonstrated. No SAEs were related to vaccination. ACWY-TT was immunogenic in Asian adolescents with a reactogenicity profile that was clinically acceptable and similar to that of licensed Men-PS. The results of this study indicate that ACWY-TT could be used as a third conjugate vaccine in the protection of adolescents against meningococcal disease.

Immunogenicity of a single dose of tetravalent meningococcal serogroups A, C, W-135, and Y conjugate vaccine administered to 2- to 10-year-olds is noninferior to a licensed-ACWY polysaccharide vaccine with an acceptable safety profile

Background: Meningococcal disease remains an important cause of invasive bacterial infections in children less than 5 years of age. Immunogenicity and safety of the investigational ACWY vaccine conjugated with tetanus toxoid (ACWY-TT, GlaxoSmithKline Biologicals) were evaluated in 1501 healthy 2- to 10-year-old children in the Philippines, India, Lebanon, and Saudi Arabia. Methods: Children were randomized (3:1) to receive ACWY-TT or licensed tetravalent meningococcal polysaccharide vaccine (Mencevax, GlaxoSmithKline, Men-PS). Diary cards were used to collect solicited symptoms for 4 days after vaccination. Serious adverse events were reported for 6 months. Serum bactericidal activity (rSBA, rabbit complement) was measured before and 1 month after vaccination in the first 75% of subjects enrolled in each country. Results: The statistical criteria for noninferiority in terms of rSBA vaccine responses were reached. Exploratory analyses showed that postvaccination rSBA titers ≥1:8 and ≥1:128 were significantly higher after ACWY-TT than Men-PS for serogroups C, W-135, and Y, and rSBA vaccine responses and geometric mean antibody titers were significantly higher for all 4 serogroups after administration of ACWY-TT. Noninferiority in terms of incidences of grade 3 general symptoms was not demonstrated. ACWY-TT was well tolerated with grade 3 events reported in <1% of subjects per group. No serious adverse events were considered related to vaccination. Conclusion: ACWY-TT was immunogenic in children between 2 to 10 years of age with a clinically acceptable safety profile that resembled licensed Men-PS. These data support a positive benefit/risk ratio for the ACWY-TT vaccine.

Immunogenicity and safety of an investigational quadrivalent meningococcal ACWY tetanus toxoid conjugate vaccine in healthy adolescents and young adults 10 to 25 years of age.

Background: An investigational quadrivalent Neisseria meningitidis serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine (MenACWY-TT) has been developed to expand available options for vaccination against invasive meningococcal disease. Methods: A total of 784 healthy adolescents and young adults 11 to 25 years of age were randomized (3:1) to receive a single dose of the MenACWY-TT vaccine or a licensed MenACWY diphtheria toxoid conjugate vaccine (MenACWY-DT). An additional nonrandomized group of 88 subjects 10 years of age received the MenACWY-TT vaccine only (MenACWY-TT/10). Immunogenicity was assessed 1 month postvaccination by human complement serum bactericidal assay (hSBA) for all serogroups. Solicited local and general symptoms were recorded for 8 days postvaccination and safety outcomes for 6 months. Results: One month postvaccination, 81.9% to 96.1% of subjects had hSBA titers ≥1:8 in the MenACWY-TT group compared with 70.7% to 98.8% in the MenACWY-DT group. Exploratory analyses showed the proportion of subjects with hSBA titers ≥1:4 and ≥1:8 to be higher in the MenACWY-TT group than in the MenACWY-DT group for serogroups A, W-135, and Y. GMTs adjusted for age strata and baseline titer 1 month postvaccination were higher in the MenACWY-TT group than in the MenACWY-DT group for all 4 serogroups. The percentage of subjects reporting solicited local and general symptoms of any or Grade 3 severity or serious adverse events was similar between the 2 groups. Immune response and reactogenicity in the MenACWY-TT/10 group was similar to that in the MenACWY-TT group, except for higher hSBA-MenA GMTs in the MenACWY-TT/10 group. Conclusions: The investigational MenACWY-TT vaccine was immunogenic in adolescents and young adults, with an acceptable safety profile.

Immunogenicity and Safety of an Investigational Combined haemophilus influenzae Type B- neisseria meningitidis Serogroups C and Y-tetanus Toxoid Conjugate Vaccine

Background: Neisseria meningitidis serogroups B, C, and Y cause most meningococcal disease in industrialized countries. A Haemophilus influenzae type b-meningococcal serogroups C and Y-tetanus toxoid conjugate vaccine (HibMenCY-TT) was evaluated. Methods: A total of 1104 infants (randomized 3:1:1) were vaccinated at 2, 4, and 6 months with HibMenCY-TT, MenC-CRM197 + Hib-TT, or Hib-TT. At 12 to 15 months, HibMenCY-TT and MenC-CRM-primed children received HibMenCY-TT; Hib-TT-primed received N. meningitidis serogroup B Hib-outer membrane protein complex. Antibody concentrations and rabbit/human complement serum bactericidal antibody titers (rSBA/hSBA) were determined. Safety was monitored after each dose (diary cards for first 31 days) until 6 months postdose 4. Results: Postdose 3, rates of antipolyribosylribitol phosphate ≥1 &mgr;g/mL and rSBA-MenC ≥1:128 in HibMenCY-TT recipients were noninferior to licensed controls. Percentages reaching 0.15 &mgr;g/mL (1.0 &mgr;g/mL postdose 3) and antipolyribosylribitol phosphate GMC were significantly higher after HibMenCY-TT than Hib-TT postdose 2 and postdose 3. The GMC remained significantly higher before and after dose 4. Proportions of HibMenCY-TT recipients with rSBA ≥1:8 were 95.6% (MenC), 98.6% (MenY) postdose-2, ≥99% for MenC/Y postdose 3 and 4; hSBA ≥1:4 were 95.5% (MenC), 89.8% (MenY) postdose 2, >97% for MenC/Y postdose 3 and 4. HibMenCY-TT had a similar safety profile to control vaccines. Conclusions: HibMenCY-TT induced noninferior Hib and MenC responses compared with monovalent Hib and MenC conjugates with a comparable safety profile. Bactericidal antibodies against MenC/Y were induced after 2 doses of HibMenCY-TT.

The immunogenicity and safety of an investigational meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine (ACWY-TT) compared with a licensed meningococcal tetravalent polysaccharide vaccine: A randomized, controlled non-inferiority study

Immunogenicity and safety of ACWY-TT compared with licensed ACWY polysaccharide vaccine (MenPS) in healthy adults, and lot-to-lot consistency of three ACWY-TT lots were evaluated in a phase 3, open, controlled study. Adults aged 18–55 y were randomized to receive ACWY-TT (one of three lots) or MenPS. Serum bactericidal antibodies (rSBA) were measured pre- and 1 mo post-vaccination. Adverse events (AEs) were assessed 4 d (solicited symptoms) and 31 d (unsolicited symptoms) post-vaccination. Serious AEs were reported up to 6 mo after vaccination. The number of vaccinated subjects was 1247 (ACWY-TT, n = 935; MenPS, n = 312). ACWY-TT lot-to-lot consistency and non-inferiority of ACWY-TT as compared with MenPS groups were demonstrated according to pre-specified criteria. The percentages of subjects with a vaccine response (VR = rSBA titer ≥ 1:32 in initially seronegative; ≥ 4-fold increase in initially seropositive) to ACWY-TT vs. MenPS were 80.1%/69.8% (serogroup A), 91.5%/ 92.0% (C), 90.2%/85.5% (W-135), 87.0%/78.8% (Y). Exploratory analyses showed that for serogroups A, W-135 and Y, VR rates and GMTs were significantly higher for ACWY-TT compared with MenPS. For each serogroup, ≥ 98.0% of subjects had rSBA titers ≥ 1:128. Grade 3 solicited AEs were reported in ≤ 1.6% of subjects in any group. The immunogenicity of ACWY-TT vaccine was non-inferior to MenPS for all four serogroups in adults, with significantly higher VR rates to serogroups A, W-135 and Y and an acceptable safety profile. Consistency of 3 ACWY-TT production lots was demonstrated. These data suggest that, if licensed, ACWY-TT conjugate vaccine may be used for protection against invasive meningococcal disease in healthy adults. This study is registered at clinicaltrials.gov NCT00453986

Immunogenicity and Safety of H influenzae Type b–N meningitidis C/Y Conjugate Vaccine in Infants

BACKGROUND: Meningococcal disease incidence is highest in children younger than 2 years of age, yet there is no US-licensed vaccine for this age group. A phase III study evaluated the immunogenicity and safety of an investigational Haemophilus influenzae type b (Hib)–Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine (HibMenCY). MATERIALS AND METHODS: A total of 4180 infants were randomly assigned to receive the HibMenCY at the ages of 2, 4, 6, and 12 to 15 months or the licensed Hib tetanus toxoid conjugate vaccine (ActHIB) at 2, 4, and 6 months and Hib conjugated to N meningitidis outer membrane protein (PedvaxHIB) at 12 to 15 months. Routinely scheduled vaccines were coadministered. Serum bactericidal activity using human complement and anti–polyribosylribitol phosphate antibodies were assessed in 991 subjects. Local and systemic adverse reactions were recorded for 4 days after each dose. RESULTS: The percentage of HibMenCY recipients with serum bactericidal assay using human complement titers of 1:8 or higher after dose 3 was 98.8% for N meningitidis serogroup C (MenC) and 95.8% for N meningitidis serogroup Y (MenY). After dose 4, the percentages were 98.5% and 98.8%, respectively. The percentage of HibMenCY recipients with postdose 3 anti-polyribosylribitol phosphate antibody levels of ≥1.0 μg/mL was noninferior to that of control (96.3% vs 91.2%). After dose 4, MenC and MenY serum bactericidal assay using human complement antibody titers increased 12-fold over pre–dose 4 levels. Incidence of pain, redness, and swelling at the HibMenCY injection sites tended to be lower than with Hib type b after the first 3 doses and after the fourth dose. Rates of systemic symptoms were similar across groups. CONCLUSIONS: The HibMenCY was immunogenic against MenC and MenY and induced anti–polyribosylribitol phosphate antibody levels noninferior to those of licensed Hib conjugate vaccine. The safety profile of the HibMenCY was clinically acceptable and comparable to Hib conjugate vaccine.

A randomized study to assess the immunogenicity, antibody persistence and safety of a tetravalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine in children aged 2-10 years.

Incidence of meningococcal diseases is high in children, and effective vaccines are needed for this age group. In this phase II, open, controlled study, 309 children aged 2–10 y from Finland were randomized (3:1) into two parallel groups to receive one dose of meningococcal ACWY-tetanus toxoid conjugate vaccine (ACWY-TT group; n = 231) or a licensed meningococcal ACWY polysaccharide vaccine (Men-PS group; n = 78). Serum bactericidal activity using rabbit complement (rSBA) was evaluated up to three years post-vaccination. Exploratory comparisons suggested that rSBA vaccine response rates and geometric mean titers (GMTs) for each serogroup at one month post-vaccination and rSBA GMTs for serogroups A, W-135 and Y up to three years post-vaccination were higher in the ACWY-TT compared with Men-PS group, but did not detect any difference between groups in terms of rSBA-MenC GMTs at three years post-vaccination; this is explained by the higher proportion of children from the Men-PS group who were excluded because they were re-vaccinated with a monovalent meningococcal serogroup C vaccine due to loss of protective antibody levels against this serogroup. Although there was a higher incidence of local reactogenicity in the ACWY-TT group, general and unsolicited symptoms reporting rates were comparable in both groups. This study showed that MenACWY-TT was immunogenic with a clinically acceptable safety profile in children aged 2–10 y. MenACWY-TT induced higher functional antibody titers for all serogroups, which persisted longer for serogroups A, W-135 and Y, than the MenACWY polysaccharide vaccine. This study has been registered at www.clinicaltrials.gov NCT00427908.

Randomized trial to assess immunogenicity and safety of Haemophilus influenzae type b and Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine in infants.

Background: Study assessed the immunogenicity and safety of an investigational Haemophilus influenzae type b-Neisseria meningitidis serogroups C and Y–tetanus toxoid conjugate vaccine (HibMenCY-TT) in infants. Methods: In a single-blinded, controlled study, 609 infants were randomized 1:1 to receive primary vaccination (2, 4, and 6 months) with either HibMenCY-TT or monovalent Haemophilus influenzae type b tetanus toxoid conjugate vaccine (Hib-TT), co-administered with combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus vaccine and 7-valent pneumococcal conjugate vaccine. A second control group of 3- to 5-year-old children received a single dose of licensed meningococcal ACWY polysaccharide vaccine (MPSV4). Immunogenicity was measured before and 1 month after dose 3/MPSV4 using human (hSBA) and rabbit complement bactericidal assays (rSBA) and enzyme-linked immunosorbent assay assays for IgG antibodies to MenC and MenY polysaccharides. Anti-polyribosylribitol phosphate antibody concentrations were measured 1 month after the third dose. Safety was also assessed. Results: One month after primary vaccination statistically significantly more HibMenCY-TT than Hib-TT vaccines had anti-PRP antibody concentrations ≥1.0 μg/mL (93.5% vs. 85.8%). The percentage of HibMenCY-TT recipients with hSBA titers ≥1:8 (MenC: 95.9%, MenY: 89.4%) was statistically significantly higher than for MPSV4 recipients (MenC: 30.2%, MenY: 47.5%). The percentage of subjects reporting any severe (grade 3) symptom within 4 days of each vaccination was: 11.5% (HibMenCY-TT) and 24.8% (Hib-TT) (group difference, 13.27%, 95% CI: [7.22;19.29], P < 0.001). Conclusion: The investigational HibMenCY-TT vaccine was well tolerated and immunogenic in infants, induced Hib immune responses that were comparable to licensed Hib-TT vaccine, and induced high levels of bactericidal antibodies against N. meningitidis serogroups C and Y.