Devayani Kolhe

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

BackgroundLong-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 5xa0years post-vaccination.MethodsThis 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 3xa0years 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.ResultsOf 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 64.9–86.3xa0% of MenACWY-TT recipients had rSBA titers ≥1:8 and ≥1:128, respectively, compared to 24.8–74.3 and 21.0–68.6xa0% 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.ConclusionThese results suggest that a single dose of MenACWY-TT could protect at least 72xa0% of vaccinated adolescents and adults against meningococcal disease at least 5xa0years post-vaccination.Trial registrationClinicalTrials.gov NCT00356369

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.

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

ABSTRACT 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.

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

ABSTRACT 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.

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

ABSTRACT 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.

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

BACKGROUNDnWe 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.nnnMETHODSnIn this phase III, open-label, controlled, multicentre study (NCT01939158), healthy toddlers aged 12-14u202fmonths 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 1u202fmonth post-each vaccination. Solicited and unsolicited symptoms were recorded for 4 and 31u202fdays post-each vaccination, respectively; serious adverse events (SAEs) and new onset of chronic illnesses (NOCIs) up to M9 from first vaccination.nnnRESULTSn802 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.nnnCONCLUSIONnMenACWY-TT was immunogenic when administered as a single dose at 12-14u202fmonths 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

BACKGROUNDnIndividuals 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.nnnMETHODSnThis 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 31u202fdays post-vaccination, and serious AEs (SAEs) and new onset of chronic illnesses (NOCIs) throughout the study.nnnRESULTSnThe 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 ≥2.0u202fμg/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.nnnCONCLUSIONnIn 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 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

ABSTRACT 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.)