Structured Benefit-Risk Assessment of a New Quadrivalent Meningococcal Conjugate Vaccine (MenACYW-TT) in Individuals Ages 12 Months and Older.

INTRODUCTION: A favorable benefit-risk balance is required to support licensure of biologics, in keeping with regulatory agencies' evolving recommendations, including the United States Food and Drugs Administration. We present a structured semi-quantitative benefit-risk analysis of MenACYW-TT, a quadrivalent meningococcal conjugate vaccine against Neisseria meningitidis serogroups, A, C, W and Y versus licensed comparators in individuals aged ≥ 12 months. METHODS: We used data from six MenACYW-TT clinical trials, stratified by age group, versus licensed vaccines: toddlers (12-23 months; Nimenrix® [MCV4-TT]), children (2-9 years; Menveo® [MCV4-CRM]), adolescents (10-17 years; MCV4-CRM or Menactra® [MCV4-DT]), adults (18-55 years; MCV4-DT) and older adults (≥ 56 years; Menomune®-A/C/Y/W-135 [MPSV4]). Eight benefit (seroresponse and seroprotection for A, C, W and Y) and five risk outcomes (any and grade 3 solicited injection site and systemic reactions, and serious adverse events) were measured at Day 30 after initial vaccination. Analyses were conducted by baseline vaccination status (meningococcal vaccine-naïve or vaccine-primed). RESULTS: MenACYW-TT showed favorable seroresponse and seroprotection among vaccine-naïve participants aged ≥ 2 years, against all serogroups, compared with MCV4-CRM, MCV4-DT and MPSV4. In vaccine-naïve toddlers, there was a favorable effect for serogroup C, but no difference between MenACYW-TT and MCV4-TT for serogroups A, Y and W. A favorable effect for MenACYW-TT against serogroup C was observed in all vaccine-naïve and combined vaccine-naïve and MenC conjugate vaccine-primed groups. For all risk criteria, there were no differences between MenACYW-TT and MCV4s in toddlers, children, adolescents and adults. Results for solicited injection site and systemic reactions favored MPSV4 in older adults. CONCLUSIONS: The benefit-risk profile for MenACYW-TT showed favorable seroresponse and seroprotection in individuals aged ≥ 2 years and no difference in risk criteria between MenACYW-TT and MCV4s. MenACYW-TT may provide an alternative to the standard-of-care for meningococcal disease prevention in those aged ≥ 12 months.

Immunogenicity and safety of an investigational quadrivalent meningococcal conjugate vaccine administered as a booster dose in children vaccinated against meningococcal disease 3 years earlier as toddlers: A Phase III, open-label, multi-center study.

Booster doses of meningococcal conjugate vaccines induce long-term protection against invasive meningococcal disease. We evaluated the immunogenicity and safety of a booster dose of MenACYW-TT in pre-school children who were primed 3 years earlier with MenACYW-TT or MCV4-TT (Nimenrix®). In this Phase III, open-label, multi-center study (NCT03476135), children (4-5 years old), who received a primary dose of MenACYW-TT or MCV4-TT as toddlers in a previous study, received a booster dose of MenACYW-TT. Titers of antibody against meningococcal serogroups A, C, W and Y were measured by serum bactericidal assay using human (hSBA) and baby rabbit (rSBA) complement in samples collected before (D0) and 30 days after (D30) booster vaccination. Safety was assessed over the 30-day study period. Ninety-one participants received the booster dose. In both study groups, hSBA titers increased from D0 to D30; serogroup C titers [95% confidence interval] were higher in the MenACYW-TT-primed vs MCV4-TT-primed group at D0 (106 [73.2, 153] vs 11.7 [7.03, 19.4], respectively) and D30 (5894 [4325, 8031] vs 1592 [1165, 2174], respectively); rSBA results were similar. Nearly all participants achieved ≥1:8 hSBA and rSBA titers at D30, which were higher or comparable to those observed post-primary dose, suggesting rapid booster responses. At D0, all hSBA and rSBA titers were higher than those observed pre-primary dose, suggesting persistence of immunogenicity. The MenACYW-TT booster dose was well-tolerated and had similar safety outcomes across study groups. These findings suggest that MenACYW-TT elicits robust booster responses in children primed 3 years earlier with MenACYW-TT or MCV4-TT.

Safety and immunogenicity of an investigational quadrivalent meningococcal tetanus toxoid conjugate vaccine (MenACYW-TT) co-administered with routine pediatric vaccines in infants and toddlers: A Phase II study.

BACKGROUND: The MenACYW-TT conjugate vaccine is approved for prevention of invasive meningococcal disease (IMD) as a single dose in individuals ≥2 years of age in the United States and ≥12 months in EU and some other countries. This Phase II study evaluated the safety and immunogenicity of this vaccine and of concomitant pediatric vaccines in infants/toddlers (6 weeks-15 months of age). METHODS: Five schedules of the MenACYW-TT conjugate vaccine were evaluated in the United States: 2, 4, 6, and 12 months; 2, 4, 6, and 15 months; 2, 4, and 12 months; 6 and 12 months; and 12 months alone. Routine pediatric vaccines (DTaP-IPV/Hib, PCV7/PCV13, MMR, and varicella) were administered per approved schedules. Proportions of participants with serum bactericidal antibodyassay with human complement (hSBA) titers ≥1:4 and ≥1:8, SBA with baby rabbit complement (rSBA) titers ≥1:8 and ≥1:128, and immune responses against concomitant vaccines were determined. RESULTS: Tenderness and irritability were the most frequent solicited injection site and systemic reactions. Similar proportions of participants achieved an hSBA titer ≥1:8 for all four serogroups regardless of whether 2 or 3 doses were administered in the first year of life. Following a second-year dose, 91-100% of participants achieved the threshold for all 4 serogroups in all schedules regardless of the number of doses in the first year of life. Similar responses were seen with rSBA. Immunogenicity and safety profile of concomitant vaccines was similar whether the MenACYW-TT conjugate vaccine was administered or not. CONCLUSION: MenACYW-TT conjugate vaccine administered with pediatric vaccines is safe and immunogenic regardless of the schedule and does not affect the immunogenicity or safety of the concomitant vaccines. CLINICAL TRIAL REGISTRY: NCT01049035.

Post-Marketing Surveillance Observational Study of Quadrivalent Meningococcal Diphtheria Toxoid Conjugate Vaccine (MenACWY-DT, MCV4/Menactra®) in the Republic of Korea, 2014-2019.

BACKGROUND: Invasive meningococcal disease is a notifiable disease in the Republic of Korea. The meningococcal (groups A, C, Y, and W) polysaccharide diphtheria toxoid conjugate vaccine (MenACWY-DT, Menactra®) was licensed in the Republic of Korea in 2014. This post-marketing surveillance (PMS) observational study aims to assess the safety of MenACWY-DT administration of routine clinical care to individuals aged 9-23 months as a two-dose series at least 3 months apart and to individuals 2-55 years as a single dose. METHODS: The PMS observational study (NCT02864927) included participants aged 9 months to 55 years and who were given MenACWY-DT during routine healthcare visits. The study participants were followed-up for up to 30 days following vaccination (additional time was allowed for the visit or phone call to be conducted). Study outcomes included solicited and unsolicited adverse reactions, unexpected adverse events, and serious adverse events (SAEs). RESULTS: A total of 640 participants 9-23 months of age and 671 participants 2-55 years of age were eligible for safety analysis. Overall, AEs were reported by 35.3% of participants aged < 2 years and 45% of participants aged 2-55 years. Solicited adverse reactions were reported by 21.4% and 17.4% of participants aged < 2 years and 2-55 years, respectively. Unsolicited adverse reactions were reported by 26.1% and 37.9%, respectively. No vaccine-related SAEs occurred during the study. The AEs reported in Korean population were consistent with the known safety profile of MenACWY-DT, and most were of grade 1-2 in severity. CONCLUSIONS: This study did not detect any unanticipated or new safety findings of concern with MenACWY-DT in either of the study age groups, and provides reassurance that MenACWY-DT can be used as part of routine immunization care for the prevention of invasive meningococcal disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT02864927.

Immunogenicity and safety of a quadrivalent meningococcal tetanus toxoid-conjugate vaccine (MenACYW-TT) in ≥56-year-olds: A Phase III randomized study.

BACKGROUND: Invasive meningococcal disease has a high mortality rate in individuals aged ≥56 years, but no vaccine is currently licensed in the USA for this age group. This study assessed the safety and immunogenicity of an investigational quadrivalent meningococcal tetanus toxoid conjugate vaccine (MenACYW-TT) compared with a meningococcal quadrivalent polysaccharide vaccine (MPSV4) in this age group. METHODS: This was a Phase III, modified double-blind, randomized, non-inferiority study (NCT02842866) across 35 clinical sites in the USA and Puerto Rico in individuals aged ≥56 years. A single dose of the MenACYW-TT (n = 451) or MPSV4 vaccine (n = 455) was administered on Day 0. A serum bactericidal assay with human (hSBA) and baby rabbit (rSBA) complement was used to measure antibodies against serogroups A, C, W, and Y test strains at baseline and Day 30. Safety data were collected up to six months post-vaccination. RESULTS: The seroresponse to MenACYW-TT was non-inferior to MPSV4 for each of the serogroups (A: 58.2% vs. 42.5%; C: 77.1% vs. 49.7%; W: 62.6% vs. 44.8%, Y: 74.4% vs. 43.4%, respectively). At Day 30, participants achieving hSBA titers ≥1:8 were higher for all serogroups after MenACYW-TT vs. MPSV4 (77.4-91.7 vs. 63.1-84.2%, respectively). No safety concerns were identified for either vaccine. CONCLUSION: MenACYW-TT was well-tolerated and immunogenic in ≥56-year-olds, offering the potential to replace MPSV4 in this age group.

Immunogenicity, safety and inter-lot consistency of a meningococcal conjugate vaccine (MenACYW-TT) in adolescents and adults: A Phase III randomized study.

BACKGROUND: MenACYW-TT is an investigational quadrivalent (serogroups A, C, W and Y) meningococcal conjugate vaccine that is being developed for protection against invasive meningococcal disease. METHODS: In this Phase 3, blinded, randomized study, 3344 meningococcal vaccine-naïve 10-55-year-olds were randomized (3:3:3:2) to receive one of three lots of MenACYW-TT or licensed quadrivalent meningococcal conjugate vaccine, MCV4-DT (NCT02842853). Antibody titers were assessed by human and rabbit complement serum bactericidal antibody assays. The co-primary objectives were to demonstrate lot-to-lot consistency of MenACYW-TT by the between-lot geometric mean titer ratios (GMTR) at Day 30, and non-inferiority of Day 30 vaccine seroresponses (titers ≥ 1:16 if pre-vaccination titers < 1:8, or ≥ 4-fold increase if pre-vaccination titers ≥ 1:8) with MenACYW-TT vs MCV4-DT. Further objectives included safety and immunogenicity. RESULTS: Lot consistency was demonstrated for all three lots, with GMTRs ranging from 0.87 to 1.1. The proportion of participants achieving seroresponse in the MenACYW-TT group (data pooled from the 3 lots) was non-inferior to MCV4-DT (A: 74% vs 55%; C: 89% vs 48%; W: 80% vs 61%; Y: 91% vs 73%, respectively). MenACYW-TT and MCV4-DT had similar safety profiles; no safety concerns were identified. CONCLUSIONS: The study met both co-primary endpoints, demonstrating lot-to-lot consistency and non-inferiority of MenACYW-TT vs MCV4-DT in adolescents and adults.

Safety and immunogenicity of the pneumococcal pneumolysin derivative PlyD1 in a single-antigen protein vaccine candidate in adults.

BACKGROUND: Pneumococcal vaccines based on conserved protein antigens have the potential to offer expanded protection against Streptococcus pneumoniae. OBJECTIVE: This study examined the safety and immunogenicity in adults of three doses of a pneumococcal single-antigen protein vaccine candidate formulated with aluminum hydroxide adjuvant and recombinantly derived, highly detoxified, genetically mutated pneumolysin protein (PlyD1). METHODS: This phase I, randomized, placebo-controlled, observer-blinded, dose-escalating study enrolled adults (18-50 years). In a pilot safety study, participants received a single injection of 10 µg PlyD1 and were observed for 24 h. Following review of the pilot safety data, participants were randomized (2:1) to receive two injections of PlyD1 at one of three doses or placebo 30 days apart. Assignment of second injection and successive dose cohorts was made after blinded safety reviews after each injection at each dose level. Safety endpoints included rates of solicited injection site reactions, solicited systemic reactions, unsolicited adverse events (AEs), serious AEs (SAEs), and safety laboratory tests. Immunogenicity endpoints included geometric mean concentrations of anti-PlyD1 IgG as determined by ELISA and functional assessment in an in vitro toxin neutralization assay. RESULTS: The study included a total of 100 participants, including 10 in the pilot study and 90 in the randomized study. None of the participants in the pilot study had SAEs, allergic reactions, or other safety concerns. Ninety participants received two doses of or placebo (n=30) or active vaccine candidate at 10 (n=20), 25 (n=20), or 50 µg (n=20). No vaccine-related SAE or discontinuation due to an AE occurred. Most solicited reactions were mild and transient. The most frequently reported solicited reactions were pain at the injection site and myalgia. Antigen-specific IgG levels and functional activity showed dose-related increases. When comparing the three dose levels, a plateau effect was observed at the 25 µg dose. CONCLUSIONS: All dose levels were safe and immunogenic. Repeat vaccination significantly increased the level of anti-PlyD1 antibodies. Functional antibody activity was demonstrated in sera from vaccinated individuals (ClinicalTrials.gov no. NCT01444352).

Safety and immunogenicity of a pneumococcal histidine triad protein D vaccine candidate in adults.

BACKGROUND: Pneumococcal vaccines based on conserved protein antigens have the potential to offer expanded protection against Streptococcus pneumoniae. OBJECTIVE: To explore safety and immunogenicity of a recombinant protein vaccine candidate against S. pneumoniae composed of adjuvanted pneumococcal histidine triad protein D (PhtD). METHODS: This phase I, exploratory, open-label, single-center clinical study enrolled adults (18-50 years). Participants in a pilot safety cohort received a single intramuscular injection of 6 µg. Following safety review, 3 dose cohorts were enrolled (6, 25, and 100 µg); participants received 2 injections administered approximately 30 days apart. Assignment of the second injection and successive dose cohorts were made after blinded safety reviews after each injection at each dose level. Safety endpoints included rates of solicited injection site and systemic reactions, unsolicited adverse events, serious adverse events, and safety laboratory tests. Immunogenicity endpoints included levels of anti-PhtD antibodies as measured by ELISA. RESULTS: Sixty-three participants were enrolled and received the pilot safety dose (n=3) or at least 1 dose of PhtD vaccine candidate at 6 µg (n=20), 25 µg (n=20), or 100 µg (n=20). No safety concerns were identified. No vaccine-related serious adverse event was reported. The most common solicited injection site reaction was pain and most common solicited systemic reactions were myalgia and headache; most reactions were mild and transient. Observed geometric mean concentrations (95% CI) were 200.99 ELISA units (148.46, 272.10), 352.07 (193.49, 640.63), and 699.15 (405.49, 1205.48) post-injection 1 in the 6, 25, and 100 µg dose cohorts, respectively, and 378.25 (275.56, 519.21), 837.32 (539.29, 1300.04), and 1568.62 (1082.92, 2272.16) post-injection 2. CONCLUSIONS: All dose levels were safe and immunogenic. The frequency of solicited reactions was highest at the 100 µg dose. Administration of a second injection significantly increased the levels of anti-PhtD antibodies (ClinicalTrials.gov registry no. NCT01444001).