Efficacy and safety of respiratory syncytial virus prefusion F protein vaccine (RSVPreF3 OA) in older adults over 2 RSV seasons.

BACKGROUND: The adjuvanted RSV prefusion F protein-based vaccine (RSVPreF3 OA) was efficacious against RSV-related lower respiratory tract disease (RSV-LRTD) in ≥60-year-olds over 1 RSV season. We evaluated efficacy and safety of 1 RSVPreF3 OA dose and of 2 RSVPreF3 OA doses given 1 year apart against RSV-LRTD over 2 RSV seasons post-dose 1. METHODS: In this phase 3, blinded trial, ≥60-year-olds were randomized (1:1) to receive RSVPreF3 OA or placebo pre-season 1. RSVPreF3 OA recipients were re-randomized (1:1) to receive a second RSVPreF3 OA dose (RSV_revaccination group) or placebo (RSV_1dose group) pre-season 2; participants who received placebo pre-season 1 received placebo pre-season 2 (placebo group). Efficacy of both vaccine regimens against RSV-LRTD was evaluated over 2 seasons combined (confirmatory secondary objective, success criterion: lower limits of 2-sided confidence intervals [CIs] around efficacy estimates >20%). RESULTS: The efficacy analysis comprised 24,967 participants (RSV_1dose: 6227, RSV_revaccination: 6242, placebo: 12,498). Median efficacy follow-up was 17.8 months. Efficacy over 2 seasons of 1 RSVPreF3 OA dose was 67.2% (97.5% CI: 48.2-80.0) against RSV-LRTD and 78.8% (95% CI: 52.6-92.0) against severe RSV-LRTD. Efficacy over 2 seasons of a first dose followed by revaccination was 67.1% (97.5% CI: 48.1-80.0) against RSV-LRTD and 78.8% (95% CI: 52.5-92.0) against severe RSV-LRTD. Reactogenicity/safety of the revaccination dose were similar to dose 1. CONCLUSION: One RSVPreF3 OA dose was efficacious against RSV-LRTD over 2 RSV seasons in ≥60-year-olds. Revaccination 1 year post-dose 1 was well tolerated but did not seem to provide additional efficacy benefit in the overall study population. ClinicalTrials.gov registration: NCT04886596.

Respiratory Syncytial Virus Prefusion F Protein Vaccine Is Efficacious in Older Adults With Underlying Medical Conditions.

BACKGROUND: Older adults with chronic cardiorespiratory or endocrine/metabolic conditions are at increased risk of respiratory syncytial virus (RSV)-related acute respiratory illness (RSV-ARI) and severe respiratory disease. In an ongoing, randomized, placebo-controlled, multicountry, phase 3 trial in ≥60-year-old participants, an AS01E-adjuvanted RSV prefusion F protein-based vaccine (RSVPreF3 OA) was efficacious against RSV-related lower respiratory tract disease (RSV-LRTD), severe RSV-LRTD, and RSV-ARI. We evaluated efficacy and immunogenicity among participants with coexisting cardiorespiratory or endocrine/metabolic conditions that increase the risk of severe RSV disease ("conditions of interest"). METHODS: Medically stable ≥60-year-old participants received 1 dose of RSVPreF3 OA or placebo. Efficacy against first RSV-LRTD and RSV-ARI episodes was assessed in subgroups with/without coexisting cardiorespiratory or endocrine/metabolic conditions of interest. Immunogenicity was analyzed post hoc in these subgroups. RESULTS: In total, 12 467 participants received RSVPreF3 OA and 12 499 received placebo. Of these, 39.6% (RSVPreF3 OA) and 38.9% (placebo) had ≥1 coexisting condition of interest. The median efficacy follow-up was 6.7 months. Efficacy against RSV-LRTD was high in participants with ≥1 condition of interest (94.6%), ≥1 cardiorespiratory (92.1%), ≥1 endocrine/metabolic (100%), and ≥2 conditions of interest (92.0%). Efficacy against RSV-ARI was 81.0% in participants with ≥1 condition of interest (88.1% for cardiorespiratory, 79.4% for endocrine/metabolic conditions) and 88.0% in participants with ≥2 conditions of interest. Postvaccination neutralizing titers were at least as high in participants with ≥1 condition of interest as in those without. CONCLUSIONS: RSVPreF3 OA was efficacious against RSV-LRTD and RSV-ARI in older adults with coexisting medical conditions associated with an increased risk of severe RSV disease. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov: NCT04886596.

Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults.

BACKGROUND: Respiratory syncytial virus (RSV) is an important cause of acute respiratory infection, lower respiratory tract disease, clinical complications, and death in older adults. There is currently no licensed vaccine against RSV infection. METHODS: In an ongoing, international, placebo-controlled, phase 3 trial, we randomly assigned, in a 1:1 ratio, adults 60 years of age or older to receive a single dose of an AS01E-adjuvanted RSV prefusion F protein-based candidate vaccine (RSVPreF3 OA) or placebo before the RSV season. The primary objective was to show vaccine efficacy of one dose of the RSVPreF3 OA vaccine against RSV-related lower respiratory tract disease, confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR), during one RSV season. The criterion for meeting the primary objective was a lower limit of the confidence interval around the efficacy estimate of more than 20%. Efficacy against severe RSV-related lower respiratory tract disease and RSV-related acute respiratory infection was assessed, and analyses according to RSV subtype (A and B) were performed. Safety was evaluated. RESULTS: A total of 24,966 participants received one dose of the RSVPreF3 OA vaccine (12,467 participants) or placebo (12,499). Over a median follow-up of 6.7 months, vaccine efficacy against RT-PCR-confirmed RSV-related lower respiratory tract disease was 82.6% (96.95% confidence interval [CI], 57.9 to 94.1), with 7 cases (1.0 per 1000 participant-years) in the vaccine group and 40 cases (5.8 per 1000 participant-years) in the placebo group. Vaccine efficacy was 94.1% (95% CI, 62.4 to 99.9) against severe RSV-related lower respiratory tract disease (assessed on the basis of clinical signs or by the investigator) and 71.7% (95% CI, 56.2 to 82.3) against RSV-related acute respiratory infection. Vaccine efficacy was similar against the RSV A and B subtypes (for RSV-related lower respiratory tract disease: 84.6% and 80.9%, respectively; for RSV-related acute respiratory infection: 71.9% and 70.6%, respectively). High vaccine efficacy was observed in various age groups and in participants with coexisting conditions. The RSVPreF3 OA vaccine was more reactogenic than placebo, but most adverse events for which reports were solicited were transient, with mild-to-moderate severity. The incidences of serious adverse events and potential immune-mediated diseases were similar in the two groups. CONCLUSIONS: A single dose of the RSVPreF3 OA vaccine had an acceptable safety profile and prevented RSV-related acute respiratory infection and lower respiratory tract disease and severe RSV-related lower respiratory tract disease in adults 60 years of age or older, regardless of RSV subtype and the presence of underlying coexisting conditions. (Funded by GlaxoSmithKline Biologicals; AReSVi-006 ClinicalTrials.gov number, NCT04886596.).

A chimeric hemagglutinin-based universal influenza virus vaccine approach induces broad and long-lasting immunity in a randomized, placebo-controlled phase I trial.

Seasonal influenza viruses constantly change through antigenic drift and the emergence of pandemic influenza viruses through antigenic shift is unpredictable. Conventional influenza virus vaccines induce strain-specific neutralizing antibodies against the variable immunodominant globular head domain of the viral hemagglutinin protein. This necessitates frequent re-formulation of vaccines and handicaps pandemic preparedness. In this completed, observer-blind, randomized, placebo-controlled phase I trial (NCT03300050), safety and immunogenicity of chimeric hemagglutinin-based vaccines were tested in healthy, 18-39-year-old US adults. The study aimed to test the safety and ability of the vaccines to elicit broadly cross-reactive antibodies against the hemagglutinin stalk domain. Participants were enrolled into five groups to receive vaccinations with live-attenuated followed by AS03-adjuvanted inactivated vaccine (n = 20), live-attenuated followed by inactivated vaccine (n = 15), twice AS03-adjuvanted inactivated vaccine (n = 16) or placebo (n = 5, intranasal followed by intramuscular; n = 10, twice intramuscular) 3 months apart. Vaccination was found to be safe and induced a broad, strong, durable and functional immune response targeting the conserved, immunosubdominant stalk of the hemagglutinin. The results suggest that chimeric hemagglutinins have the potential to be developed as universal vaccines that protect broadly against influenza viruses.

Ten-Year Antibody Persistence and Booster Response to MenACWY-TT Vaccine After Primary Vaccination at 1-10 Years of Age.

This phase 3B, open-label, extension study (NCT01962207) evaluated long-term persistence of antibodies induced by the quadrivalent meningococcal vaccine conjugated to tetanus toxoid (MenACWY-TT) compared with the meningococcal serogroup C vaccine conjugated to CRM (MenC-CRM) and the quadrivalent meningococcal polysaccharide vaccine (MenACWY-PS) 6 to 10 y after primary vaccination in toddlers (aged 1-<2 y; MenACWY-TT and MenC-CRM) and children (aged 2-<11 y; MenACWY-TT and MenACWY-PS). Antibody responses against meningococcal serogroups A, C, W, and Y were assessed by serum bactericidal antibody assays using rabbit (rSBA) or human (hSBA) complement. A MenACWY-TT booster dose at Year 10 was given to all eligible subjects regardless of the primary vaccine received. At Year 10, the percentages of subjects with rSBA titers ≥1:8 for serogroups A, C, W, and Y were as follows: MenACWY-TT (toddlers), 65.6%, 82.8%, 31.3%, 43.8%, respectively; MenC-CRM, 88.2% for serogroup C; MenACWY-TT (children), 88.9%, 84.1%, 67.1%, 65.9%; and MenACWY-PS, 28.6%, 81.0%, 23.8%, and 23.8%. Corresponding percentages for hSBA titers ≥1:4 were as follows: MenACWY-TT (toddlers), 31.1%, 91.9%, 44.4%, 41.4%; MenC-CRM, 93.8% for serogroup C; MenACWY-TT (children), 34.8%, 91.1%, 61.2%, 72.6%; and MenACWY-PS, 33.3%, 100.0%, 26.3%, and 44.4%. One month after the MenACWY-TT booster, the percentage of subjects with vaccine response ranged from 75.7% to 100.0% across serogroups in all study groups. Postbooster vaccine responses were generally comparable between groups across serogroups. No new safety signals were identified. Antibody responses persisted 10 y after MenACWY-TT vaccination. The MenACWY-TT booster dose was well tolerated and elicited robust immune responses.

A phase 2b/3b MenACWY-TT study of long-term antibody persistence after primary vaccination and immunogenicity and safety of a booster dose in individuals aged 11 through 55 years.

BACKGROUND: A previous phase 2 study demonstrated the immunogenicity of a single dose of meningococcal A, C, W, Y-tetanus toxoid conjugate (MenACWY-TT) or polysaccharide (MenACWY-PS) vaccine for up to 5 years in individuals aged 11-55 years. This follow-up study evaluated long-term antibody persistence up to 10 years and the immunogenicity and safety of a single MenACWY-TT booster dose given 10 years after primary vaccination. METHODS: Blood draws were conducted annually in Years 7-10. At Year 10, all subjects received a MenACWY-TT booster dose. Blood was drawn at 1 month and safety data were collected ≤6 months postbooster. Study endpoints included immunogenicity during the persistence phase (primary), and immunogenicity and safety during the booster phase (secondary). Statistical analyses were descriptive. RESULTS: A total of 311 subjects were enrolled in the persistence phase (MenACWY-TT, 235; MenACWY-PS, 76); 220 were enrolled in the booster phase (MenACWY-TT, 164; MenACWY-PS, 56). Descriptive analyses indicated that at Years 7-10, the percentages of subjects achieving serum bactericidal antibody assay using baby rabbit complement (rSBA) titers ≥1:8 and ≥1:128 were higher for serogroups A, W, and Y in the MenACWY-TT versus MenACWY-PS group; percentages were similar across groups for serogroup C. rSBA geometric mean titers (GMTs) for serogroups A, W, and Y were higher in the MenACWY-TT group and slightly higher in the MenACWY-PS group for serogroup C. One month postbooster, all primary MenACWY-TT and ≥98.1% of primary MenACWY-PS recipients had rSBA titers ≥1:8. For all serogroups, rSBA GMTs postbooster were higher in the MenACWY-TT versus MenACWY-PS group. Most local and general reactogenicity events were similar between groups and mild to moderate in severity. Adverse events at 1 month postbooster were 9.1% for the MenACWY-TT and 3.6% for the MenACWY-PS groups; all were nonserious. CONCLUSIONS: Immune responses to a single MenACWY-TT primary dose administered at age 11-55 years persisted in >70% of individuals evaluated at Years 7-10. A MenACWY-TT booster dose administered at Year 10 was safe and immunogenic with no new safety signals observed. These results provide important insights regarding long-term protection from primary vaccination and the benefits of booster dosing. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01934140. Registered September 2013.

Efficacy and safety of a booster dose of the meningococcal A, C, W, Y-tetanus toxoid conjugate vaccine administered 10 years after primary vaccination and long-term persistence of tetanus toxoid conjugate or polysaccharide vaccine.

A previous phase 3, randomized, multicenter study showed the immunogenicity of a primary vaccination of subjects aged 11 to 17 years with the quadrivalent meningococcal vaccine conjugated to tetanus toxoid (MenACWY-TT) or the quadrivalent meningococcal polysaccharide vaccine (MenACWY-PS). This extension study evaluated the safety and immunogenicity of a MenACWY-TT booster 10 years after receiving a primary dose of either MenACWY-TT or MenACWY-PS. The primary immunogenicity endpoint was booster response, evaluated using serum bactericidal antibody assays with rabbit complement (rSBA), 1 month postbooster. Safety endpoints included the percentage of subjects experiencing local and general adverse events (AEs) ≤4 days after MenACWY-TT booster. Of 229 subjects enrolled, 169 and 58 in the MenACWY-TT and MenACWY-PS groups, respectively, completed the booster phase. The 1 month postbooster response for each serogroup ranged from 81.5% to 95.7% for MenACWY-TT and 66.7% to 94.1% for MenACWY-PS. Similar percentages of MenACWY-TT and MenACWY-PS recipients had a booster response to serogroups A, W, and Y, whereas more MenACWY-TT recipients than MenACWY-PS recipients had a booster response to serogroup C. For the MenACWY-TT and MenACWY-PS groups, respectively, the MenACWY-TT booster elicited rSBA titers ≥1:8 in 100% and ≥98.0% of subjects across all serogroups; 100% and ≥96.1% of all subjects had titers ≥1:128. No new safety signals were observed during the booster phase. In conclusion, a MenACWY-TT booster dose after receiving either a primary dose of MenACWY-TT or MenACWY-PS elicited robust immune responses and was well tolerated. Functional antibody responses last up to 10 years after primary MenACWY-TT vaccination.

Long-term antibody persistence after a booster dose of quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine in healthy 5-year-old children.

BACKGROUND: To provide continuing protection, available meningococcal vaccines must provide long-term persistence of circulating functional antibodies against prevalent serogroups causing invasive meningococcal disease (IMD). This study assessed antibody persistence and safety of the quadrivalent meningococcal vaccine conjugated to tetanus toxoid (MenACWY-TT) and the meningococcal serogroup C vaccine conjugated to Corynebacterium diphtheriae CRM197 protein (MenC-CRM) for up to 6 years after booster dosing in children. METHODS: In the primary vaccination study, children were vaccinated at age 12 to 23 months. In the first extension study, children who completed the primary study received a booster dose 4 years later with the same primary vaccine. The current study assessed antibody persistence at 2 to 6 years postbooster against each of the 4 meningococcal serogroups using serum bactericidal assays using rabbit (rSBA) or human (hSBA) complement with antibody titer thresholds of ≥1:8 or ≥1:4, respectively, and geometric mean titers (GMTs). Safety evaluations during this period included serious adverse events (SAEs) related to vaccination and any event related to lack of vaccine efficacy. RESULTS: A total of 184 subjects were enrolled (MenACWY-TT = 159; MenC-CRM = 25). For MenACWY-TT, the percentages of subjects with rSBA titers ≥1:8 ranged from 96.7% to 100% across serogroups at 2 years postbooster and 71.6% to 94.0% at 6 years postbooster; rSBA GMTs decreased from Year 2 to 4 and generally remained stable thereafter. The percentages of subjects in the MenACWY-TT group with hSBA titers ≥1:4 were 70.0% to 100% across serogroups at 2 years postbooster and 58.5% to 98.5% at 6 years postbooster. No lack of efficacy, SAEs, or vaccine-related adverse events were reported. CONCLUSIONS: The persistence of rSBA and hSBA antibodies was shown up to 6 years postbooster (10 years postprimary vaccination) with either MenACWY-TT or MenC-CRM, suggesting that this schedule may provide long-term protection against IMD. Clinicaltrials.gov: NCT01900899.

Immunogenicity of chimeric haemagglutinin-based, universal influenza virus vaccine candidates: interim results of a randomised, placebo-controlled, phase 1 clinical trial.

BACKGROUND: Influenza viruses cause substantial annual morbidity and mortality globally. Current vaccines protect against influenza only when well matched to the circulating strains. However, antigenic drift can cause considerable mismatches between vaccine and circulating strains, substantially reducing vaccine effectiveness. Moreover, current seasonal vaccines are ineffective against pandemic influenza, and production of a vaccine matched to a newly emerging virus strain takes months. Therefore, there is an unmet medical need for a broadly protective influenza virus vaccine. We aimed to test the ability of chimeric H1 haemagglutinin-based universal influenza virus vaccine candidates to induce broadly cross-reactive antibodies targeting the stalk domain of group 1 haemagglutinin-expressing influenza viruses. METHODS: We did a randomised, observer-blinded, phase 1 study in healthy adults in two centres in the USA. Participants were randomly assigned to one of three prime-boost, chimeric haemagglutinin-based vaccine regimens or one of two placebo groups. The vaccine regimens included a chimeric H8/1, intranasal, live-attenuated vaccine on day 1 followed by a non-adjuvanted, chimeric H5/1, intramuscular, inactivated vaccine on day 85; the same regimen but with the inactivated vaccine being adjuvanted with AS03; and an AS03-adjuvanted, chimeric H8/1, intramuscular, inactivated vaccine followed by an AS03-adjuvanted, chimeric H5/1, intramuscular, inactivated vaccine. In this planned interim analysis, the primary endpoints of reactogenicity and safety were assessed by blinded study group. We also assessed anti-H1 haemagglutinin stalk, anti-H2, anti-H9, and anti-H18 IgG antibody titres and plasmablast and memory B-cell responses in peripheral blood. This trial is registered with ClinicalTrials.gov, number NCT03300050. FINDINGS: Between Oct 10, 2017, and Nov 27, 2017, 65 participants were enrolled and randomly assigned. The adjuvanted inactivated vaccine, but not the live-attenuated vaccine, induced a substantial serum IgG antibody response after the prime immunisation, with a seven times increase in anti-H1 stalk antibody titres on day 29. After boost immunisation, all vaccine regimens induced detectable anti-H1 stalk antibody (2·2-5·6 times induction over baseline), cross-reactive serum IgG antibody, and peripheral blood plasmablast responses. An unsolicited adverse event was reported for 29 (48%) of 61 participants. Solicited local adverse events were reported in 12 (48%) of 25 participants following prime vaccination with intramuscular study product or placebo, in 12 (33%) of 36 after prime immunisation with intranasal study product or placebo, and in 18 (32%) of 56 following booster doses of study product or placebo. Solicited systemic adverse events were reported in 14 (56%) of 25 after prime immunisation with intramuscular study product or placebo, in 22 (61%) of 36 after immunisation with intranasal study product or placebo, and in 21 (38%) of 56 after booster doses of study product or placebo. Disaggregated safety data were not available at the time of this interim analysis. INTERPRETATION: The tested chimeric haemagglutinin-based, universal influenza virus vaccine regimens elicited cross-reactive serum IgG antibodies that targeted the conserved haemagglutinin stalk domain. This is the first proof-of-principle study to show that high anti-stalk titres can be induced by a rationally designed vaccine in humans and opens up avenues for further development of universal influenza virus vaccines. On the basis of the blinded study group, the vaccine regimens were tolerable and no safety concerns were observed. FUNDING: Bill & Melinda Gates Foundation.

Immunogenicity and Safety of a Quadrivalent Meningococcal ACWY-tetanus Toxoid Conjugate Vaccine 6 Years After MenC Priming as Toddlers.

BACKGROUND: We assessed immunogenicity, antibody persistence and safety of the meningococcal serogroups A, C, W and Y-tetanus toxoid (TT) conjugate vaccine (MenACWY-TT) in children primed as toddlers with MenC vaccine. METHODS: This open, multicenter extension study enrolled children 84-95 months of age who had received one dose of the combined Haemophilus influenzae type b (Hib)-MenC-TT conjugate vaccine (HibMenC group) or Hib-TT and monovalent MenC (MCC)-CRM197 vaccines (Hib+MCC group) at 12-18 months of age, in the primary study. All participants received one dose of MenACWY-TT. We assessed immunogenicity against MenA, MenC, MenW and MenY at 1 month and 2 years postvaccination by serum bactericidal assay using baby rabbit complement (rSBA). Safety and reactogenicity were evaluated. RESULTS: Six years post-MenC vaccination, <20% of children retained rSBA-MenC titers ≥1:8. At 1 month post-MenACWY-TT vaccination, vaccine response rates against all serogroups were high for both groups with ≥97.1% of children having rSBA ≥1:8. Two years postvaccination, ≥63.6% of children retained rSBA-MenA ≥1:8, and ≥87.9% for other serogroups. Geometric mean titers for all serogroups declined at 2 years post-MenACWY-TT vaccination, but remained ≥13 times higher than prevaccination levels. For both groups, pain (≤58.5%), redness (≤51.4%) and fatigue (≤27.0%) were the most frequently reported adverse events. No serious adverse events were reported. CONCLUSIONS: One dose of MenACWY-TT boosts protection against MenC in primed children, is safe and extends protection against MenA, MenW and MenY. Immunogenicity and safety were comparable in infants vaccinated with conjugated vaccine (HibMenC-TT) or the separate vaccines (Hib-TT and MCC-CRM197).

Chimeric Hemagglutinin-Based Influenza Virus Vaccines Induce Protective Stalk-Specific Humoral Immunity and Cellular Responses in Mice.

The high variation of the influenza virus hemagglutinin (HA), particularly of its immunodominant head epitopes, makes it necessary to reformulate seasonal influenza virus vaccines every year. Novel influenza virus vaccines that redirect the immune response toward conserved epitopes of the HA stalk domain should afford broad and durable protection. Sequential immunization with chimeric HAs (cHAs) that express the same conserved HA stalk and distinct exotic HA heads has been shown to elicit high levels of broadly cross-reactive Abs. In the current mouse immunization studies, we tested this strategy using inactivated split virion cHA influenza virus vaccines (IIV) without adjuvant or adjuvanted with AS01 or AS03 to measure the impact of adjuvant on the Ab response. The vaccines elicited high levels of cross-reactive Abs that showed activity in an Ab-dependent, cell-mediated cytotoxicity reporter assay and were protective in a mouse viral challenge model after serum transfer. In addition, T cell responses to adjuvanted IIV were compared with responses to a cHA-expressing live attenuated influenza virus vaccine (LAIV). A strong but transient induction of Ag-specific T cells was observed in the spleens of mice vaccinated with LAIV. Interestingly, IIV also induced T cells, which were successfully recalled upon viral challenge. Groups that received AS01-adjuvanted IIV or LAIV 4 wk before the challenge showed the lowest level of viral replication (i.e., the highest level of protection). These studies provide evidence that broadly cross-reactive Abs elicited by cHA vaccination demonstrate Fc-mediated activity. In addition, cHA vaccination induced Ag-specific cellular responses that can contribute to protection upon infection.

Immunogenicity and safety of the quadrivalent meningococcal vaccine MenACWY-TT co-administered with a combined diphtheria-tetanus-acellular pertussis vaccine versus their separate administration in adolescents and young adults: A phase III, randomized study.

BACKGROUND: This study evaluated the immunogenicity and safety of quadrivalent meningococcal conjugate vaccine using tetanus (T) toxoid as carrier protein (MenACWY-TT) co-administered with combined diphtheria-tetanus-acellular pertussis vaccine (Tdap) versus their separate administration in adolescents and young adults. METHODS: In this phase III, randomized, partially-blind study (NCT01767376), healthy 11-25-year-olds (N = 660) were randomized (1:1:1) to receive MenACWY-TT and Tdap at Month 0 (Co-ad group), MenACWY-TT at Month 0 and Tdap at Month 1 (ACWY_Tdap group) or Tdap at Month 0 and MenACWY-TT at Month 1 (Tdap_ACWY group). Immune responses to MenACWY-TT were measured by serum bactericidal assay using rabbit complement (rSBA). Anti-diphtheria (D), anti-tetanus (T), anti-pertussis toxin (PT), anti-filamentous hemagglutinin (FHA) and anti-pertactin (PRN) antibody concentrations were assessed using enzyme-linked immunosorbent assays. Non-inferiority of immunogenicity was assessed using pre-defined clinical criteria. Safety was also evaluated. RESULTS: Non-inferiority of immunogenicity of MenACWY-TT and Tdap when co-administered versus their separate administration was demonstrated in terms of rSBA geometric mean titers (GMTs) for 4 meningococcal serogroups and of the percentage of participants with antibody concentrations >1 IU/ml for D and T. Among the pertussis antigens, non-inferiority criteria for geometric mean concentrations (GMCs) were reached for PT, but not met for FHA and PRN. Across all groups, ≥93.2% of participants had vaccine responses to each meningococcal serogroup, ≥99.1% were seroprotected against T and D, and ≥85.5% had booster responses to each pertussis antigen. Robust increases in antibody GMTs/GMCs were observed for all antigens between pre-and post-vaccination. Both vaccines had clinically acceptable safety profiles. CONCLUSION: Immune responses to MenACWY-TT and to the T and D antigens from Tdap were not impacted by their co-administration. The lower antibody concentrations observed against the pertussis components may be of limited clinical relevance since robust anti-pertussis booster responses were observed. This study supports concurrent administration of the 2 vaccines in adolescents.

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.

MenACWY-TT is immunogenic when co-administered with Tdap and AS04-HPV16/18 in girls and young women: Results from a phase III randomized trial.

BACKGROUND: Co-administration of vaccines in adolescents may improve coverage. We assessed co-administration of quadrivalent meningococcal serogroups A, C, W and Y tetanus toxoid-conjugate vaccine (MenACWY-TT), human papillomavirus 16/18 AS04-adjuvanted vaccine (AS04-HPV16/18) and tetanus-diphtheria-acellular pertussis vaccine (Tdap) in girls and young women. METHODS: In this phase IIIb study (NCT01755689), 1300 healthy 9-25-year-old females were randomized (1:1:1:1:1) to receive: MenACWY-TT at month (M) 0 and AS04-HPV16/18 at M1, M2, M7; MenACWY-TT and AS04-HPV16/18 at M0 and AS04-HPV16/18 at M1, M6; AS04-HPV16/18 at M0, M1, M6; MenACWY-TT, Tdap and AS04-HPV16/18 at M0 and AS04-HPV16/18 at M1, M6; Tdap and AS04-HPV16/18 at M0 and AS04-HPV16/18 at M1, M6. Immunogenicity, safety and reactogenicity were evaluated. RESULTS: Immunogenicity of MenACWY-TT and AS04-HPV16/18 when co-administered was non-inferior to that of the 2 vaccines given separately. Co-administration of MenACWY-TT, AS04-HPV16/18 and Tdap was non-inferior to MenACWY-TT administered alone or to Tdap co-administered with AS04-HPV16/18 in terms of immunogenicity for all vaccine components, except pertussis antigens. Post-vaccination, ≥89.5% of participants reached antibody levels above the pre-specified threshold for all antigens. No safety concerns were identified. CONCLUSION: Our data support co-administration of MenACWY-TT with Tdap and AS04-HPV16/18 vaccines in adolescents.

Immunogenicity and safety of MenACWY-TT, a meningococcal conjugate vaccine, co-administered with routine childhood vaccine in healthy infants: A phase III, randomized study.

BACKGROUND: Invasive meningococcal disease has a high burden in young children, particularly during infancy. We investigated the immunogenicity and safety of a quadrivalent meningococcal conjugated vaccine (MenACWY-TT) co-administered with routine vaccines in healthy infants. METHODS: In this phase IIIb study (NCT01340898) conducted in 2 centers in Lebanon and Mexico, 750 infants were randomized (2:1:1) to receive MenACWY-TT according to 3 schedules: 3+1 (at ages 2, 4, 6 and 15-18 months; group ACWY3+1); 1+1 (at 6 and 15-18 months; group ACWY1+1) or single-dose at 15-18 months (group ACWY1). All infants received PHiD-CV and DTPa-IPV/Hib at ages 2, 4, 6, 15-18 months. Immune responses to MenACWY-TT were assessed by rSBA and hSBA at 7 months (groups ACWY3+1, ACWY1+1) and pre- and post-vaccination at 15-18 months of age (all groups). Immune responses to co-administered vaccines, reactogenicity and safety were also evaluated. RESULTS: Immunogenicity of MenACWY-TT at 1 month post-primary vaccination was demonstrated in group ACWY3+1: the lower limit of the 95% confidence interval for the percentage of infants with rSBA titers ≥8 was >80% for each serogroup. At 7 months of age, ≥93.9% of MenACWY-TT-primed infants had rSBA titers ≥8. Post-MenACWY-TT vaccination at age 15-18 months, ≥96.3% of participants in all groups had rSBA titers ≥8, regardless of the number of doses received previously. The percentage of infants with hSBA titers ≥4 were ≥87.2% and ≥89.7% at post-primary and booster/single-dose vaccination, respectively. Immune responses to PHiD-CV and DTPa-IPV/Hib did not seem impacted by co-administration with MenACWY-TT in infancy. The incidence of all adverse events was similar among groups. Serious adverse events were reported for 63/750 children in all groups; none were considered vaccine-related by investigators. CONCLUSION: Primary vaccination with 3 or 1 dose(s) of MenACWY-TT when co-administered with routine pediatric vaccines in infants is immunogenic and well-tolerated.

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.

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.