Toddler Dose Research Articles

Phase 3 Safety and Immunogenicity Study of a Three-dose Series of Twenty-valent Pneumococcal Conjugate Vaccine in Healthy Infants and Toddlers.

Global pediatric immunization programs with pneumococcal conjugate vaccines (PCVs) have reduced vaccine-type pneumococcal disease, but a substantial disease burden of non-PCV serotypes remains. This phase 3, randomized (1:1), double-blind study evaluated safety and immunogenicity of 20-valent PCV (PCV20) relative to 13-valent PCV (PCV13) in healthy infants. Participants received 2 infant doses and a toddler dose of PCV20 or PCV13, with diphtheria-tetanus-acellular pertussis combination vaccine at all doses and measles, mumps, rubella and varicella vaccines at the toddler dose. Primary pneumococcal immunogenicity objectives were to demonstrate noninferiority (NI) of PCV20 to PCV13 for immunoglobulin G geometric mean concentrations after infant and toddler doses and percentages of participants with predefined serotype-specific immunoglobulin G concentrations after infant doses. Safety endpoints included local reactions, systemic events and adverse events. Overall, 1204 participants were vaccinated (PCV20, n = 601; PCV13, n = 603). One month after the toddler dose, 19/20 serotypes met NI for immunoglobulin G geometric mean concentrations; serotype 6B narrowly missed NI [PCV20/PCV13 geometric mean ratio: 0.57 (2-sided 95% confidence interval: 0.48-0.67); NI criterion: lower 2-sided 95% confidence interval >0.5]. Sixteen/twenty serotypes met NI for ≥1 primary objective after 2 infant doses. PCV20 induced robust opsonophagocytic activity, and boosting responses were observed for all vaccine serotypes, including those missing statistical NI. The safety/tolerability profile of PCV20 was like that of PCV13. PCV20 3-dose series in infants was safe and elicited robust immune responses. Based on these results and PCV13 experience, PCV20 3-dose series is expected to be protective for all 20 vaccine serotypes. NCT04546425.

A phase 3 randomized study to evaluate safety and immunogenicity of 20-valent pneumococcal conjugate vaccine in healthy Japanese infants

ObjectivesSafety and immunogenicity evaluation of a 4-dose series with 20-valent pneumococcal conjugate vaccine (PCV20). MethodsThis phase 3, double-blind study randomized healthy Japanese infants to receive 4 doses (3 infant doses, 1 toddler dose) of PCV20 by subcutaneous (SC) or intramuscular (IM) injection or 13-valent PCV (PCV13) SC. A primary immunogenicity objective was to demonstrate noninferiority of PCV20 SC to PCV13 SC for percentages of participants meeting predefined serotype-specific immunoglobulin G concentrations 1 month after Dose 3. The 7 additional PCV20 serotypes were compared with the lowest vaccine serotype result in the PCV13 group. Safety and tolerability were assessed as the primary safety objective. ResultsOverall, 668 participants were randomized (PCV20 SC, n = 226; PCV13 SC, n = 224; PCV20 IM, n = 218). The primary noninferiority objective for PCV20 SC to PCV13 SC was met for 11/13 matched and 5/7 additional serotypes. Additional data showed PCV20 SC and IM elicited robust functional opsonophagocytic activity and boosting responses to all 20 vaccine serotypes. PCV20 had a similar safety/tolerability profile to PCV13, although local reactions were less frequent with PCV20 IM. ConclusionsA 4-dose series of PCV20 SC or IM elicited immune responses expected to be protective against all 20 serotypes in Japanese infants. NCT04530838

Safety and immunogenicity of 15-valent pneumococcal conjugate vaccine in Japanese healthy infants: A phase III study (V114-033)

BackgroundThis phase III study evaluated safety, tolerability, and immunogenicity of V114 (15-valent pneumococcal conjugate vaccine) in Japanese infants. V114 contains all 13 serotypes in PCV13 plus additional serotypes 22F and 33F. MethodsHealthy Japanese infants were randomized to receive three primary doses of V114 or PCV13 (dose 1 at 2–6 months of age; doses 2 and 3 ≥ 27 days after prior dose), plus a toddler dose at 12–15 months of age. Adverse events (AEs) were collected on Days 1–14 following each vaccination. Serotype-specific anti-pneumococcal immunoglobulin G (IgG) was measured 30 days post-dose 3, pre-dose 4, and 30 days post-dose 4. Primary objectives included non-inferiority of V114 to PCV13 for the 13 shared serotypes based on serotype-specific IgG response rates (IgG ≥ 0.35 μg/mL) and geometric mean concentration (GMC) ratios, and for serotypes 22F and 33F based on IgG response rates and compared with the lowest response of any serotype in the PCV13 group, at 30 days post-dose 3. ResultsOverall, 694 infants were randomized to V114 (n = 347) or PCV13 (n = 347). Proportions of participants with solicited and serious AEs were comparable between vaccination groups. V114 met non-inferiority criteria for all 13shared serotypes, based on difference in proportion of responders (lower bound of two-sided 95 % confidence interval [CI] > −10.0) and IgG GMC ratios (V114/PCV13, lower bound of two-sided 95 % CI > 0.5) at 30 days post-dose 3. The non-inferiority criterion based on IgG response rates was met for serotype 22F, but narrowly missed for serotype 33F (90.9 %, lower bound of two-sided 95 % CI −10.6). ConclusionIn Japanese infants, a four-dose series of V114 was generally well tolerated. Compared with PCV13, V114 provided non-inferior immune responses to the 13 shared serotypes and higher immune responses to serotype 22F and 33F post-primary series.Trial registration:ClinicalTrials.gov: NCT04384107; EudraCT 2019-003644-68.

A Phase III, multicenter, randomized, double-blind, active comparator-controlled study to evaluate the safety, tolerability, and immunogenicity of V114 compared with PCV13 in healthy infants (PNEU-PED-EU-1)

BackgroundV114 (15-valent pneumococcal conjugate vaccine [PCV]) contains all serotypes in 13-valent PCV (PCV13) and additional serotypes 22F and 33F. This study evaluated safety and immunogenicity of V114 compared with PCV13 in healthy infants, and concomitant administration with DTPa–HBV–IPV/Hib and rotavirus RV1 vaccines. MethodsV114 and PCV13 were administered in a 2+1 schedule at 2, 4, and 11–15 months of age. Adverse events (AEs) were collected on Days 1–14 following each vaccination. Serotype-specific anti-pneumococcal immunoglobulin G (IgG) was measured 30 days post-primary series (PPS), immediately prior to a toddler dose, and 30 days post-toddler dose (PTD). Primary objectives included non-inferiority of V114 to PCV13 for 13 shared serotypes and superiority of V114 to PCV13 for the two additional serotypes. Results1184 healthy infants 42–90 days of age were randomized 1:1 to V114 (n = 591) or PCV13 (n = 593). Proportions of participants with solicited AEs and serious AEs were comparable between vaccination groups. V114 met pre-specified non-inferiority criteria for all 13 shared serotypes, based on the difference in proportions of participants with serotype-specific IgG concentrations ≥0.35 μg/mL (response rate; lower bound of two-sided 95% confidence interval [CI] >−10.0) and IgG geometric mean concentration (GMC) ratios (lower bound of two-sided 95% CI >0.5), and pre-specified superiority criteria for serotypes 22F and 33F (lower bound of two-sided 95% CI >10.0 for response rates and >2.0 for GMC ratios). Antibody responses to DTPa–HBV–IPV/Hib and RV1 vaccines met pre-specified non-inferiority criteria, based on antigen-specific response rates to DTPa–HBV–IPV/Hib and anti-rotavirus IgA geometric mean titers. ConclusionsAfter a 2+1 schedule, V114 elicited non-inferior immune responses to 13 shared serotypes and superior responses to the two additional serotypes compared with PCV13, with comparable safety profile. These results support the routine use of V114 in infants.Trial registration: ClinicalTrials.gov: NCT04031846; EudraCT: 2018-003787-31

Safety, tolerability, and immunogenicity of V114 pneumococcal vaccine compared with PCV13 in a 2+1 regimen in healthy infants: A phase III study (PNEU-PED-EU-2)

BackgroundThis phase III study evaluated safety, tolerability, and immunogenicity of V114 (15-valent pneumococcal conjugate vaccine) in healthy infants. V114 contains all 13 serotypes in PCV13 and additional serotypes 22F and 33F. MethodsHealthy infants were randomized to two primary doses and one toddler dose (2+1 regimen) of V114 or PCV13 at 3, 5, and 12 months of age; diphtheria, tetanus, pertussis (DTaP), inactivated poliovirus (IPV), Haemophilus influenzae type b (Hib), hepatitis B (HepB) vaccine was administered concomitantly. Adverse events (AEs) were collected on Days 1–14 following each vaccination. Serotype-specific anti-pneumococcal immunoglobulin G (IgG) was measured 30 days post-primary series, immediately prior to toddler dose, and 30 days post-toddler dose. Primary objectives included non-inferiority of V114 to PCV13 for 13 shared serotypes and superiority of V114 to PCV13 for serotypes 22F and 33F. Results1191 healthy infants were randomized to V114 (n = 595) or PCV13 (n = 596). Proportions of participants with solicited AEs and serious AEs were comparable between groups. V114 met non-inferiority criteria for 13 shared serotypes, based on difference in proportions with serotype-specific IgG ≥0.35 μg/mL (lower bound of two-sided 95% confidence interval [CI] >−10.0) and IgG geometric mean concentration (GMC) ratios (lower bound of two-sided 95% CI >0.5) at 30 days post-toddler dose. V114 met superiority criteria for serotypes 22F and 33F, based on response rates (lower bound of two-sided 95% CI >10.0) and IgG GMC ratios (lower bound of two-sided 95% CI >2.0) at 30 days post-toddler dose.Antibody responses to DTaP-IPV-Hib-HepB met non-inferiority criteria, based on antigen-specific response rates. ConclusionA two-dose primary series plus toddler dose of V114 was well-tolerated in healthy infants. Compared with PCV13, V114 provided non-inferior immune responses to 13 shared serotypes and superior immune responses to additional serotypes 22F and 33F.

1184. A Phase 3, Multicenter, Randomized, Double-blind Study to Evaluate the Interchangeability of V114 and Prevnar 13™ with Respect to Safety, Tolerability, and Immunogenicity in Healthy Infants (PNEU-DIRECTION)

BackgroundPneumococcal diseases (PD) caused by Streptococcus pneumoniae are a major health concern globally. In children, currently licensed pneumococcal conjugate vaccines (PCVs) provide protection against PD from vaccine serotypes, but other non-vaccine serotypes have emerged and contribute to most residual disease. V114 is a 15-valent investigational PCV containing serotypes 22F and 33F in addition to the 13 serotypes shared by Prevnar 13TM (PCV13). This phase 3 study evaluated safety and immunogenicity of mixed PCV13/V114 regimens when changing from PCV13 to V114 at doses 2, 3, or 4.MethodsIn this double-blind trial, 900 infants were randomized in equal ratios to five treatment groups using a 3 + 1 immunization schedule (3-dose infant primary series followed by one toddler dose). Groups 2, 3, and 4 started with PCV13 and switched to V114 at doses 4, 3, and 2, respectively. Groups 1 and 5 received four doses of PCV13 and V114, respectively. Immunoglobulin G (IgG) responses to the 15 pneumococcal serotypes in V114 were measured at 30 days post-dose 3, prior to dose 4, and 30 days post-dose 4 (PD4). Primary immunogenicity analysis was based on 13 shared serotype responses at PD4. Safety was evaluated as the proportion of participants with adverse events (AEs). ResultsAt 30 days PD4, IgG geometric mean concentrations (GMCs) for the 13 shared serotypes were generally comparable between V114/PCV13 mixed regimens (Groups 2-4) and participants that received the 4-dose PCV13 regimen (Group 1). Additionally, IgG GMCs for the 13 shared serotypes were generally comparable for participants that received the 4-dose V114 regimen (Group 5) and participants that received the 4-dose PCV13 regimen (Group 1). Infants given at least one dose of V114 mounted immune responses to two unique serotypes in V114 (22F and 33F). Frequency of injection-site and systemic AEs among study participants were generally comparable across all study groups. ConclusionV114 was well tolerated with a generally comparable safety profile to PCV13. For the 13 shared serotypes, both mixed-dose and 4-dose regimens of V114 induced generally comparable antibody responses to a PCV13 4-dose regimen. Study results support interchangeability of V114 with PCV13 in infants.Disclosures Adroniki Bili, MD, Merck & Co., Inc. (Employee, Shareholder) Ron Dagan, MD, Medimmune/AstraZeneca (Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support)MSD (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker’s Bureau)Pfizer (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker’s Bureau) Marissa B. Wilck, MD, Merck & Co., Inc. (Employee, Shareholder) Waldimir Vallejos, MD, Merck & Co., Inc. (Employee, Shareholder) Christine Nunn, MS, Merck & Co., Inc. (Employee, Shareholder) Richard McFetridge, B.S., Merck & Co., Inc (Employee) Rong Fu, PhD, MSD China (Employee, Shareholder) Robert Lupinacci, M.S, Merck & Co., Inc (Employee, Shareholder) Luwy Musey, MD, Merck & Co., Inc. (Employee) Kara Bickham, MD, Merck Sharp and Dohme (Employee, Shareholder)

Safety and immunogenicity of a multidose vial formulation of 13-valent pneumococcal conjugate vaccine administered with routine pediatric vaccines in healthy infants in India: A phase 4, randomized, open-label study

PurposeThis phase 4, randomized, open-label, multicenter study in healthy Indian infants and toddlers evaluated the safety, tolerability, and immunogenicity of the 13-valent pneumococcal conjugate vaccine (PCV13) formulated in a multidose vial (MDV) or single prefilled syringe (PFS). MethodsHealthy Indian infants (6 weeks of age) were randomized 1:1 to receive either PCV13-MDV or PCV13-PFS concomitant with routine pediatric vaccines. Subjects received a single dose of either PCV13-MDV or PCV13-PFS as a 4-dose schedule (infant series: 1 dose at 6, 10, and 14 weeks of age; toddler dose: 12 months of age). Safety was assessed, including local reactions, systemic events, and adverse events (AEs). Immunogenicity 1 month after both the infant series and toddler dose was measured by concentrations of serotype-specific immunoglobulin G (IgG) antibodies and opsonophagocytic activity titers. ResultsRates and severities of local reactions and systemic events up to 7 days after each dose of either PCV13-MDV or PCV13-PFS were generally similar, with the majority being of mild or moderate severity. PCV13-MDV had a safety profile comparable with PCV13-PFS; both groups experienced a similar frequency of AEs. PCV13-MDV elicited immune responses comparable with those induced by PCV13-PFS. Clear boosting of immune responses after the PCV13-MDV toddler dose was observed; ≥96% of subjects showed serotype-specific IgG concentrations at or above the defined thresholds 1 month after the PCV13-MDV toddler dose. ConclusionsPCV13-MDV was safe, well tolerated, and immunogenic in healthy Indian infants and toddlers when coadministered with routine pediatric vaccinations. Safety and immunogenicity of PCV13-MDV was comparable with PCV13-PFS. Clinical Trial RegistrationClinicaltrials.gov: NCT03548337.

Protective immune responses against Haemophilus influenzae type b elicited by a fully-liquid DTaP-IPV-Hib-HepB vaccine (VAXELIS™)

BackgroundDTaP-IPV-Hib-HepB is a fully-liquid, hexavalent combination vaccine (Vaxelis™) approved for vaccination against diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B, and invasive disease due to Haemophilus influenzae type b (Hib). Hib capsular polysaccharide, polyribosylribitol phosphate (PRP), is conjugated to Neisseria meningitidis outer membrane protein complex (OMPC). Safety and immunogenicity of DTaP-IPV-Hib-HepB were evaluated in 6 Phase III clinical studies including > 5,200 children. Studies included vaccination schedules in the United States (2, 4, 6 months of age) and Europe (2, 3, 4, 12 months of age and 2,4,11–12 months of age). MethodsData pertaining to anti-PRP responses of DTaP-IPV-Hib-Hep B compared to control vaccines from 5 Phase III studies are summarized. ResultsPost-infant series, the percentage of participants that achieved protective antibody thresholds for PRP (anti-PRP titer ≥ 0.15 μg/mL and ≥ 1.0 μg/mL, respectively) were higher in DTaP-IPV-Hib-HepB recipients compared to recipients who received control vaccines. A high level of protective responses (96.6% at ≥ 0.15 μg/mL [95% CI:94.8, 97.9%]; 72.9% at ≥ 1.0 μg/mL [95% CI:69.2,76.4%]) were seen post-dose 2 of the 2 + 1 vaccination schedule and met superiority criteria over comparator, p-value < 0.001.In the same schedule, prior to administration of the toddler dose (in the second year of life), anti-PRP titers were higher in DTaP-IPV-Hib-HepB recipients (91.4% at ≥ 0.15 μg/mL; 46.8% at ≥ 1.0 μg/mL) as compared to recipients who received control vaccines (63.4% at ≥ 0.15 μg/mL; 17.1% at ≥ 1.0 μg/mL).One-month post-toddler dose, high levels of anti-PRP titers were achieved in both DTaP-IPV-Hib-HepB recipients (99.8% at ≥ 0.15 μg/mL; 96.6% at ≥ 1.0 μg/mL) and recipients who received control vaccines (99.5% at ≥ 0.15 μg/mL; 94.9% at ≥ 1.0 μg/mL). ConclusionsThese results support that DTaP-IPV-Hib-HepB induces a robust and sustained early Hib response. During the high-risk period for Hib disease after the infant vaccine and prior to the toddler dose; >90% of recipients maintained superior protective anti-PRP levels compared to control.

Carrier-Induced Hyporesponsiveness to Pneumococcal Conjugate Vaccines: Unraveling the Influence of Serotypes, Timing, and Previous Vaccine Dose.

BackgroundPneumococcal conjugate vaccines (PCVs) elicit lower immune response against serotypes carried before or at the time of vaccination (hyporesponsiveness) in infants. The limited studies conducted to date did not permit comprehensive insights regarding this phenomenon. This study, the largest ever conducted with both carriage and serologic endpoints, attempted to add insight on serotype-specific hyporesponsiveness in relation to the number of PCV doses administered before carriage acquisition.MethodsIn a double-blind randomized clinical trial (n = 1754 infants), 7-valent or 13-valent PCV was administered at ages 2, 4, 6, and 12 months. New acquisition was defined based on nasopharyngeal swabs at ages 2, 4, 6, 7, and 12 months. Serotype-specific immunoglobulin G levels were obtained 1 month after the infant series and 1 month after the toddler dose.ResultsA lower immune response after the infant series and the toddler dose was consistently observed for carriers of serotypes 6A, 6B, 18C, and 19F at predefined time points, with a similar trend observed in carriers of serotype 23F. In contrast, carriage of serotypes 9V, 14, and 19A did not generally affect immune responses. For some but not all serotypes, hyporesponsiveness was decreased with an increased number of vaccine doses received before acquisition. A complex interrelationship between carriage and immune response was observed between cross-reacting serotypes.ConclusionsCarrier-induced hyporesponsiveness to PCVs is common, differs among serotypes, and depends on timing of carriage acquisition and prior number of administered PCV doses.Clinical Trials RegistrationNCT00508742.

2702. Infants Vaccinated with a Fully-Liquid DTaP-IPV-Hib-HepB Vaccine Are Protected During the High-Risk Period for Haemophilus Influenzae Type B Disease

BackgroundDTaP-IPV-Hib-HepB is a fully-liquid, combination vaccine (Vaxelis™) approved for vaccination in infants and toddlers against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and Haemophilus influenzae type b (Hib). Safety and immunogenicity were evaluated in 4 Phase III, randomized, active-comparator controlled clinical trials (Protocols 005 and 006 in the US [Control: PENTACEL™] and Protocols 007 and 008 in the EU [Control: INFANRIX™ hexa]). The vaccine, studied in >6,800 children, has an acceptable safety profile generally similar to that of control vaccines (Xu, PIDJ, 2019; 38:439–43). DTaP-IPV-Hib-HepB includes polyribosylribitol phosphate (PRP) conjugated to outer membrane protein complex of Neisseria meningitidis (OMPC) that elicits a rapid response to Hib.MethodsData from these studies provide a summary of the anti-PRP responses of DTaP-IPV-Hib-HepB compared with Control.ResultsAfter the infant series, the percentage of participants who achieved short-term and long-term protective antibody thresholds for PRP (i.e., anti-PRP titer ≥0.15 μg/mL and ≥1.0 μg/mL, respectively) were higher in DTaP-IPV-Hib-HepB recipients compared with Control. A high level of protective responses (96.6% ≥0.15 μg/mL and 72.9% ≥1.0 μg/mL) were seen after the second dose in the 008 study of the 2 infant series followed by toddler dose hexavalent vaccination schedule (2 + 1). Across all 4 studies, anti-PRP titers were higher in DTaP-IPV-Hib-HepB recipients (91.4% ≥0.15 μg/mL and 46.8% ≥1.0 μg/mL) when compared with Control (63.4% ≥0.15 μg/mL and 17.1% ≥1.0 μg/mL) at the pre-Toddler dose (i.e., prior to the administration of the Toddler dose in the second year of life, between 11–15 months of age). One month after the toddler dose, high levels of anti-PRP titers were achieved in both DTaP-IPV-Hib-HepB recipients (99.8% ≥0.15 μg/mL and 96.6% ≥1.0 μg/mL) and Control (99.5% ≥0.15 μg/mL and 94.9% ≥1.0 μg/mL).ConclusionThese results support that DTaP-IPV-Hib-HepB induces an early Hib response in the first 6 months of life that is sustained until the booster dose is administered in the second year of life. Thus, a high percentage of infants vaccinated with DTaP-IPV-Hib-HepB are protected during the high-risk period for Hib disease. Disclosures All authors: No reported disclosures.

A randomized study of fever prophylaxis and the immunogenicity of routine pediatric vaccinations

ObjectiveProphylactic antipyretic use during pediatric vaccination is common. This study assessed whether paracetamol or ibuprofen prophylaxis interfere with immune responses to the 13-valent pneumococcal conjugate vaccine (PCV13) given concomitantly with the combined DTaP/HBV/IPV/Hib vaccine. MethodsSubjects received prophylactic paracetamol or ibuprofen at 0, 6–8, and 12–16 h after vaccination, or 6–8 and 12–16 h after vaccination at 2, 3, 4, and 12months of age. At 5 and 13months, immune responses were evaluated versus responses in controls who received no prophylaxis. ResultsAfter the infant series, paracetamol recipients had lower levels of circulating serotype-specific pneumococcal anticapsular immunoglobulin G than controls, reaching significance (P<0.0125) for 5 serotypes (serotypes 3, 4, 5, 6B, and 23F) when paracetamol was started at vaccination. Opsonophagocytic activity assay (OPA) results were similar between groups. Ibuprofen did not affect pneumococcal responses, but significantly (P<0.0125) reduced antibody responses to pertussis filamentous hemagglutinin and tetanus antigens after the infant series when started at vaccination. No differences were observed for any group after the toddler dose. ConclusionsProphylactic antipyretics affect immune responses to vaccines; these effects vary depending on the vaccine, antipyretic agent, and time of administration. In infants, paracetamol may interfere with immune responses to pneumococcal antigens, and ibuprofen may reduce responses to pertussis and tetanus antigens. The use of antipyretics for fever prophylaxis during infant vaccination merits careful consideration.ClinicalTrials.gov identifier: NCT01392378https://clinicaltrials.gov/ct2/show/NCT01392378?term=NCT01392378&rank=1

Circulating Antibody 1 and 2 Years After Vaccination With the 13-Valent Pneumococcal Conjugate Vaccine in Preterm Compared With Term Infants.

Premature infants have lower short-term immune responses to vaccination than term infants, but patterns of antibody persistence in preterm infants over longer periods are not well established. This study assessed the persistence of antibody response to the 13-valent pneumococcal conjugate vaccine (PCV13) in formerly preterm versus term infants. In total, 100 preterm and 100 term infants received PCV13 with routine vaccines at ages 2, 3, 4 and 12 months. Serotype-specific anticapsular immunoglobulin G (IgG)-binding antibodies and opsonophagocytic activity were determined 1 and 2 years after the last PCV13 dose. At 1 and 2 years after the last vaccination (toddler dose), IgG geometric mean concentrations (GMCs) for all serotypes had declined from levels measured 1 month after the toddler dose but remained above pretoddler dose levels. IgG GMCs were significantly lower in preterm than term subjects for a majority of serotypes at both follow-up time points. IgG GMCs increased in both groups for some serotypes from the 1-year to 2-year follow-up, whereas others declined. Opsonophagocytic activity results supported the IgG results. The routine (3 + 1) vaccination schedule is likely to offer long-term protection against invasive pneumococcal disease in preterm infants and should be initiated regardless of gestational age or weight at birth, without delay of the toddler dose.

Lot-to-lot Consistency, Safety, Tolerability and Immunogenicity of an Investigational Hexavalent Vaccine in US Infants

This multicenter phase III study (NCT01340937) evaluated the consistency of immune responses to 3 separate lots of diphtheria-tetanus toxoids-acellular pertussis 5, inactivated poliovirus vaccine, Haemophilus influenzae type b, and hepatitis B (DTaP5-IPV-Hib-HepB), an investigational hexavalent vaccine (HV). Healthy infants were randomized (2:2:2:1) to receive HV or Pentacel (Control). Groups 1, 2 and 3 received HV at 2, 4 and 6 months, and Control at 15 months. Group 4 received Control at 2, 4, 6 and 15 months, plus Recombivax HB (HepB) at 2 and 6 months. Concomitant Prevnar 13 was given to all groups at 2, 4, 6 and 15 months; pentavalent rotavirus vaccine (RV5) was given to all groups at 2, 4 and 6 months. Blood specimens (3-5 mL) were collected immediately before administration of dose 1, postdose 3, immediately before toddler dose, and after toddler dose. Adverse events were recorded after each vaccination. The 3 manufacturing lots of HV induced consistent antibody responses to all antigens. Immunogenicity of HV was noninferior to Control for all antibodies, except for pertussis filamentous hemagglutinin geometric mean concentration postdose 3, and pertussis pertactin (PRN) geometric mean concentration after toddler dose. Postdose 3 immunogenicity of concomitantly administered Prevnar 13 was generally similar (except for serotype 6B) when given with HV or Control. Adverse events of HV were similar to Control, except for a higher rate of fever ≥38.0°C [49.2% vs. 35.4%, estimated difference 13.7% (8.4, 18.8)]. HV demonstrated lot-to-lot manufacturing consistency; safety and immunogenicity were comparable with the licensed vaccines. HV provides a new combination vaccine option within the US 2-month, 4-month and 6-month vaccine series.

Do Dose Numbers Matter?: Evaluation of Differing Infant and Toddler Meningococcal C Conjugate Vaccine Programs in Canadian Children.

The diversity of Canadian infant meningococcal C conjugate (MenC) vaccine programs is unique among countries providing MenC vaccines and offers a valuable opportunity to determine the optimal vaccine program. This longitudinal study assessed differences in seroprotection by 3 different vaccine schedules in children two years after receiving either 1 toddler MenC vaccine dose (1 dose), 1 infant and 1 toddler dose (2 doses), or 2 infant and 1 toddler MenC vaccine dose (3 doses). Three similar cohorts of healthy infants from 1, 2 and 3 dose program areas were enrolled before to their 12 month toddler dose and vaccinated with MenC-tetanus toxoid (MenC-TT) conjugate vaccine. Sera obtained 2 years later were assayed for serogroup C bactericidal activity using standardized procedures with rabbit as the exogenous complement source. Serum bactericidal activity titers ≥1:8 were considered protective. Results were available for 384 children. Rates of seroprotection at 36 months of age were significantly different between the 1 and 3 dose programs, but confidence intervals overlapped between the 1 and 2 dose programs and between the 2 and 3 dose programs: 1 dose 92% (95% confidence interval: 86%-96%) versus 99% (95%-100%) with 2 doses and 100% (97%-100%) with 3 doses. Geometric mean titers were significantly different at 12.1 (10.8-13.5), 32.4 (28.9-36.2) and 50.6 (45.7-55.9) in the 1, 2 and 3 dose programs, respectively. At 36 months of age, evidence of seroprotection remained for greater than 90% of participants. Our results indicate that 1 toddler dose or 1 infant plus 1 toddler dose with MenC-TT vaccine provides seroprotection against MenC disease in early childhood.

Long-term antibody persistence study (3 years after last dose) of the 7-valent pneumococcal conjugate vaccine in young children in China

BackgroundIn a previous study, Chinese infants were vaccinated with 7-valent pneumococcal conjugate vaccine (PCV7) ⩾7days before routine diphtheria, tetanus, and acellular pertussis vaccine (DTaP); PCV7 administered concomitantly with DTaP (PCV7+DTaP); or DTaP alone. This study examined antibody persistence at a single time point 3years after the last vaccination. MethodsChildren who participated in the prior PCV7 study were eligible to participate. A single blood sample was drawn at enrollment. Immunoglobulin G (IgG) geometric mean concentrations (GMCs) specific to the PCV7 serotypes and percentages of subjects with IgG ⩾0.35μg/mL were compared for subjects receiving PCV7 versus PCV7+DTaP (concomitant) and for PCV7 or PCV7+DTaP (concomitant) versus DTaP alone. IgG concentrations at 3years after the last vaccination were also compared with those after the infant series and toddler dose. ResultsThree years after the last vaccination with PCV7 or PCV7+DTaP (concomitant), IgG GMCs for most PCV7 serotypes were lower than after the infant series or toddler dose but remained above prevaccination concentrations. IgG GMC were similar between the PCV7 and PCV7+DTaP (concomitant) groups for 5 out of 7 serotypes but serotypes 4 and 19F were significantly lower in the PCV7+DTaP (concomitant) recipients. Three years after the last vaccination, IgG GMCs were significantly higher for 6 of 7 PCV7 serotypes among those receiving PCV7 or PCV7+DTaP (concomitant) compared with recipients of DTaP alone. Among subjects receiving DTaP alone, serotype-specific antibody concentrations were significantly higher for all serotypes 3years after the last vaccination compared with after the infant series. ConclusionThree years after PCV7 vaccination, serotype-specific antibodies were lower than after the primary infant series but higher than prevaccination levels and higher among subjects who received PCV7 compared with those who did not. The immune response was comparable in children who received PCV7 with and without concomitant DTaP.Clinical Trial Registration: NCT01298544

Immunogenicity, Safety, and Tolerability of a Hexavalent Vaccine in Infants

DTaP5-IPV-Hib-HepB is a fully liquid investigational hexavalent vaccine directed against 6 diseases. This multicenter, open-label, comparator-controlled, phase III study randomly assigned healthy infants 2-to-1 as follows: group 1 received DTaP5-IPV-Hib-HepB, PCV13, and RV5 at 2, 4, and 6 months of age followed by DTaP5, Hib-OMP, and PCV13 at 15 months of age; group 2 received DTaP5-IPV/Hib, PCV13, and RV5 at 2, 4, and 6 months of age, with HepB at 2 and 6 months of age, followed by DTaP5, Hib-TT, and PCV13 at 15 months of age. Overall, 981 participants were vaccinated in group 1 and 484 in group 2. Immune responses in group 1 to all antigens contained in DTaP5-IPV-Hib-HepB 1 month after dose 3 and for concomitant rotavirus vaccine were noninferior to those in group 2, with the exception of antipertussis filamentous hemagglutinin (FHA) geometric mean concentrations (GMCs). Vaccine response rates for FHA were noninferior to control. After the toddler dose, group 1 immune responses were noninferior to group 2 for all pertussis antigens. Solicited adverse event rates after any dose were similar in both groups, with the exceptions of increased injection-site erythema, increased fever, and decreased appetite in group 1. Fever was not associated with hospitalization or seizures. The safety and immunogenicity of DTaP5-IPV-Hib-HepB are comparable with the analogous licensed component vaccines. Decreased FHA GMCs and increased injection-site reactions and fever are unlikely to be clinically significant. DTaP5-IPV-Hib-HepB provides a new combination vaccine option aligned with the recommended US infant immunization schedule.

Immunogenicity and safety of a quadrivalent meningococcal polysaccharide CRM conjugate vaccine in infants and toddlers

This phase III study assessed the safety and immunogenicity of MenACWY-CRM, a quadrivalent meningococcal conjugate vaccine, administered with routine vaccines starting at 2 months of age. Healthy infants received MenACWY-CRM in a two- or three-dose primary infant series plus a single toddler dose. In addition, a two-dose toddler catch-up series was evaluated. Immune responses to MenACWY-CRM were assessed for serum bactericidal activity with human complement (hSBA). Reactogenicity and safety results were collected systematically. After a full infant/toddler series or two-dose toddler catch-up series, MenACWY-CRM elicited immune responses against the four serogroups in 94-100% of subjects. Noninferiority of the two- versus three-dose MenACWY-CRM infant dosing regimen was established for geometric mean titers for all serogroups. Following the three-dose infant primary series, 89-98% of subjects achieved an hSBA ≥ 8 across all serogroups. Immune responses to concomitant routine vaccines given with MenACWY-CRM were noninferior to responses to routine vaccines alone, except for pertactin after the two-dose infant series. Noninferiority criteria were met for all concomitant antigens after the three-dose infant series. MenACWY-CRM vaccination regimens in infants and toddlers were immunogenic and well tolerated. No clinically meaningful effects of concomitant administration with routine infant and toddler vaccines were observed.

Safety and Immunogenicity of a Toddler Dose Following an Infant Series of a Hexavalent Diphtheria, Tetanus, Acellular Pertussis, Inactivated Poliovirus, Haemophilus influenzae Type b, Hepatitis B Vaccine Administered Concurrently or at Separate Visits With a Heptavalent Pneumococcal Conjugate Vaccine

Combination diphtheria-tetanus-5 component acellular pertussis-inactivated poliovirus-Haemophilus influenzae b conjugate-hepatitis B vaccine (DTaP5-IPV-Hib-HepB) administered either concurrently with 7-valent pneumococcal conjugate vaccine (PCV7) or 1 month apart was generally safe and immunogenic at 2, 4 and 6 months of age. This study examined the effects of a booster dose at age 15 months. Participants were randomized to DTaP5-IPV-Hib-HepB plus PCV7, DTaP5-IPV-Hib-HepB with PCV7 administered 1 month later or a pentavalent DTaP5-IPV/Hib plus HepB plus PCV7 at 15 months of age in a randomized, open-label, phase IIb clinical trial. Immunogenicity endpoints were rates of seroresponse to pertussis toxoid, filamentous hemagglutinin, pertactin and fimbriae types 2 and 3; rates of seroprotection against (Hib) polyribosylribitol phosphate capsular polysaccharide, hepatitis B surface antigen, diphtheria toxoid, tetanus toxoid and poliovirus types 1, 2 and 3; and geometric mean titers to all vaccine antigens. Safety endpoints included solicited injection-site reactions and systemic and serious adverse events. Seroresponse/seroprotection rates for all antigens exceeded prespecified criteria in both groups that received the hexavalent DTaP5-IPV-Hib-HepB; in the group that received the currently licensed pentavalent vaccine, seroresponse/seroprotection rates exceeded the criteria for all antigens except filamentous hemagglutinin. Seroresponse rates were ≥88.9% for pertussis antigens and seroprotection rates against polyribosylribitol phosphate capsular polysaccharide, hepatitis B surface antigen, diphtheria toxoid, tetanus toxoid and poliovirus antigens were ≥95.1% in recipients of DTaP5-IPV-Hib-HepB. DTaP5-IPV-Hib-HepB administered concomitantly with PCV7 or 1 month apart at 15 months of age following the infant series was well-tolerated and elicited antibody responses to all vaccine antigens, with no significant interference from concomitant PCV7 administration (clinicaltrials.gov registration number NCT00362427).

Decreased immune response to pneumococcal conjugate vaccine after 23-valent pneumococcal polysaccharide vaccine in children

BackgroundPneumococcal polysaccharide vaccine (PPV) is used in children at high risk of IPD. PPV is generally not considered to induce immunologic memory, whereas pneumococcal conjugate vaccines (PCVs) elicit protective antibody responses in infants and induce immunologic memory. Little is known about the characteristics of immune responses to PCV in children who previously received PCV and PPV in series. ObjectiveTo characterize immune responses to 13-valent pneumococcal CRM197 conjugate vaccine (PCV13; serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) in children vaccinated in infancy with 9-valent pneumococcal–meningococcal C-CRM197 conjugate combination vaccine (PCV9-MnCC), followed by a toddler dose of PCV9-MnCC or 23-valent pneumococcal polysaccharide vaccine (PPV23). MethodsChildren (n=89) who received PCV9-MnCC in infancy and PPV23 or PCV9-MnCC at age 12 months in a previous (2002–2003) study were vaccinated at age 7.5 years with PCV13; groups PPV23/PCV13 (n=50) and PCV9/PCV13 (n=39). Immunoglobulin (Ig)G antibodies, avidity, and opsonophagocytic activity (OPA) were measured before and at 1 and 4 weeks postvaccination. ResultsOne week postvaccination, IgG levels increased significantly for all serotypes in both groups, and >97% of vaccinees achieved IgG ≥0.35μg/ml 4 weeks after PCV13 vaccination. The PCV9/PCV13 group had higher IgG responses compared with the PPV23/PCV13 group. The upper limits of the 95% confidence intervals of the PPV23/PCV13:PCV9/PCV13 IgG geometric mean concentration ratios were <1.0 for serotypes 1, 4, 5, 9V, 18C, and 23F at 1 week. OPA and avidity results supported these findings. ConclusionsPPV23 vaccination of toddlers may compromise subsequent responses to pneumococcal conjugate vaccines. The clinical relevance of this finding is unclear.

Safety and Immunogenicity of a Toddler Dose Following an Infant Series of a Hexavalent Diphtheria, Tetanus, Acellular Pertussis, Inactivated Poliovirus, Haemophilus influenzae type b, Hepatitis B Vaccine Administered Concurrently or at Separate Visits With a Heptavalent Pneumococcal Conjugate Vaccine

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