The immunogenicity and safety of a tetravalent measles-mumps-rubella-varicella vaccine when co-administered with conjugated meningococcal C vaccine to healthy children: A phase IIIb,randomized, multi-center study in Italy

IntroductionMultiple vaccination visits and administrations can be stressful for infants, parents and healthcare providers. Multivalent combination vaccines can deliver the required number of antigens in fewer injections and clinic visits, while vaccine co-administration can also reduce the number of visits. This non-inferiority study was undertaken to evaluate the feasibility of co-administering a combined measles-mumps-rubella-varicella (MMRV) vaccine with conjugated meningococcal C (MenC) vaccine in a large cohort of healthy Italian toddlers.MethodsHealthy subjects aged 13–15 months were randomized (2:1:1) to receive single doses of either: co-administered MMRV + MenC at the same visit (MMRV + MenC group); or MMRV followed 42 days later by MenC (MMRV group); or MenC followed 42 days later by MMRV (MenC group). Blood samples were collected before and 43 days after vaccination. Antibody titers against MMRV were measured using ELISA. Functional-anti-meningococcal-serogroup activity (rSBAMenC) was assessed using a serum bactericidal test. Solicited local and general reactions were recorded for up to 4 and 42 days post-vaccination, respectively. Non-inferiority of MMRV + MenC to MMRV (post-dose-1 seroconversion rates) and MMRV + MenC to MenC (post-dose-1 seroprotection rates) was achieved if the lower limit (LL) of the 95% confidence interval (CI) for the group difference was ⩾−10% for each antigen.Results716 subjects were enrolled in the study. At 42 days post-vaccination, the MMRV seroconversion rates were 99.3% (measles), 94.5% (mumps), 100% (rubella) and 99.7% (varicella) in the MMRV + MenC group, and 99.4%, 93.2%, 100% and 100%, respectively, in the MMRV group. The seroprotection rates against rSBA-MenC were 98.3% in the MMRV + MenC group and 99.3% in the MenC group. Non-inferiority was reached for all the vaccine antigens. The safety profiles were as expected for these vaccines.ConclusionThe immune responses elicited by co-administered MMRV + MenC were non-inferior to those elicited by MMRV or MenC alone and support vaccination of children with both vaccines at a single visit.Clinical Trials registration: NCT01506193.     

Concomitant administration of a fully liquid ready-to-use DTaP-IPV-HB-PRP-T hexavalent vaccine with a meningococcal ACWY conjugate vaccine in toddlers

Invasive meningococcal disease caused by Neisseria meningitidis is a life-threatening disease. Several countries now include meningococcal serogroup C (MenC) conjugate and, more recently, a meningococcal serogroup ACWY conjugate (MenACWY) vaccination in their national immunization schedules. DTaP-IPV-HB-PRP-T is a hexavalent vaccine that provides protection against six diseases. The phase III, open-label, randomised, multicentre study enrolled healthy toddlers who received the DTaP-IPV-HB-PRP-T vaccine (at 2, 3 and 4 months) with or without a MenC vaccine (at 2 and 4 months) in the primary series study. At 12 months of age, 312 toddlers were randomised to receive DTaP-IPV-HB-PRP-T co-administered with MenACWY-TT vaccine (Group A; n = 104); DTaP-IPV-HB-PRP-T vaccine alone (Group B; n = 105); or MenACWY-TT vaccine alone (Group C; n = 103). At 12 months of age, there were no notable differences in terms of antibody persistence for any DTaP-IPV-HB-PRP-T vaccine antigen, whether MenC-TT conjugate vaccine was co-administered or not during the primary series. Following booster vaccination, immune responses to DTaP-IPV-HB-PRP-T and MenACWY-TT vaccines were not affected by co-administration. One month after vaccination, the immune responses elicited by both vaccines were high, whether administered concomitantly or separately. The administration of MenC vaccine during infancy did not preclude the use of a MenACWY-TT vaccine for booster vaccination. Even though the reactogenicity after co-administration was somewhat higher, the results of this study support the concomitant administration of the DTaP-IPV-HB-PRP-T vaccine with a MenACWY-TT conjugate vaccine when given from 12 months of age.The clinical trial registration numbers are: clinicaltrial.gov: NCT01839175; EudraCT: 2012-005547-24.     

Use of a booster dose of capsular group C meningococcal glycoconjugate vaccine to demonstrate immunologic memory in children primed with one or two vaccine doses in infancy

BackgroundUse of a polysaccharide vaccine challenge to demonstrate immunologic memory after priming with capsular group C meningococcal conjugate vaccines (MenCC) risks induction of immunologic hyporesponsiveness. For this reason, MenCC vaccines are now used as probes of immunologic memory, however, no studies have demonstrated their ability to distinguish primed from unprimed children.MethodsThis study was part of a randomised controlled trial investigating the immunogenicity of a booster dose of the combined Haemophilus influenzae type b and MenC-tetanus toxoid vaccine (Hib-MenC-TT) in infants receiving reduced dose MenCC vaccine priming schedules (one MenC-CRM/MenC-TT or two MenC-CRM vaccine doses) compared with an unprimed group. Antibody kinetics were studied in a subset of 269 children by measuring changes in the MenC serum bactericidal antibody, using rabbit complement, (MenC rSBA) titres and MenC specific IgG memory B-cells before and at 6 and 28 days following the 12 month booster vaccination.ResultsAt 6 days after the 12 month MenCC vaccine, the rise in MenC rSBA titres and MenC specific IgG memory B-cells of the primed groups were significantly higher than the infant MenCC naïve group. Participants primed with one MenC-TT dose had the highest increase in MenC rSBA titres compared with all other groups. The MenC rSBA titres at the 28th compared with the 6th day after boosting was significantly higher in those primed with a single MenC-TT/MenC-CRM vaccine in infancy compared with those who were not primed or who were primed with two doses of the MenC-CRM vaccine.ConclusionImmunologic memory can be demonstrated by a MenCC booster vaccination but is affected by the type and number of MenCC doses used for infant priming. The MenC rSBA responses can be used to demonstrate successful immunologic priming.     

Interchangeability of meningococcal group C conjugate vaccines with different carrier proteins in the United Kingdom infant immunisation schedule

An open, non-randomised study was undertaken in England during 2011–12 to evaluate vaccine antibody responses in infants after completion of the routine primary infant immunisation schedule, which included two doses of meningococcal group C (MenC) conjugate (MCC) vaccine at 3 and 4 months. Any of the three licensed MCC vaccines could be used for either dose, depending on local availability. Healthy term infants registered at participating general practices (GPs) in Hertfordshire and Gloucestershire, UK, were recruited prospectively to provide a single blood sample four weeks after primary immunisation, which was administered by the GP surgery. Vaccination history was obtained at blood sampling. MenC serum bactericidal antibody (SBA) and IgG antibodies against Haemophilus influenzae b (Hib), pertussis toxin (PT), diphtheria toxoid (DT), tetanus toxoid (TT) and thirteen pneumococcal serotypes were analysed according to MCC vaccines received. MenC SBA responses differed significantly (P < 0.001) according to MCC vaccine schedule as follows: MenC SBA geometric mean titres (GMTs) were significantly lower in infants receiving a diphtheria cross-reacting material-conjugated MCC (MCC-CRM) vaccine followed by TT-conjugated MCC (MCC-TT) vaccine (82.0; 95% CI, 39–173; n = 14) compared to those receiving two MCC-CRM (418; 95% CI, 325–537; n = 82), two MCC-TT (277; 95% CI, 223–344; n = 79) or MCC-TT followed by MCC-CRM (553; 95% CI, 322–949; n = 18). The same group also had the lowest Hib geometric mean concentrations (0.60 μg/mL, 0.27–1.34) compared to 1.85 μg/mL (1.23–2.78), 2.86 μg/mL (2.02–4.05) and 4.26 μg/mL (1.94–9.36), respectively. Our results indicate that MCC vaccines with different carrier proteins are not interchangeable. When several MCC vaccines are available, children requiring more than one dose should receive MCC vaccines with the same carrier protein or, alternatively, receive MCC-TT first wherever possible.     

Safety and immunogenicity of a trivalent recombinant PcpA,PhtD, and PlyD1 pneumococcal protein vaccine in adults,toddlers, and infants: A phase I randomized controlled study

BackgroundPneumococcal protein vaccines (PPrVs) may provide improved protection over currently available polysaccharide and conjugated polysaccharide vaccines. Here, we examined the safety and immunogenicity of a trivalent recombinant PPrV containing PcpA, PhtD, and PlyD1.MethodsThis was a phase I, single-center, randomized, observer-blind study with safety review between cohorts. Adults (18–50 years; n = 30) and then toddlers (12–13 months; n = 30) were randomized 2:1 to receive aluminum-adjuvanted trivalent PPrV (PPrV + adj) containing 50 μg per antigen or placebo. Infants (42–49 days; n = 220) were next randomized to be injected at 6, 10, and 14 weeks of age with 10 μg PPrV + adj or placebo (n = 60; 2:1); 25 μg PPrV + adj, 25 μg unadjuvanted PPrV, or placebo (n = 100; 2:2:1); and 50 μg PPrV + adj or placebo (n = 60; 2:1). Solicited reactions were recorded for 7 days and unsolicited adverse events for 30 days after each vaccination. Concentrations of antibodies to the three vaccine antigens were measured by enzyme-linked immunosorbent assay.ResultsTenderness/pain was the most frequent injection-site reaction. Abnormal crying and irritability (infants), loss of appetite (toddlers), and headache, malaise, and myalgia (adults) were the most frequent systemic reactions. Reactions were mostly mild or moderate, resolved within 3 days, were not adjuvant- or dose-dependent, and were not increased by repeated vaccination. No immediate adverse events, hypersensitivity reactions, or treatment-related serious adverse events were reported. In all PPrV + adj cohorts, at least 75% of subjects had a ≥2-fold increase in all three antibody concentrations. In infants, antibody concentrations were higher with PPrV + adj than with unadjuvanted PPrV, higher with three than two vaccinations, and similar at the different vaccine doses.ConclusionsThe candidate trivalent PPrV was safe and immunogenic in adults, toddlers, and infants. Addition of aluminum adjuvant improved immunogenicity in infants without changing the safety profile.     

Exonic single nucleotide polymorphisms within TLR3 associated with infant responses to serogroup C meningococcal conjugate vaccine

The introduction of the serogroup C meningococcal (MenC) conjugate vaccination has successfully controlled the burden of disease associated with this serogroup in many countries. However, considerable inter-individual variation is observed in immune responses to MenC vaccine, and little is understood of the determinants of this variability. Previously, we reported an association between single nucleotide polymorphisms (SNPs) in TLR3 and CD44 and the persistence of MenC vaccine immunity. Here we further examine polymorphisms within these two candidate genes and immune responses to MenC vaccine. MenC-specific IgG concentrations and serum bactericidal assay (SBA) titres were measured one month after a primary course of MenC vaccination in 318 human infants. Tagging SNPs (TagSNPs) within TLR3 and CD44 were genotyped and regional imputations carried out to screen these genes for variations associated with immunological responses to MenC vaccine. This study reports an association between an exonic variant (rs3775290, P = 0.025) in TLR3 and MenC IgG concentrations, as well as an association between three SNPs in CD44 (rs3794109, P = 0.021; rs3794110, P = 0.022; rs112762, P = 0.049) and MenC SBA titres. These data support our previous findings of an association between SNPs in TLR3 and CD44, and present novel findings implicating exonic variants in these genes with MenC vaccine responses.     

Immunogenicity and safety of a fully liquid aluminum phosphate adjuvanted Haemophilus influenzae type b PRP-CRM197-conjugate vaccine in healthy Japanese children: A phase III,randomized, observer-blind,multicenter, parallel-group study

BackgroundBroad use of monovalent Haemophilus influenzae type b (Hib) conjugate vaccines based on the capsular polysaccharide polyribosyl-ribitol phosphate (PRP), has significantly reduced invasive Hib disease burden in children worldwide, particularly in children aged <1 year. In Japan, PRP conjugated to tetanus toxoid (PRP-T) vaccine has been widely used since the initiation of public funding programs followed by a routine vaccination designation in 2013.MethodsWe compared the immunogenicity and safety of PRP conjugated to a non-toxic diphtheria toxin mutant (PRP-CRM₁₉₇) vaccine with the PRP-T vaccine when administered subcutaneously to healthy Japanese children in a phase III study. Additionally, we evaluated the immunogenicity and safety profiles of a diphtheria–tetanus acellular pertussis (DTaP) combination vaccine when concomitantly administered with either PRP-CRM₁₉₇ or PRP-T vaccines. The primary endpoint was the “long-term seroprotection rate”, defined as the group proportion with anti-PRP antibody titers ⩾1.0 μg/mL, after the primary series.ResultsLong-term seroprotection rates were 99.3% in the PRP-CRM₁₉₇ group and 95.6% in the PRP-T group. The intergroup difference (PRP-CRM₁₉₇ group – PRP-T group) was 3.7% (95% confidence interval: 0.099–7.336), demonstrating that PRP-CRM₁₉₇ vaccine was non-inferior to PRP-T vaccine (p < 0.0001). Furthermore, the “short-term seroprotection rate” (anti-PRP antibody titer ⩾0.15 μg/mL) before booster vaccination was higher in the PRP-CRM₁₉₇ group than in PRP-T. Concomitant administration of PRP-CRM₁₉₇ vaccine with DTaP vaccine showed no differences in terms of immunogenicity compared with concomitant vaccination with PRP-T vaccine and DTaP vaccine. Although CRM₁₉₇ vaccine had higher local reactogenicity, overall, both Hib vaccines had acceptable safety and tolerability profiles.ConclusionThe immunogenicity of PRP-CRM₁₉₇ vaccine administered subcutaneously as a three-dose primary series in children followed by a booster vaccination 1 year after the primary series induced protective levels of Hib antibodies with no safety or tolerability concerns.Clinical trial registry: Registered on ClinicalTrials.gov: NCT01379846     

Immunogenicity and safety of concomitant administration of meningococcal serogroup B (4CMenB) and serogroup C (MenC-CRM) vaccines in infants: A phase 3b,randomized controlled trial

BackgroundAfter implementation of routine infant MenC vaccination, MenB remains a serious cause of meningococcal disease, yet to be targeted by vaccination programs in several countries. This study (NCT01339923) investigated the immunogenicity and safety of MenC CRM-conjugated vaccine (MenC-CRM) concomitantly administered with MenB vaccine (4CMenB).MethodsInfants (N = 251) were randomised 1:1 to receive 4CMenB and MenC-CRM (Group 1) or MenC-CRM alone (Group 2) at 3 and 5 months (M3, M5) and a booster at 12 months of age (M12), and pneumococcal vaccine at M3, M5, M7, M12. Antibody responses to meningococcal vaccines were measured at M3, M6, M12, and M13. Non-inferiority of MenC-CRM response in Group 1 vs Group 2 was demonstrated at M6 and M13, if the lower limit of the 95% confidence interval (LL95%CI) of the difference in percentage of infants with hSBA titres ≥1:8 was >−10%. Sufficiency of MenB response was achieved if LL95%CI of the percentage of infants with hSBA titres ≥1:4 against fHbp, NadA and PorA strains was ≥70% at M6 or ≥75% at M13. Adverse events (AEs) were collected for 7 days post-vaccination, and serious AEs (SAEs) and medically attended AEs throughout the study.ResultsNon-inferiority of MenC response in Group 1 vs Group 2 (LL95%CI −6.4% [M6]; −5.2% [M13]) and sufficiency of MenB response in Group 1 (LL95%CI 92%, 90%, 89% [M6]; 97%, 92%, 93% [M13] against fHbp, NadA, PorA, respectively) were demonstrated. Higher rates of mild to moderate solicited AEs were reported in Group 1. Unsolicited AEs and SAEs incidences were similar across groups.ConclusionsConcomitant administration of MenC-CRM and 4CMenB in infants was immunogenic, resulting in non-inferior responses against MenC compared to MenC-CRM alone and demonstration of sufficient immune response to MenB, after primary and booster vaccination. Reactogenicity was higher for concomitant vaccines administration, but no safety concerns were identified.     

Evaluation of the safety,immunogenicity and efficacy of three capripoxvirus vaccine strains against lumpy skin disease virus

The safety, immunogenicity and efficacy of three commercially available vaccines against lumpy skin disease (LSD) in cattle have been evaluated using a combination of vaccine challenge experiments and the monitoring of immune responses in vaccinated animals in the field. The three vaccines evaluated in the study included two locally produced (Ethiopian) vaccines (lumpy skin disease virus (LSDV) Neethling and Kenyan sheep and goat pox (KSGP) O-180 strain vaccines) and a Gorgan goat pox (GTP) vaccine manufactured by Jordan Bio-Industries Centre (JOVAC). The latter vaccine was evaluated for the first time in cattle against LSDV. The Ethiopian Neethling and KSGPO-180 vaccines failed to provide protection in cattle against LSDV, whereas the Gorgan GTP vaccine protected all the vaccinated calves from clinical signs of LSD. There was no significant difference in protective efficacy detected between two dosage levels (P = 0.2, P = 0.25, and P = 0.1 for KSGP, Neethling and Gorgan vaccines, respectively). Additionally, the Gorgan GTP vaccinated cattle showed stronger levels of cellular immune responses measured using Delayed-Type Hypersensitivity (DTH) reactions at the vaccination site indicating higher levels of immunogenicity produced by the GTPV vaccine in cattle, as opposed to the other two vaccines. This study indicated, for the first time, that the Gorgan GTP vaccine can effectively protect cattle against LSDV and that the Neethling and KSGP O-180 vaccine were not protective. The results emphasise the need for molecular characterization of the Neethling and KSGP O-180 vaccine seed viruses used for vaccine production in Ethiopia. In addition, the potency and efficacy testing process of the Ethiopian LSD Neethling and KSGP O-180 vaccines should be re-evaluated.     

Lot-to-lot consistency,safety and immunogenicity of 3 lots of Haemophilus influenzae type b conjugate vaccine: results from a phase III randomized,multicenter study in infants

BackgroundVaccination against Haemophilus influenzae type b (Hib) is included in routine pediatric immunization schedule in the United States. Previous vaccine shortages have created the need for additional options for Hib vaccination.MethodsThis phase III, randomized, multi-centered study (NCT01000974) evaluated the safety and immunogenicity of a monovalent tetanus toxoid-conjugate Hib vaccine (Hib-TT) compared to a monovalent (Hib-TT control) and a combination Hib-TT vaccine. We hierarchically assessed lot-to-lot consistency of 3 Hib-TT lots and non-inferiority of Hib-TT to Hib-TT control. We co-administered routine pediatric vaccines with Hib-TT vaccines at 2, 4, 6 months (primary vaccination) and 15–18 months of age (booster vaccination). We recorded adverse events (AEs) for 4 (solicited) and 31 days (unsolicited) post-vaccination and serious AEs (SAEs) throughout the study.ResultsOf 4009 enrolled children, 3086 completed booster phase. Lot-to-lot consistency was not demonstrated. The study met statistical criteria for non-inferiority of Hib-TT to Hib-TT control in terms of immune responses to Hib and co-administered vaccines’ antigens, but not in terms of participants achieving post-primary vaccination anti-PRP levels ≥1 µg/mL. Because of the hierarchical nature of the objectives, non-inferiority could not be established. In all groups, 92.5–96.7% and 99.6–100% of participants achieved anti-PRP levels ≥0.15 µg/mL, while 78.3–89.8% and 97.9–99.1% had anti-PRP levels ≥1 µg/mL, post-primary and post-booster vaccination, respectively. Immune responses to co-administered vaccines and reported incidence of AEs were comparable among groups. We recorded SAEs for 107/2963 (3.6%), 24/520 (4.6%), and 21/520 (4.0%) children post-primary vaccination, and 29/2337 (1.2%), 4/435 (0.9%), and 2/400 (0.5%) children post-booster vaccination with Hib-TT, Hib-TT control and combination Hib-TT vaccine, respectively; 6/5330 (0.1%) SAEs in the Hib-TT groups were considered vaccine-related.ConclusionHib-TT induced seroprotective antibody concentrations in the majority of participants and was well-tolerated when co-administered with routine pediatric vaccines according to a 3 + 1 schedule.     

Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine and an MF59-adjuvanted influenza vaccine after concomitant vaccination in ⩾60-year-old adults

BackgroundConcomitant administration of influenza and pneumococcal vaccines could be an efficient strategy to increase vaccine uptake among older adults. Nevertheless, immune interference and safety issues have been a concern when more than one vaccines are administered at the same time.MethodsSubjects aged ⩾60 years were randomized in a 1:1:1 ratio to receive MF59-adjuvanted trivalent inactivated influenza vaccine (MF59-aTIV) + 13-valent pneumococcal conjugate vaccine (PCV13) (Group 1), PCV13 alone (Group 2), or MF59-aTIV alone (Group 3). Hemagglutination inhibition (HI) and opsonophagocytic activity (OPA) assays were used to compare immunogenicity after single or concomitant vaccination.ResultsA total of 1149 subjects (Group 1, N = 373; Group 2, N = 394; Group 3, N = 382) were available for the assessment of immunogenicity and safety. All groups met immunogenicity criteria for the influenza vaccine in older adults with similar seroprotection rates, seroconversion rates, and geometric mean titer (GMT) fold-increases, irrespective of concomitant vaccination. For each pneumococcal serotype, OPA titers increased markedly after the PCV13 vaccination, irrespective of the concomitant influenza vaccination. After concomitant administration, the non-inferiority criteria of GMT ratios were met for all three influenza subtypes and 13 pneumococcal serotypes. No vaccine-related serious adverse events occurred.ConclusionsConcomitant MF59-aTIV and PCV13 administration showed no interference with antibody response and showed good safety profiles.(Clinical Trial Number – NCT02215863).     

Incompatibility of lyophilized inactivated polio vaccine with liquid pentavalent whole-cell-pertussis-containing vaccine

A hexavalent vaccine containing diphtheria toxoid, tetanus toxoid, whole cell pertussis, Haemophilius influenza type B, hepatitis B and inactivated polio vaccine (IPV) may: (i) increase the efficiency of vaccination campaigns, (ii) reduce the number of injections thereby reducing needlestick injuries, and (iii) ensure better protection against pertussis as compared to vaccines containing acellular pertussis antigens. An approach to obtain a hexavalent vaccine might be reconstituting lyophilized polio vaccine (IPV-LYO) with liquid pentavalent vaccine just before intramuscular delivery. The potential limitations of this approach were investigated including thermostability of IPV as measured by D-antigen ELISA and rat potency, the compatibility of fluid and lyophilized IPV in combination with thimerosal and thimerosal containing hexavalent vaccine.The rat potency of polio type 3 in IPV-LYO was 2 to 3-fold lower than standardized on the D-antigen content, suggesting an alteration of the polio type 3 D-antigen particle by lyophilization. Type 1 and 2 had unaffected antigenicity/immunogenicity ratios. Alteration of type 3 D-antigen could be detected by showing reduced thermostability at 45 °C compared to type 3 in non-lyophilized liquid controls.Reconstituting IPV-LYO in the presence of thimerosal (TM) resulted in a fast temperature dependent loss of polio type 1-3 D-antigen. The presence of 0.005% TM reduced the D-antigen content by ∼20% (polio type 2/3) and ∼60% (polio type 1) in 6 h at 25 °C, which are WHO open vial policy conditions. At 37 °C, D-antigen was diminished even faster, suggesting that very fast, i.e., immediately after preparation, intramuscular delivery of the conceived hexavalent vaccine would not be a feasible option. Use of the TM-scavenger, l-cysteine, to bind TM (or mercury containing TM degradation products), resulted in a hexavalent vaccine mixture in which polio D-antigen was more stable.     

Assessment of preparation time with fully-liquid versus non-fully liquid paediatric hexavalent vaccines. A time and motion study

Background and aimsSimplified vaccine preparation steps would save time and reduce potential immunisation errors. The aim of the study was to assess vaccine preparation time with fully-liquid hexavalent vaccine (DTaP-IPV-HB-PRP-T, Sanofi Pasteur MSD) versus non-fully liquid hexavalent vaccine that needs reconstitution (DTPa-HBV-IPV/Hib, GlaxoSmithKline Biologicals).MethodsNinety-six Health Care Professionals (HCPs) participated in a randomised, cross-over, open-label, time and motion study in Belgium (2014). HCPs prepared each vaccine in a cross-over manner with a wash-out period of 3–5 min. An independent nurse assessed preparation time and immunisation errors by systematic review of the videos. HCPs satisfaction and preference were evaluated by a self-administered questionnaire.ResultsAverage preparation time was 36 s for the fully-liquid vaccine and 70.5 s for the non-fully liquid vaccine. The time saved using the fully-liquid vaccine was 34.5 s (p ≤ 0.001). On 192 preparations, 57 immunisation errors occurred: 47 in the non-fully liquid vaccine group (including one missing reconstitution of Hib component), 10 in the fully-liquid vaccine group. 71.9% of HCPs were very or somewhat satisfied with the ease of handling of both vaccines; 66.7% and 67.7% were very or somewhat satisfied with speed of preparation in the fully-liquid vaccine and the non-fully liquid vaccine groups, respectively. Almost all HCPs (97.6%) stated they would prefer the use of the fully-liquid vaccine in their daily practice.ConclusionsPreparation of a fully-liquid hexavalent vaccine can be completed in half the time necessary to prepare a non-fully liquid vaccine. The simplicity of the fully-liquid hexavalent vaccine preparation helps optimise reduction of immunisation errors.     

A phase 1, open-label,randomized study to compare the immunogenicity and safety of different administration routes and doses of virosomal influenza vaccine in elderly

BackgroundInfluenza remains a significant problem in elderly despite widespread vaccination coverage. This randomized, phase-I study in elderly compared different strategies of improving vaccine immunogenicity.MethodsA total of 370 healthy participants (⩾65 years) were randomized equally 1:1:1:1:1:1 to six influenza vaccine treatments (approximately 60–63 participants per treatment arm) at day 1 that consisted of three investigational virosomal vaccine formulations at doses of 7.5, 15, and 45 μg HA antigen/strain administered intradermally (ID) by MicronJet600™ microneedle device (NanoPass Technologies) or intramuscularly (IM), and three comparator registered seasonal vaccines; Inflexal V™ (Janssen) and MF59 adjuvanted Fluad™ (Novartis) administered IM and Intanza™ (Sanofi Pasteur) administered ID via Soluvia™ prefilled microinjection system (BD). Serological evaluations were performed at days 22 and 90 and safety followed-up for 6 months.ResultsIntradermal delivery of virosomal vaccine using MicronJet600™ resulted in significantly higher immunogenicity than the equivalent dose of virosomal Inflexal V™ administered intramuscularly across most of the parameters and strains, as well as in some of the readouts and strains as compared with the 45 μg dose of virosomal vaccine formulation. Of 370 participants, 300 (81.1%) reported ⩾1 adverse event (AE); more participants reported solicited local AEs (72.2%) than solicited systemic AEs (12.2%).ConclusionsIntradermal delivery significantly improved influenza vaccine immunogenicity compared with intramuscular delivery. Triple dose (45 μg) virosomal vaccine did not demonstrate any benefit on vaccine’s immunogenicity over 15 μg commercial presentation. All treatments were generally safe and well-tolerated.     

Immunogenicity and safety of a quadrivalent inactivated influenza virus vaccine compared with a comparator quadrivalent inactivated influenza vaccine in a pediatric population: A phase 3, randomized noninferiority study

BackgroundSeqirus 2010 Southern Hemisphere split-virion trivalent inactivated influenza vaccine (IIV3) was associated with increased febrile reactions in children. Studies in vitro concluded that increasing concentrations of splitting agent decreased residual lipids and attenuated proinflammatory cytokine signals associated with fever. We assessed immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4; produced using higher concentration of splitting agent) versus a United States-licensed comparator IIV4 in healthy children aged 5–17 years.MethodsParticipants (N = 2278) were randomized 3:1 and stratified by age (5–8 years; 9–17 years) to receive IIV4 (n = 1709) or comparator IIV4 (n = 569). Primary objective was to demonstrate noninferiority of IIV4 versus comparator IIV4 as assessed by hemagglutination inhibition (HI) geometric mean titer (GMT) ratio (upper bound of two-sided 95% confidence interval [CI] ≤ 1.5) and difference in seroconversion rate (upper bound of two-sided 95% CI ≤ 10%) for all four vaccine strains. HI antibody titers were assessed at baseline and 28 days postvaccination. Solicited and unsolicited adverse events were assessed during each 7- and 28-day postvaccination period, respectively.ResultsIIV4 met immunogenicity criteria for noninferiority. Adjusted GMT ratios (comparator IIV4/IIV4) for A/H1N1, A/H3N2, B/Yamagata, and B/Victoria strains were 1.01 (95% CI; 0.93, 1.09), 1.05 (0.96, 1.15), 0.89 (0.81, 0.98), and 0.92 (0.83, 1.02), respectively. Corresponding values for differences (95% CI) in seroconversion rates (comparator IIV4 minus IIV4) were −3.1 (−8.0, 1.8), 0.4 (−4.5, 5.3), −3.4 (−8.3, 1.5), and −2.0 (−6.9, 2.9). Fever rates were numerically higher, but not statistically different, with IIV4 versus comparator IIV4. No new safety signals were reported.ConclusionIIV4 demonstrated immunological noninferiority to the comparator IIV4 with a clinically acceptable safety profile in children aged 5–17 years. Increased levels of virus splitting agent seem to have reduced fever rates observed in children with Seqirus IIV3, particularly those aged 5–8 years.Funding: Seqirus Pty Ltd; Clinicaltrials.gov identifier: NCT02545543.     

Immunogenicity and safety of concomitant MF59-adjuvanted influenza vaccine and 23-valent pneumococcal polysaccharide vaccine administration in older adults

BackgroundConcomitant administration of influenza and pneumococcal vaccines facilitates their uptake by older adults; however, data on immunogenicity and safety of concomitant administration of adjuvanted trivalent inactivated influenza vaccine (aIIV3) and 23-valent pneumococcal polysaccharide vaccine (PPSV23) have not been reported.MethodsSubjects aged ≥65 years (N = 224) were randomized 1:1:1:1 to receive MF59-aIIV3 alone, MF59-aIIV3 + PPSV23 in contralateral arms, MF59-aIIV3 + PPSV23 in the same arm or PPSV23 alone (Clinical Trial Number – NCT02225327). Hemagglutination inhibition assay and multiplex opsonophagocytic killing assay were used to compare immunogenicity after single or concomitant vaccination.ResultsAll groups met immunogenicity criteria for the influenza vaccine in older adults with similar seroconversion rates and geometric mean fold-increases, irrespective of concomitant vaccinations and injection site. For each pneumococcal serotype, opsonic index (OI) increased markedly after the PPSV23 vaccination, irrespective of the concomitant influenza vaccine. All subjects showed an OI ≥ 8 for serotypes 6B, 18C and 19A post-vaccination, with a suggestion that the ipsilateral concomitant vaccination might be associated with higher OIs for some antigens. Local and systemic adverse events were more common in subjects receiving PPSV23 compared to those receiving aIIV3 alone.ConclusionsNo interference was observed with antibody responses to influenza or pneumococcal antigens when aIIV3 and PPSV23 were administered concomitantly.     

Antibody persistence after serogroup C meningococcal conjugate vaccine in children with sickle cell disease

BackgroundA decline of protective antibody titers after MCC vaccine has been demonstrated in healthy children, this may be an issue of concern for risk groups. The aim of this study was to evaluate the persistence of bactericidal antibodies after MCC vaccine in sickle cell disease (SCD) patients. The type of vaccine used and booster response were also analyzed.MethodsSCD patients (n = 141) previously immunized with MCC vaccines had blood drawn 2–8 years after the last priming dose. They were distributed according to age at primary immunization into groups: <2 years and 2–13 years and evaluated by years since vaccination (2–3, 4–5 and 6–8). Serum bactericidal antibodies with baby rabbit complement (rSBA) and serogroup C-specific IgG concentrations were measured. The correlate of protection was rSBA titer ⩾8. Subjects with rSBA <8 received a booster dose and antibody levels re-evaluated after 4–6 weeks.ResultsFor children primed under 2 years of age rSBA titer ⩾8 was demonstrated in 53.3%, 21.7% and 35.0%, 2–3, 4–5, 6–8 years, respectively, after vaccination, compared with 70.0%, 45.0% and 53.5%, respectively, for individuals primed at ages 2–13 years. rSBA median titers and IgG median levels were higher in the older group. Six to eight years after vaccination the percentage of patients with rSBA titers ⩾8 was significantly higher in the group primed with MCC-TT (78.5%) compared with those primed with MCC-CRM₁₉₇ [Menjugate® (33.3%) or Meningitec® (35.7%)] (p = 0.033). After a booster, 98% achieved rSBA titer ⩾8.ConclusionImmunity to meningococcal serogroup C in SCD children declines rapidly after vaccination and is dependent on the age at priming. Booster doses are needed to maintain protection in SCD patients. Persistence of antibodies seems to be longer in individuals primed with MCC-TT vaccine comparing to those immunized with MCC-CRM₁₉₇.     

Uptake of rotavirus vaccine among US infants at Immunization Information System Sentinel Sites

ObjectiveCoverage with rotavirus vaccine among US children has been lower compared to that with other routine childhood vaccines. Our objectives were to examine rotavirus vaccine (RV) uptake over time compared to other routine vaccinations, ages at administration, and quantitate potential missed opportunities for RV receipt.MethodsWe analyzed data from 6 Immunization Information System (IIS) Sentinel Sites, which represent approximately 10% of the United States (US) pediatric population. Among infants aged 5 months, we compared uptake of ⩾1 dose of RV, to that of Diphtheria, Tetanus, and acellular Pertussis (DTaP) and pneumococcal conjugate vaccine (PCV), for each quarter during 2006–2013. We used data from infants in the 2012 birth cohort to examine RV receipt in more detail.ResultsAmong infants aged 5 months, the average site coverage with ⩾1 dose of RV reached 78% in 2010 and subsequently stayed steady at 79–81% through 2013. The average difference between ⩾1 dose DTaP coverage and RV coverage remained between about 6 and 8 percentage points during mid-2012 through 2013. Infants born in 2012 received RV doses closely in line with the timing recommended by the ACIP. Approximately one-third of the difference in coverage between ⩾1 dose of DTaP and ⩾1 dose of RV among infants could be due to the maximum age restriction of the first RV dose. The other two-thirds of the difference appears to have been a result of potential missed opportunities for starting the RV series--these infants received another routine immunization when age eligible to receive RV dose 1, but did not receive RV.ConclusionUptake with RV during infancy remains below that of other routine vaccines. Understanding the barriers to administration of RV among age-eligible infants could help improve vaccine coverage.     

A randomized trial of rotavirus vaccine versus sucrose solution for vaccine injection pain

ObjectiveSucrose solutions are analgesic in infants. Oral rotavirus vaccine contains sucrose, however, it is not known if it possesses analgesic properties. The objective was to compare the analgesic effectiveness of rotavirus vaccine to sucrose solution when administered prior to injectable vaccines.MethodsInfants 2–4 months of age receiving oral rotavirus vaccine and two separate injectable vaccines on the same day were randomized to rotavirus vaccine (Rotarix™) first followed by the injectable vaccines and sucrose (Tootsweet™) afterwards, or vice versa. Pain was assessed by blinded raters using the Numerical Rating Scale (NRS, range 0–10) (parents, clinicians), or Modified Behavioural Pain Scale (MBPS, range 0–10) and cry duration (observers). Data were analyzed using t-tests or χ²-tests; Bonferroni correction was applied to correct for multiple comparisons, as appropriate.ResultsAltogether, 120 infants participated: 60 were randomized to rotavirus vaccine first. Groups did not differ in demographics, including; age (p = 0.448) and sex (p = 0.464). The mean pain score (standard deviation) for both vaccine injections did not differ between infants given rotavirus vaccine first versus sucrose solution first: observer MBPS, parent NRS and clinician NRS scores were 7.4 (1.6) vs. 7.7 (1.6), 4.9 (2.1) vs. 5.8 (2.1), and 4.2 (2.1) vs. 4.6 (2.2), respectively. Similarly, there was no difference between groups in cry duration.ConclusionRotavirus vaccine did not differ from sucrose solution in reducing injection-induced pain. Based on the findings, it is recommended that rotavirus vaccine be administered prior to injectable vaccines in infants aged 2 and 4 months.