Comparison of serum bactericidal and antibody titers induced by two Haemophilus influenzae type b conjugate vaccines: A phase III randomized double-blind study

Haemophilus influenzae type b (Hib) conjugate vaccines have drastically reduced disease incidence worldwide. Protection against Hib infection has relied on the serum bactericidal activity (SBA) of antibodies to the Hib capsular polysaccharide (polyribosylribitol phosphate). However, licensure usually relies on measuring induction of antibodies to PRP as a surrogate for SBA. In a phase III clinical trial we compared a PRP-conjugate vaccine using the nontoxic diphtheria toxin mutant, CRM₁₉₇, as carrier protein with the licensed tetanus toxoid conjugate when administered subcutaneously as a three dose primary series in Japanese infants. As an addition to the phase III study, we have now evaluated SBA and show PRP-CRM₁₉₇ induces higher levels of SBA than PRP-T four weeks after the primary series, with a statistically significant correlation with anti-PRP titers. This data confirms the superior immunogenicity of PRP-CRM₁₉₇ compared with PRP-T assessed as SBA following a three-dose primary series by subcutaneous administration.Clinical trial registry: Registered on ClinicalTrials.gov (NCT01379846).     

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.     

A Phase III randomized,double-blind,clinical trial of an investigational hexavalent vaccine given at 2, 4, and 11–12 months

BackgroundCombination vaccines simplify vaccination visits and improve coverage and timeliness. DTaP5-HB-IPV-Hib is a new investigational, fully-liquid, combination vaccine designed to protect against 6 infectious diseases, including 5 pertussis antigens and OMPC instead of PT as conjugated protein for Hib component.MethodsIn this multicenter, double-blind, comparator-controlled, Phase III study (NCT01480258) conducted in Sweden, Italy, and Finland, healthy infants were randomized 1:1 to receive one two immunization regimens. The DTaP5-HB-IPV-Hib Group received the investigational hexavalent vaccine (DTaP5-HB-IPV-Hib) and the Control Group received Infanrix-hexa (DTPa3-HBV-IPV/Hib) at 2, 4 and 11–12 months of age. Both groups received concomitantly Prevnar 13 (PCV13) and Rotateq (RV5) or Rotarix (RV1) at 2, 4 months of age and PCV13 at 11–12 months. Subjects administered RV5 received a 3rd dose at 5 months of age.ResultsA total of 656 subjects were randomized to the DTaP5-HB-IPV-Hib Group and 659 subjects to Control Group. Immune responses to all vaccine antigens post-toddler dose were non-inferior in the DTaP5-HB-IPV-Hib Group as compared to the Control Group. Additionally, the post-dose 2 and pre-toddler DTaP5-HB-IPV-Hib anti-PRP responses were superior. The DTaP5-HB-IPV-Hib Group responses to concomitant RV1 were non-inferior compared to the Control Group.Solicited adverse event rates after any dose were similar in both groups, except for higher rates of pyrexia (6.4% difference; 95% CI: 1.5, 11.3) and somnolence (5.8% difference; 95% CI: 1.7, 9.8) in the DTaP5-HB-IPV-Hib Group. Vaccine-related serious adverse events occurred infrequently in the DTaP5-HB-IPV-Hib Group (0.3%) and the Control Group (0.5%).ConclusionsThe safety and immunogenicity of DTaP5-HB-IPV-Hib is generally comparable to Control when administered in the 2, 4, 11–12 month schedule. Early Hib responses were superior versus Control. DTaP5-HB-IPV-Hib could provide a new hexavalent option for pediatric combination vaccines, aligned with recommended immunizations in Europe.Study identification: V419-008CLINICALTRIALS.GOV identifier: NCT01480258     

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).     

Concomitant administration of a fully liquid,ready-to-use DTaP-IPV-HB-PRP-T hexavalent vaccine with a meningococcal serogroup C conjugate vaccine in infants

DTaP-IPV-HB-PRP-T or hexavalent vaccines are indicated for primary and booster vaccination of infants and toddlers against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and invasive diseases caused by Haemophilus influenzae type b (Hib). The present study evaluates the safety and immunogenicity of a ready-to-use hexavalent vaccine when co-administered with a meningococcal serogroup C conjugate (MenC) vaccine in infants.This was a phase III, open-label, randomised, multicentre study conducted in Finland. Healthy infants, aged 46–74 days (n = 350), were randomised in a ratio of 1:1 to receive DTaP-IPV-HB-PRP-T vaccine at two, three and four months, either with a MenC vaccine co-administered at two and four months (Group 1; n = 175) or without MenC vaccine (Group 2; n = 175). All infants also received routine rotavirus and 13-valent pneumococcal conjugate vaccines.The proportion of participants with an anti-HBs concentration ⩾10 mIU/mL assessed one month after the third dose of DTaP-IPV-HB-PRP-T vaccine was 97.5% [95%CI: 93.1–99.3] in the coadministration group and 96.1% [95%CI: 91.8–98.6] in the group without MenC vaccine. The proportion of participants with an anti-MenC SBA titre ⩾8 assessed one month after the second dose of MenC vaccine was 100% in the coadministration group. Both primary objectives were achieved.Secondary immunogenicity and safety analyses showed that co-administration of DTaP-IPV-HB-PRP-T and MenC vaccines did not impact the immune response to the antigens of each of the two vaccines. All vaccines were well tolerated and the safety profile of DTaP-IPV-HB-PRP-T vaccine was similar in both groups.ClinicalTrials.gov identifier: NCT01839175; EudraCT number: 2012-005547-24.     

中国婴幼儿接种吸附无细胞百白破灭活脊髓灰质炎和b型流感嗜血杆菌(结合)联合疫苗的安全性和免疫原性研究

目的 比较吸附无细胞百白破灭活脊髓灰质炎和b型流感嗜血杆菌(结合)联合疫苗(DTaP-IPV//PRP～T联合疫苗)与吸附无细胞百白破联合疫苗(DTaP)、b型流感嗜血杆菌结合疫苗(Hib结合疫苗)、注射用灭活脊髓灰质炎疫苗(IPV)的免疫原性和安全性.方法 受试者随机分为三组.试验组(A组和B组)分别于2、3、4月龄...     

Priming effect, immunogenicity and safety of an Haemophilus influenzae type b-tetanus toxoid conjugate (PRP-T) and diphtheria-tetanus-acellular pertussis (DTaP) combination vaccine administered to infants in Belgium and Turkey

To evaluate the priming effect, immunogenicity and safety of an Haemophilus influenzae type b (Hib) tetanus toxoid conjugate (PRP-T) and diphtheria-tetanus-acellular (two component) pertussis (DTaP) combination vaccine, a randomized, comparative study was conducted in two centers, one in Belgium and one in Turkey. A total of 410 healthy infants, 160 in Belgium and 250 in Turkey, randomly received DTaP and PRP-T vaccines in one of three fashions. One group (N = 138) received DTaP and PRP-T vaccines reconstituted immediately prior to injection at 3, 4 and 5 months of age, and are referred to as the combined, short schedule group (Co-S). A second group (N = 135) received DTaP + PRP-T simultaneously but injected at different sites according to the same schedule, and are referred to as the associated, short schedule group (As-S). The third group (N = 137) also received DTaP + PRP-T at separate sites, but at 2, 4 and 6 months, and are referred to as the associated, long schedule group (As-L). The As-L group allowed for serological bridging with a Senegalese two-component pertussis vaccine efficacy trial, using the same batch of DTaP vaccine. Children of both short-schedule groups (Co-S and As-S) received, at the age of 12-14 months, a booster dose of DTaP vaccine associated with unconjugated PRP vaccine. Mixing of the vaccines did not affect the immune response to the antigens included in the DTaP vaccine. The immune response to Hib capsular polysaccharide, however, was significantly lower after combined administration (Co-S group) than after associated (As-S group) administration (P < 0.0001), with a similar trend among both countries (GMTs, 1.78 microg/ml and 6.19 microg/ml in Belgium, and 5.02 microg/ml and 11.67 microg/ml in Turkey). Booster vaccination with the unconjugated PRP induced a vigorous and similar anamnestic response in both groups. Belgian infants showed a significantly lower immune response to all antigens than Turkish infants (P < or = 0.001 for all antigens), with a similar trend among each study group. In all groups, the incidence of adverse events was lower than that usually reported after DTwP(whole-cell) vaccine. Higher rates of systemic reactions were observed in the Belgian population, possibly due to differences in reporting practice. Our results indicate (1) that the combination vaccine, DTaP//PRP-T, represents an important improvement over the existing uncombined vaccines; (2) that immunogenicity studies should include at least one booster injection to evaluate priming effects by combined vaccines; and (3) that it is feasible and valuable to co-randomize combination vaccine studies in sufficiently different geographical areas and child populations.     

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) ⩾7 days 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 3 years 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 ⩾0.35 μg/mL were compared for subjects receiving PCV7 versus PCV7 + DTaP (concomitant) and for PCV7 or PCV7 + DTaP (concomitant) versus DTaP alone. IgG concentrations at 3 years 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 3 years 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     

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.     

Quadrivalent meningococcal (MenACWY-TT) conjugate vaccine or a fourth dose of H. influenzae–N. meningitidis C/Y conjugate vaccine (HibMenCY-TT) is immunogenic in toddlers who previously received three doses of HibMenCY-TT in infancy

BackgroundImmunogenicity and safety of a single dose of MenACWY-TT or a fourth dose of HibMenCY-TT were evaluated in the second year of life in HibMenCY-TT-primed toddlers.MethodsHealthy infants were randomized (5:1) and primed at 2, 4 and 6 months of age with HibMenCY-TT and diphtheria–tetanus–acellular pertussis–hepatitis B-inactivated poliovirus (DTaP–HBV–IPV) vaccine; or Hib-TT and DTaP–HBV–IPV (control). Recipients of HibMenCY-TT + DTaP–HBV–IPV were re-randomized (2:2:1) to receive MenACWY-TT at 12–15 months and DTaP at 15–18 months; MenACWY-TT co-administered with DTaP at 15–18 months; or HibMenCY-TT at 12–15 months and DTaP at 15–18 months. Controls received DTaP only at 15–18 months due to Hib conjugate vaccine shortage. Serum bactericidal activity using human complement (hSBA) and safety were assessed one month after meningococcal vaccination.ResultsAfter vaccination with MenACWY-TT at 12–15 months or MenACWY-TT + DTaP at 15–18 months, all subjects previously primed for serogroups C/Y had hSBA ≥1:8 for these serogroups. At least 96.1% also had hSBA ≥1:8 for serogroups A/W. All subjects in the HibMenCY-TT group had hSBA ≥1:8 for serogroups C/Y. All pre-defined statistical criteria for meningococcal immunogenicity were satisfied. All vaccination regimens had acceptable safety profiles.ConclusionChildren primed with three doses of HibMenCY-TT who then received a single dose of MenACWY-TT or a fourth dose of HibMenCY-TT had robust increases in hSBA titers for serogroups C/Y. These data provide support that MenACWY-TT, given with or without the fourth scheduled dose of DTaP could be administered as an alternative to a fourth dose of HibMenCY-TT in the second year of life.This study (110870/110871) is registered at www.clinicaltrials.gov NCT00614614.     

Immunogenicity and reactogenicity of Infanrix™ when co-administered with meningococcal MenACWY-TT conjugate vaccine in toddlers primed with MenHibrix™ and Pediarix™

BackgroundCo-administration of an investigational quadrivalent meningococcal serogroups A, C, W and Y tetanus toxoid conjugate vaccine (MenACWY-TT) with the fourth dose of diphtheria–tetanus–acellular pertussis vaccine (DTaP) at age 15–18 months was investigated in 3-dose Haemophilus influenzae type b-meningococcal serogroups C/Y conjugate vaccine (HibMenCY-TT)-primed toddlers.MethodsInfants were randomized (5:1) and primed at 2, 4 and 6 months of age with HibMenCY-TT and DTaP-hepatitis B-inactivated poliovirus (DTaP-HBV-IPV) vaccine, or Hib-TT and DTaP-HBV-IPV (Control). HibMenCY-TT+ DTaP-HBV-IPV vaccinees were re-randomized (2:2:1) to receive MenACWY-TT at 12–15 months and DTaP at 15–18 months (MenACWY-TT group); MenACWY-TT co-administered with DTaP at 15–18 months (Coad group); or HibMenCY-TT at 12–15 months and DTaP at 15–18 months (HibMenCY-TT group). Controls received DTaP at 15–18 months. Only children in the HibMenCY-TT group received a fourth dose of Hib conjugate vaccine due to Hib conjugate vaccine shortage at the time of the study. DTaP immunogenicity and reactogenicity were assessed one month post-vaccination.ResultsPre-defined statistical non-inferiority criteria between Coad and Control groups were met for diphtheria, tetanus and filamentous haemagglutinin but not pertussis toxoid and pertactin. Following vaccination ≥99% of children had anti-diphtheria/anti-tetanus concentrations ≥1.0 IU/ml. Pertussis GMCs were lower in all investigational groups versus Control. In post hoc analyses, pertussis antibody concentrations were above those in infants following 3-dose DTaP primary vaccination in whom efficacy against pertussis was demonstrated (Schmitt, von König, et al., 1996; Schmitt, Schuind, et al., 1996). The reactogenicity profile of the Coad group was similar to DTaP administered alone.ConclusionRoutine booster DTaP was immunogenic with an acceptable safety profile when co-administered with MenACWY-TT vaccine in HibMenCY-TT-primed toddlers. These data support the administration of a fourth DTaP dose following a 4-dose HibMenCY-TT vaccination series, or co-administered with MenACWY-TT in HibMenCY-TT-primed children.     

Hexavalent vaccines: What can we learn from head-to-head studies?

BackgroundThree hexavalent vaccines against diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B virus (HBV), and Haemophilus influenzae type b (Hib) are licensed in Europe: Infanrix hexa (DT3aP-HBV-IPV/Hib), Hexyon (DT2aP-HBV-IPV-Hib) and Vaxelis (DT5aP-HBV-IPV-Hib).MethodsA systematic literature search was performed in various electronic databases to identify published peer-reviewed head-to-head studies comparing any licensed hexavalent vaccine to another.ResultsPredefined inclusion criteria were met by 12 articles. Individual studies concluded that the 3 hexavalent vaccines have acceptable safety profiles although some significant differences were observed in their reactogenicity profiles. The immunogenicity of DT2aP-HBV-IPV-Hib and DT5aP-HBV-IPV-Hib was non-inferior versus DT3aP-HBV-IPV/Hib. Some differences in immune responses to common antigens were observed, but their clinical relevance was not established. Anti-filamentous hemagglutinin (FHA) from pertussis and anti-polyribosylribitol phosphate (PRP) from Hib antibody concentrations tended to be higher, and anti-HBV and anti-pertussis toxin (PT) from pertussis antibody concentrations lower in DT2aP-HBV-IPV-Hib versus DT3aP-HBV-IPV/Hib vaccinees. Anti-PT and post-primary anti-PRP antibody concentrations tended to be higher, and anti-HBV, anti-FHA, anti-pertactin from pertussis and post-booster anti-PRP antibody concentrations lower in DT5aP-HBV-IPV-Hib versus DT3aP-HBV-IPV/Hib recipients. Slightly lower immune responses towards most vaccine antigens were observed with 2 + 1 versus 3 + 1 schedules post-primary vaccination, suggesting that 2 + 1 schedules should only be considered in countries with very high vaccination coverage.ConclusionAlthough the licensed hexavalent vaccines are generally considered similar, analyses of immunogenicity data from head-to-head trials highlighted differences that could be related to differences in composition and formulation. In addition, the demonstrated non-inferiority of the immunogenicity of the more recent vaccines versus DT3aP-HBV-IPV/Hib does not allow a full bridging to similar efficacy, effectiveness and safety. The availability of DT3aP-HBV-IPV/Hib over > 20 years allowed to collect a wealth of data on its long-term immunogenicity, safety and effectiveness in clinical and post-marketing studies, and makes it a key pillar of pediatric immunization.     

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.     

Antibody persistence, PRP-specific immune memory, and booster responses in infants immunised with a combination DTPa-HBV-IPV/Hib vaccine

A new single-injection combination vaccine against six diseases has been developed to accommodate the growing number of recommended paediatric vaccines. A pentavalent liquid diphtheria, tetanus, acellular pertussis (3-component), hepatitis B, and inactivated polio (types 1-3) combined vaccine (DTPa-HBV-IPV) is extemporaneously mixed with a lyophilized Haemophilus influenza type B (Hib) conjugate vaccine (polyribosyl-ribitol phosphate (PRP)-T) and given as a single-injection. A cohort of 368 healthy infants was initially studied to evaluate the immunogenicity and reactogenicity of this hexavalent combination given as a primary course at 2, 4, and 6 months of age. At 15 months of age, from this cohort, 219 children received a booster dose of a licensed DTPa/Hib (PRP-T) vaccine to assess the booster response, while 70 received a challenge dose of unconjugated PRP (PRP) vaccine (to evaluate Hib-specific memory) plus a separate DTPa vaccine. Seven to 10 days following plain PRP challenge, anti-PRP geometric mean antibody concentrations (GMCs) had increased 13-fold to 5.67 microg/ml, and thirty days after conjugated PRP booster vaccination, anti-PRP antibody GMCs increased 102-fold. Both responses are indicative of immune memory. Vaccination was well tolerated following all primary and booster doses, although 10.5% of booster recipients experienced >50-mm local swelling at the site of DTPa vaccination. We conclude that DTPa-HBV-IPV/Hib is safe and immunogenic for primary vaccination, and that Hib-specific memory is induced by primary vaccination.     

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.     

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 12 months of age. At 5 and 13 months, 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: NCT01392378 https://clinicaltrials.gov/ct2/show/NCT01392378?term=NCT01392378&rank=1     

Lasting immune memory against hepatitis B following challenge 10–11 years after primary vaccination with either three doses of hexavalent DTPa-HBV-IPV/Hib or monovalent hepatitis B vaccine at 3, 5 and 11–12 months of age

BackgroundThe combined hexavalent diphtheria–tetanus–pertussis–hepatitis B-inactivated poliomyelitis – Haemophilus influenzae type b conjugate vaccine (Infanrix hexa™; DTPa-HBV-IPV/Hib: GlaxoSmithKline Vaccines) induces robust responses to the HBV component when administered at 3, 5 and 11–12 months of age. We assessed long term HBV antibody persistence 10–11 years after primary vaccination in infancy.MethodsAntibody persistence and immune memory were assessed post-primary vaccination at 3, 5, 11–12 months with DTPa-HBV-IPV/Hib, or monovalent HBV vaccine (Engerix™ B, GlaxoSmithKline Vaccines) co-administered with DTPa-IPV/Hib (Infanrix™-IPV/Hib, GlaxoSmithKline Vaccines) in 185 children aged 11–12 years. Blood samples were collected before and 1 month after a challenge dose of Engerix™ B (10 μg dose).Results10–11 years after primary vaccination the percentage of subjects with persisting anti-HBs antibody concentrations ≥10 mIU/ml was 48.4% in the DTPa-HBV-IPV/Hib group and 58.4% in the DTPa-IPV/Hib + HBV group. After the HBV challenge dose, the percentage with anti-HBs ≥100 mIU/ml increased from 14.7% to 93.6% in the DTPa-HBV-IPV/Hib group and 19.1% to 94.4% in the DTPa-IPV/Hib + HBV group. Anti-HBs GMCs increased by at least 187-fold in each group. An anamnestic response (≥4-fold increase in initially seropositive or anti-HBs concentration ≥10 mIU/ml in initially seronegative subjects) was observed in 96.8% and 96.6% of subjects in the DTPa-HBV-IPV/Hib and DTPa-IPV/Hib + HBV groups, respectively. No serious adverse events occurred that were considered related to challenge vaccination.ConclusionAdministration of HBV as part of a combination vaccine or as a monovalent vaccine induced long lasting immune memory against HBV in children primed at 3, 5 and 11 months of age. Antibody persistence and immune memory were similar, suggesting that protection afforded by DTPa-HBV-IPV/Hib and monovalent HBV vaccines, is likely to be of similar duration. The administration of HBV challenge dose 10–11 years after the 3, 5, 11–12 months primary schedule induced strong anamnestic responses and was well tolerated.This study is registered at www.clinicaltrials.gov NCT01138098.     

Associated or combined vaccination of Brazilian infants with a conjugate Haemophilus influenzae type b (Hib) vaccine, a diphtheria-tetanus-whole-cell pertussis vaccine and IPV or OPV elicits protective levels of antibodies against Hib

This study investigated the immunogenicity and safety of including a Haemophilus influenzae type b vaccine (polyribosylribitol phosphate conjugated to tetanus toxoid, PRP-T) in three different vaccination schemes: (1) PRP-T reconstituted with a combined diphtheria-tetanus-pertussis-inactivated poliovirus vaccine (DTP-IPV//PRP-T); (2) PRP-T reconstituted with DTP and administered concomitantly with an oral poliovirus vaccine (DTP//PRP-T+OPV); and (3) PRP-T administered concomitantly with DTP at a different injection site and OPV (DTP+PRP-T+OPV). Vaccines were given at 2, 4, and 6 months of age. A total of 252 infants were enrolled, and randomly assigned to one of the three vaccination groups (84 infants in each group); 241 infants were followed until the end of the study. Antibody production against PRP, diphtheria, tetanus and pertussis antigens was satisfactory for each vaccination scheme used. A good response to Hib vaccine was elicited in each group, and 3 months after the third vaccine dose, at least 97% of children in each group had levels of PRP antibody considered to be seroprotective (>0.15 microg/ml), and over 90% of children in each group had levels over 1. 0 microg/ml. The solicited local and systemic adverse events following vaccination were mild in all groups and resolved within 4 days without medical intervention. With the exception of fever, which was more common after the second dose in children who received DTP-IPV//PRP-T, local and systemic reactions did not differ between the vaccination groups. Due to the practical advantages of combined vaccines, their use in routine immunization programs in developing countries is highly desirable. Our results show that Hib conjugate vaccine can be included in routine immunization programs that include either OPV or IPV with satisfactory immunogenicity and safety profiles. This flexible approach should facilitate the inclusion of the Hib conjugate vaccine in routine immunization programs on a world-wide scale.     

Immunogenicity of a Japanese encephalitis chimeric virus vaccine as a booster dose after primary vaccination with SA14-14-2 vaccine in Thai children

BackgroundJapanese Encephalitis chimeric virus vaccine (JE-CV) and SA14-14-2 vaccine are live-attenuated JE vaccines produced from the same virus strain. Data on interchangeability is limited.ObjectivesTo evaluate the immunogenicity and safety of JE-CV booster after primary vaccination with SA14-14-2 vaccine.MethodsThis study was an open-label clinical trial in Thai children who had received a primary SA14-14-2 vaccination at 12–24 months before enrollment (ClinicalTrials.gov NCT02602652). JE-CV was administered. A 50% plaque reduction neutralization test (PRNT₅₀) against three virus strains; JE-CV, SA-14-14-2 and wild-type JE virus was measured before and 28-days post vaccination. The laboratory was performed at PRNT₅₀ titers ⩾10 (1/dil) were considered seroprotective against JE. Geometric mean titer (GMT) of PRNT₅₀ was calculated. Adverse events were observed for 28 days.ResultsFrom March 2014 to June 2015, 50 children (64% male) were enrolled. Mean age and duration after primary vaccination was 26.9 (SD 4.6) and 12.8 (SD 2.7) months, respectively. The proportion of participants who had PRNT₅₀pre and post-booster vaccination were 92% and 96% against JE-CV virus, 56% and 98% against SA-14-14-2 strain and 70% and 98% against wild-type JE virus, respectively. Solicited injection site reactions including erythema, pain and swelling occurred in 18%, 10% and 4% of subjects, respectively. Four children (8%) had fever (⩾37.7 Celsius). Eight children (16%) had adverse events, which were not related to the vaccine.ConclusionsAJE-CV booster dose is highly immunogenic and safe among children who previously received SA14-14-2 vaccine.     

Safety and immunogenicity of inactivated varicella-zoster virus vaccine in adults with hematologic malignancies receiving treatment with anti-CD20 monoclonal antibodies

BackgroundImmunocompromised patients can experience significant morbidity and occasional mortality from complications associated with herpes zoster (HZ), but live attenuated HZ vaccine is contraindicated for these patients. Inactivated zoster vaccine (ZV_IN) is in development for prevention of HZ in immunocompromised patients. However, there are limited data in the literature regarding the effect of anti-CD20 monoclonal antibodies on vaccine-related cell-mediated immune response. This study evaluated safety and immunogenicity of ZV_IN in patients with hematologic malignancies (HM) receiving anti-CD20 monoclonal antibodies (alone or in combination chemotherapy regimens) and not likely to undergo hematopoietic cell transplant (HCT) (n = 80).MethodsThis was an open-label, single-arm, multicenter Phase I study (NCT01460719) of a 4-dose ZV_IN regimen (∼30 days between doses) in patients ⩾18 years old. Blood samples were collected prior to dose 1 and 28 days Postdose 4 to measure varicella zoster virus (VZV)-specific T-cell responses using interferon-γ enzyme-linked immunospot (IFN-γ ELISPOT). The primary hypothesis was that ZV_IN would elicit significant VZV-specific immune responses at ∼28 days Postdose 4, with a geometric fold rise (GMFR) >1.0. All vaccinated patients were evaluated for adverse events (AE) through 28 days Postdose 4.ResultsZV_IN elicited a statistically significant VZV-specific immune response measured by IFN-γ ELISPOT at 28 days Postdose 4 (GMFR = 4.34 [90% CI:3.01, 6.24], p-value < 0.001), meeting the pre-specified success criterion.Overall, 85% (68/80) of patients reported ⩾1 AE, 44% (35/80) reported ⩾1 injection-site AE, and 74% (59/80) reported ⩾1 systemic AE. The majority of systemic AEs were non-serious and considered unrelated to vaccination by the investigator. Frequencies of AEs did not increase with subsequent doses of vaccine. No recipient of ZV_IN had rash polymerase chain reaction (PCR) positive for VZV vaccine strain.ConclusionsIn adults with HM receiving anti-CD20 monoclonal antibodies, ZV_IN was well-tolerated and elicited statistically significant VZV-specific T-cell responses ∼28 days Postdose 4.CLINICALTRIALS.GOV identifier: NCT01460719.