Immunogenicity and induction of immunological memory of the heptavalent pneumococcal conjugate vaccine in preterm UK infants

Data on the immunogenicity and memory induction of pneumococcal conjugate vaccines in very preterm infants is limited. We vaccinated 69 full term and 68 preterm infants (median gestational age (GA) 30 weeks) with a 7-valent pneumococcal conjugate vaccine (PCV7) at 2/3/4 months of age, followed by a plain polysaccharide booster at 12 months of age. IgG-GMC (ELISA) was significantly lower in preterm infants to six vaccine serotypes (ST) at 2 months and 5 months of age, to five ST at 12 months of age and to three ST at 13 months of age. A significantly lower proportion of preterm infants achieved IgG levels>or=0.35 microg/ml to ST 4, 6B and 9V at 5 months and to ST 4, 6B, 18C, 19F and 23F at 12 months of age. Fold rises following the polysaccharide booster were comparable to those of term infants. At least 93% of both cohorts achieved IgG>or=0.35 microg/ml to all STs following booster vaccination. Pneumococcal conjugate vaccine at an accelerated schedule of 2/3/4 months of age is likely to provide protection against pneumococcal disease for preterm infants. Antibody concentrations wane over the first year of life in both preterm and term infants and booster vaccination is therefore likely to be important.     

Two versus three doses of a meningococcal C conjugate vaccine concomitantly administered with a hexavalent DTaP-IPV-HBV/Hib vaccine in healthy infants

The immunogenicity and reactogenicity of a meningococcal serogroup C (MenC) conjugate vaccine given concomitantly with DTaP-IPV-HBV/Hib vaccine according to a two- or three-dose schedule in healthy infants was evaluated. At 1 month post-vaccination, 98% (two doses) and 100% (three doses) of subjects had serum bactericidal antibody using human complement assay (hSBA) titres > or =1:8; at 12 months of age > or =89% of subjects in each group remained seroprotected. Induction of immunological memory, as evaluated by administration of a meningococcal serogroup A/C polysaccharide vaccine challenge dose, was similar for both regimens and no interference was observed in the immune response to MenC or hepatitis B virus antigens. Reactogenicity was similar in each group. MenC conjugate vaccine given concomitantly with DTaP-IPV-HBV/Hib to healthy infants in the first year of life using a two-dose schedule is as safe and immunogenic as a three-dose regimen.     

Response of steroid-treated former preterm infants to a single dose of meningococcal C conjugate vaccine

Attenuated antibody responses have been reported in preterm infants who received neonatal dexamethasone treatment. The duration of immunosuppression may extend into later infancy. This study assessed the immune response of former preterm infants to a single meningococcal serogroup C conjugate (MCC) immunisation given after infancy. A cohort of 49 toddlers born at less than 33 weeks' gestation were given an initial dose of MCC vaccine at a median age of 13 months; 11 had received dexamethasone in the neonatal period. Sera obtained 4 weeks post immunisation were analysed for serum bactericidal antibody (SBA) and serogroup C-specific IgG antibody concentrations. Immune responses were compared with those of an historical cohort of 70 term toddlers given a single dose of the same vaccine at age 13 months. An SBA titre of > or =8 was taken to indicate a protective response. Following a single MCC dose, the SBA geometric mean titre (GMT) for former preterm infants was 249 (95% C.I. 111, 558), not significantly different from that of the historical term cohort whose SBA GMT was 141 (95% C.I. 89, 224) (p=0.06). A significantly lower proportion of former preterm infants achieved a protective SBA titre of > or =8 compared with term infants, 37/48 (77%) versus 64/70 (91%), (p=0.03). For steroid-treated and non steroid-treated subgroups, SBA GMTs were 1237 (95% C.I. 250, 6132) and 154 (62, 385), respectively, and numbers achieving an SBA titre of > or =8 were 10/11 (91%) and 27/37 (73%), (p=0.42). Most children born at <33 weeks' gestation mount a protective immune response to a single MCC vaccine dose given at age 13 months, but fewer former preterm infants attain a protective SBA titre of 8 compared with term infants. Previous neonatal dexamethasone treatment does not appear to attenuate immune response after infancy.     

Single priming dose of meningococcal group C conjugate vaccine (NeisVac-C) in infants

Since the introduction of the meningococcal C conjugate (MCC) vaccine in the pediatric population in 1999, numerous clinical studies have confirmed the immunogenicity and safety of the NeisVac-C^® vaccine, and several have observed a strong immune response after a single priming dose, which could be successfully boosted. Maximizing protection of infants with as few vaccine doses as possible would increase the general acceptability of the immunization strategies and support broader coverage without increasing vaccination costs.     

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.     

Evaluation of 13-valent pneumococcal conjugate vaccine and concomitant meningococcal group C conjugate vaccine in healthy infants and toddlers in Spain

Background

Given the concurrent administration of multiple vaccines during routine pediatric immunizations, efforts to elucidate the potential interference of any vaccine on the immune response to the concomitantly administered antigens are fundamental to prelicensure clinical research.

Methods

This phase 3 randomized controlled trial of 13-valent pneumococcal conjugate vaccine (PCV13) versus 7-valent PCV (PCV7) assessed immune responses of concomitantly administered meningococcal group C conjugated to diphtheria toxin cross-reactive material 197 (MnCCV-CRM₁₉₇) in a 2-dose infant series and 15-month toddler dose.

Results

619 subjects were randomized, 315 to PCV13 and 304 to PCV7. MnCCV-CRM₁₉₇-induced immune responses were similar between the PCV13 and PCV7 groups, with >97% of the subjects achieving a ≥1:8 meningococcal serum bactericidal assay (SBA) titer after both dose 2 and the toddler dose. Geometric mean titers were lower in the PCV13 group 191.22 (167.72, 218.02) versus 266.19 (234.86, 301.71) following dose 2 and 432.28 (361.22, 517.31) versus 730.84 (642.05, 831.91) following the toddler dose. The geometric mean (GM) meningococcal SBA titer ratios (PCV13/PCV7) were 0.72 after dose 2 and 0.59 after the toddler dose. The criteria for MnCCV-CRM₁₉₇ non-inferiority for GM titers were satisfied after dose 2. Percent responders was similar up to titers of 1:128. PCV13 elicited substantial antipneumococcal responses against all 13 serotypes, with ≥90% of the subjects achieving an antibody concentration ≥0.35 μg/mL after dose 3 in the infant series. Safety and tolerability were similar between the vaccine groups.

Conclusions

Immunogenicity results of MnCCV-CRM₁₉₇ for PCV13 compared with PCV7 included lower GMTs, but the clinical significance of this is unknown as the proportion of infants achieving protective MenC antibody titers was comparable in the two groups. Percent responders were similar up to titers of 1:128. PCV13 has an acceptable safety profile in infants and toddlers, while providing expanded coverage against pneumococcal disease.     

Determination of hydrazine in a meningococcal C conjugate vaccine intermediary product

In Brazil, polysaccharide–protein conjugate vaccine against Neisseria meningitidis group C (MenCPS-TT) using hydrazine-activated-tetanus toxoid (TT) as a carrier protein has been developed. Because of the toxicity of hydrazine in humans, it is necessary to monitor this substance's process control step during the vaccine production. The electroanalytical methodology was developed and validated for the determination of hydrazine during the process control of MenCPS-TT vaccine production by differential pulse polarography. The reduction potential was −0.95 V in acetone and sulphuric acid solution. The method presented linear range between 30 and 150 μg L⁻¹and recovery of 93.5 ± 0.8%.     

Prior meningococcal A/C polysaccharide vaccine does not reduce immune responses to conjugate vaccine in young adults

The immune responses induced in young adults by a meningococcal A/C polysaccharide-diphtheria toxoid conjugate vaccine (Mcj) and a meningococcal A/C plain polysaccharide vaccine (Mps) were evaluated in unvaccinated subjects and those who had received either vaccine previously. 195 subjects aged 17-30 years received either Mps or Mcj. After 12 months, they were randomised again to receive a second dose of either vaccine. Serogroup specific serum bactericidal assay (SBA) titers and IgG antibody responses were assayed before and 4-8 weeks after primary and booster immunisation. Both vaccines were immunogenic in previously unvaccinated subjects. Administration of a dose of Mps after previous Mps or Mcj induced lower bactericidal titers to group C Neisseria meningitidis than those seen after a single dose of Mps. Bactericidal antibody responses to Mcj were not reduced in subjects who had previously received Mps.     

New meningococcal C polysaccharide-tetanus toxoid conjugate Physico-chemical and immunological characterization

The polysaccharides (Ps) are thymus-independent 2 (TI-2) antigens and poor immunogens in infants and young children; as a result of this delayed response to Ps antigens during ontogeny, infants and young children are highly susceptible to infections caused by encapsulated bacteria. Meningococcal group C polysaccharide (PsC)-proteins conjugate vaccines have been reported to induce significant serum IgG antibodies and immunologic memory in infants resulting in very effective vaccines. We describe here the obtainment, by a new method, of a neoglycoconjugate intended to immunize against Neisseria meningitidis serogroup C, its characterization by physico-chemical methods, including (1)H NMR and fluorescence spectroscopy methods, as well as the characterization of the immune response induced in mice by such conjugate. Amine groups generated by basic hydrolysis in the PsC were successfully conjugated to carboxyl groups of tetanus toxoid (TT), using carbodiimide-mediated coupling. The specific anti-Ps IgG and anti-Ps IgG subclasses (IgG1 and IgG2a) were measured by ELISA methods, the bactericidal activity in sera and the cytokines response (IFNgamma or IL5) in spleen cell of mice immunized with conjugated and native Ps were evaluated. The (1)H NMR spectra and the result obtained by the fluorescence spectroscopy method showed that the PsC and TT maintained structural identity after conjugation process. Conjugated PsC elicited an increase of anti-PsC IgG responses, anti-PsC IgG subclass (IgG1, IgG2a), an eight-fold increase in bactericidal activity in sera of mice immunized with conjugate compared with native PsC, was also observed. Higher titres of IFNgamma were observed in mice immunized with conjugated Ps. These results indicated that, the PsC and TT maintained its chemical and antigenic structure after the conjugation process. A change in the immunological pattern of responses of PsC, from TI-2 to a thymus-dependent (TD) pattern, was also demonstrated.     

Brazilian meningococcal C conjugate vaccine: Scaling up studies

Several outbreaks caused by Neisseria meningitidis group C have been occurred in different regions of Brazil. A conjugate vaccine for Neisseria meningitidis was produced by chemical linkage between periodate-oxidized meningococcal C polysaccharide and hydrazide-activated monomeric tetanus toxoid via a modified reductive amination conjugation method. Vaccine safety and immunogenicity tested in Phase I and II trials showed satisfactory results. Before starting Phase III trials, vaccine production was scaled up to obtain industrial lots under Good Manufacture Practices (GMP). Comparative analysis between data obtained from industrial and pilot scales of the meningococcal C conjugate bulk showed similar execution times in the scaling up production process without significant losses or alterations in the quality attributes of purified compounds. In conclusion, scale up was considered satisfactory and the Brazilian meningococcal conjugate vaccine production aiming to perform Phase III trials is feasible.     

Immunogenicity and reactogenicity of a group C meningococcal conjugate vaccine compared with a group A+C meningococcal polysaccharide vaccine in adolescents in a randomised observer-blind controlled trial

This study evaluated the immunogenicity and reactogenicity of a group C meningococcal conjugate vaccine (MenC) compared with a group A+C meningococcal polysaccharide vaccine (MenPS) in healthy adolescents. Subjects were randomised to receive one dose of either MenC (n=92) or MenPS (n=90). Group C meningococcal IgG antibody concentrations and bactericidal titres were higher in the MenC group than the MenPS group at 1 month (22.8 U/ml vs 4.0 U/ml, p<0.001, and 87 vs 20, p<0.001, respectively) and 12 months (6.1 U/ml vs 3.0 U/ml, p<0.001, and 81.3 vs 20.2, p<0.001, respectively). No differences in post immunisation reaction rates were noted between the two vaccinated groups. This study demonstrated the safety and enhanced immunogenicity of the candidate meningococcal conjugate vaccine as compared with the licensed polysaccharide vaccine in adolescents.     

Antibody responses to meningococcal (groups A, C, Y and W135) polysaccharide diphtheria toxoid conjugate vaccine in children who previously received meningococcal C conjugate vaccine

A randomised, modified, double-blind trial was conducted in children 2 to < 5 years of age to evaluate immunogenicity and reactogenicity of a meningococcal (serogroups A, C, Y, W135) diphtheria toxoid conjugate vaccine (MCV-4) in healthy children previously vaccinated with a monovalent meningococcal C conjugate vaccine. Participants received one dose of either MCV-4 or Haemophilus influenzae type b vaccine (Hib vaccine, control group). Serum bactericidal antibodies (SBA) were determined in sera obtained before and approximately 28 days following vaccination. MCV-4 was highly immunogenic for serogroups A, C, Y and W135, the response to serogroup C being consistent with a booster response in participants primed with monovalent C conjugate vaccine. No major between-group differences in solicited local and systemic reactions or adverse events (AEs).     

A randomised, double-blind, controlled trial of the immunogenicity and tolerability of a meningococcal group C conjugate vaccine in young British infants

A double-blind, randomised, controlled trial was conducted in 248 British infants to assess the immunogenicity and tolerability of three doses of a meningococcal group C/CRM (197) conjugate vaccine (Lederle Laboratories, USA) given at 2, 3 and 4 months. Control children received three doses of Hepatitis B vaccine (Engerix B(R); SmithKline Beecham). At 5 months of age, 100% of children receiving the conjugate vaccine had specific immunoglobulin G concentrations >2.0 microg/ml (n=116) compared with only 4% of control children (n=121). Those receiving the conjugate also had 2.5- and 1.6-fold higher geometric mean concentrations of PRP and diphtheria antibodies, respectively. The vaccine was well tolerated.     

Baseline polysaccharide-specific antibodies may not consistently inhibit booster antibody responses in infants to a serogroup C meningococcal protein-polysaccharide conjugate vaccine

Negative correlations between baseline antibody concentrations and increases in antibody concentrations (after booster doses of vaccines) have been reported previously. Such correlation coefficients are widely reported by statisticians to be subject to mathematical coupling. Negative correlations may be attributable partly or wholly to the combination of mathematical coupling and measurement error (or other short term fluctuations in measurements) and therefore not clinically interpretable. In this study we re-analysed the serum antibody responses from five clinical trials of serogroup C meningococcal conjugate vaccine (MenCV) given to infants for priming followed by boosting with MenCV or a meningococcal A/C polysaccharide vaccine (MenA/C) at 12 months of age. Using Pearson's correlation method to assess the effect of pre-booster MenC-IgG concentration on the relative increase in MenC-IgG concentration post-booster, a significant negative correlation was observed for all the groups, indicating that high pre-booster antibody was associated with a smaller rise in antibody post-booster. We tested two additional statistical methods that account for mathematical coupling. Using Blomqvist method of adjustment to assess the plausible extent of bias, correlation coefficients were still negative providing error variance was low. The other method, a multilevel modelling specification of Oldham's method appeared not to be appropriate. In contrast, using Pearson's correlation method a consistent negative correlation between carrier protein-specific baseline antibody concentration and the increase in MenC-specific antibody concentration was only observed following booster immunisation with the protein-polysaccharide conjugate vaccine but not following the MenA/C plain polysaccharide vaccine. These findings suggest that analysis of the inhibitory effect of baseline antibody on the response to booster immunisation is challenging and should account for the possibility of mathematical coupling and measurement error. That an inhibitory effect of baseline antibody cannot be assumed a priori is supported by observations in animal models, which show that baseline antibody can both suppress or enhance the antibody response to a specific antigen.     

Meningococcal serogroup C immunogenicity,antibody persistence and memory B-cells induced by the monovalent meningococcal serogroup C versus quadrivalent meningococcal serogroup ACWY conjugate booster vaccine: A randomized controlled trial

BackgroundAdolescents are considered the key transmitters of meningococci in the population. Meningococcal serogroup C (MenC) antibody levels wane rapidly after MenC conjugate vaccination in young children, leaving adolescents with low antibody levels. In this study, we compared MenC immune responses after booster vaccination in adolescence with either tetanus toxoid conjugated MenC (MenC-TT) or MenACWY (MenACWY-TT) vaccine, and aimed to establish an optimal age for this booster.MethodsHealthy 10-, 12-, and 15-year-olds, who received a single dose of MenC-TT vaccine in early childhood, were randomized to receive MenC-TT or MenACWY-TT vaccine. MenC serum bactericidal antibody (rSBA) titers, MenC polysaccharide (PS) specific IgG, IgG1 and IgG2 and MenC-specific IgG and IgA memory B-cells were determined before, one month and one year after the booster. Non-inferiority was tested by comparing geometric mean titers (GMTs) between vaccinees at one year.ResultsOf 501 participants, 464 (92.6%) were included in the ‘according to protocol’ cohort analysis. At one month, all participants developed high MenC rSBA titers (>24,000 in all groups) and MenC-PS-specific IgG levels. Non-inferiority was not demonstrated one year after the booster with higher MenC GMTs after the monovalent vaccine, but 462/464 (99.6%) participants maintained protective MenC rSBA titers. IgG levels mainly consisted of IgG1, but similar levels of increase were observed for IgG1 and IgG2. Both vaccines induced a clear increase in the number of circulating MenC-PS specific IgG and IgA memory B-cells. Between one month and one year, the highest antibody decay rate was observed in the 10-year-olds.ConclusionBoth MenC-TT and MenACWY-TT vaccines induced robust protective MenC immune responses after the booster vaccination, although non-inferiority could not be demonstrated for the MenACWY-TT vaccine after one year. Our results underline the importance of optimal timing of a meningococcal booster vaccination to protect against MenC disease in the long-term.     

某新上市国产冻干A+C群脑膜炎球菌多糖结合疫苗免疫原性及安全性观察

目的评价某新上市国产冻干A+C群脑膜炎球菌多糖结合疫苗接种婴幼儿的安全性和免疫原性。方法采用随机、盲法、对照的方法,选择900名6~23月龄健康儿童,其中6~11月龄300人,12~23月龄600人,每个年龄组按1∶1比例随机分到试验组和对照组。实验组接种某新上市疫苗,对照组接种罗益(无锡)生物制药有限公司生产的同类疫苗。每人接种2剂疫苗,间隔1个月,评价试验组和对照组疫苗免疫后不良反应发生率、抗体阳转率及抗体几何平均滴度(GMT)。结果免疫后两个年龄段A、C群抗体阳转(4倍增长)率均95%,试验组与对照组的阳转率差异无统计学意义。12~23月龄接种1剂、2剂疫苗后抗体阳转率差异无统计学意义;6~11月龄段,试验组A群抗体水平高于对照组;两个年龄段试验组的C群抗体水平均低于对照组,但均处于较高水平(1∶128)。实验组与对照组全身及局部不良反应率差异无统计学意义,未观察到与试验疫苗相关的严重不良事件。结论某新上市国产冻干A+C群脑膜炎球菌多糖结合疫苗在6~23月龄的儿童中具有良好安全性和免疫原性。     

Avidity maturation following vaccination with a meningococcal recombinant hexavalent PorA OMV vaccine in UK infants

To date, there are no data assessing the utility of avidity indices as a surrogate marker for the induction of immunological memory following meningococcal serogroup B outer membrane vesicle (OMV) vaccination. We studied infants who had been immunized with three doses of a recombinant hexavalent PorA OMV vaccine at ages 2-4 months, together with a fourth dose at age 12-18 months. A control group had received a single dose of the same vaccine at age 12-18 months. As previously reported, serum bactericidal antibody (SBA) titres increased after each of the first three doses, with a significant increase observed from 6 months post third dose to 1 month post fourth dose. The geometric mean avidity indices (GMAI), against strain H44/76 OMVs, increased from 1 month post first dose to 1 month post third dose. Significant increases in GMAI were observed at 6 months post third dose and again following the fourth dose. At 32-42 months of age, though the SBA titres had returned to post first dose levels, the GMAI remained elevated. No increase in avidity was observed in the control group. Antibody avidity indices are useful laboratory markers for the priming of immunological memory following vaccination with meningococcal serogroup B OMV vaccines.