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     

Evaluation and validation of a serum bactericidal antibody assay for Haemophilus influenzae type b and the threshold of protection

Prior to routine immunisation, Haemophilus influenzae serotype b (Hib) was a major cause of serious bacterial infections, particularly in young children. In the United Kingdom, introduction of the Hib conjugate vaccine into the national childhood immunisation schedule has led to a sustained decline in invasive Hib disease across all age-groups. Evaluation of the immune response to Hib conjugate vaccines involves measurement of serum IgG antibodies against the capsular polyribosyl-ribitol-phosphate (PRP) polysaccharide by enzyme-linked immunosorbent assay (ELISA), with accepted short-term and long-term protective thresholds of ≥0.15 μg/mL and ≥1.0 μg/mL, respectively. These levels were derived by passive immunisation or immunisation with pure polysaccharide, and their relevance for protection following immunisation with conjugate vaccines remains unclear. This study aimed to modify and optimise a serum bactericidal antibody (SBA) assay to evaluate the functional activity of Hib antibodies generated following Hib conjugate vaccination. Validation of the Hib SBA assay was deemed acceptable for all assay parameters tested. A strong correlation between anti-PRP IgG concentrations and SBA titres was observed in vaccinated adults (r = 0.81), as well as infants after primary immunisation at 2, 3, and 4 months (r = 0.635) and after the 12-month booster (r = 0.746). The assay identified some children with high anti-PRP IgG but low SBA activity and vice versa. The predictive protective SBA titre corresponding to a post-booster anti-PRP IgG of 1.0 μg/mL was 8. Thus, the optimised Hib SBA assay was specific and reproducible and correlated with anti-PRP IgG. Such assays may have a role in evaluating immune responses to conjugate vaccines in addition to measuring capsular antibodies.     

Children with Haemophilus influenzae type b (Hib) vaccine failure have long-term bactericidal antibodies against virulent Hib strains with multiple capsular loci

Children who develop invasive Haemophilus influenzae serotype b (Hib) disease after immunisation with a highly-effective conjugate vaccine are more likely to have been infected with Hib strains possessing multiple copies of the capsulation locus. Using a recently-validated serum bactericidal antibody (SBA) assay, we tested convalescent sera from 127 Hib vaccine failure cases against clinical Hib strains expressing 1–5 copies of the capsulation locus. SBA titres correlated weakly with anti-capsular IgG antibody concentrations and there was no association between SBA geometric mean titres and number of capsulation locus copies. After infection, children with Hib vaccine failure were equally protected against Hib strains with 1–5 copies of the capsulation locus.     

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...     

Increased serum bactericidal activity of autologous serum in C2 deficiency after vaccination against Haemophilus influenzae type b,and further support for an MBL-dependent C2 bypass mechanism

Deficiencies of C2 and other components of the classical pathway of complement are associated with increased risk of infections with encapsulated bacteria, such as Haemophilus (H.) influenzae. Defense against H. influenzae is dependent on specific antibodies and complement, which mediate serum bactericidal activity (SBA) and opsonization. Due to lack of normal classical and lectin complement pathway function in C2 deficiency (C2D), SBA would have to depend either on the alternative pathway or on C2 bypass mechanisms. Here we studied SBA against H. influenzae type b (Hib) before and after vaccination in a group of C2-deficient persons, as the bactericidal capacity of antibodies in autologous complement in relation to vaccination has not been investigated at group level in C2D.Sera from 22 persons with C2D and 26 healthy controls were available. Out of these, 18 persons with C2D and all controls had been vaccinated with Act-HIB®. SBA against Hib bacteria was analyzed with autologous serum as the only complement source. Antibodies to Hib capsular polysaccharide had been analyzed previously. Concentrations of mannose-binding lectin (MBL) and other complement components were measured in serum.SBA of both C2-deficient persons and controls was significantly more efficient after vaccination (p = 0.002 and p < 0.0001, respectively). After vaccination, all but two C2-deficient sera and one control serum showed sufficient SBA (<50% surviving bacteria). Before vaccination, SBA of C2-deficient sera was negatively correlated to serum concentrations of MBL (lower proportion of surviving bacteria with higher MBL concentration; r = ?0.55, p = 0.008). After vaccination, SBA of C2-deficient sera was negatively correlated to serum concentrations of IgG Hib antibodies (r = ?0.56, p = 0.01).In conclusion, SBA against Hib in autologous serum is increased after vaccination in persons with C2D. In unvaccinated C2-deficient persons SBA was correlated to MBL concentration, providing further support for an MBL-dependent C2 bypass mechanism operating in C2D.     

Immunogenicity and safety of fully liquid DTaP₅-IPV-Hib compared with DTaP₃-IPV/Hib when both coadministered with a heptavalent pneumococcal conjugate vaccine (PCV7) at 2, 3, 4, and 12 to 18 months of age: a phase III, single-blind, randomised, controlled, multicentre study

This study compared immunogenicity and safety of DTaP₅-IPV-Hib to DTaP₃-IPV/Hib coadministered with PCV7 at 2, 3, and 4 months (primary series) and a fourth-dose booster at 12-18 months of age. Seroprotection rates for DTaP₅-IPV-Hib were high (noninferior to DTaP₃-IPV/Hib for the primary series) for antigens common to both vaccines and PCV7 antigens. Geometric mean concentration (GMC) for Hib antibodies were higher in the DTaP₅-IPV-Hib group than the DTaP₃-IPV/Hib group after the primary series and booster dose; GMCs or titers for other antigens were generally similar between groups after the primary series and booster dose. Safety profiles were similar between groups.     

Immunogenicity and safety of four different doses of Haemophilus influenzae type b-tetanus toxoid conjugated vaccine, combined with diphtheria-tetanus-pertussis vaccine (DTP-Hib), in Indonesian infants

Widespread use of Haemophilus influenzae type b (Hib) conjugated vaccine in industrialized countries has resulted in a dramatic decline in the incidence of invasive Hib diseases, but the vaccine's cost has prevented its inclusion in basic immunization programs in developing countries. To overcome this problem, combination with diphtheria-tetanus-pertussis (DTP) vaccine or reduction in the dose of Hib vaccine has been proposed. To evaluate the immunogenicity and adverse reactions from lower doses of Hib-polyribosylphosphate (PRP) conjugated with tetanus toxoid (PRP-T), a double-blind study was conducted in Jakarta, Indonesia, and its suburbs. A total of 1048 infants 6 weeks to 6 months of age received three doses of DTP vaccine combined with the usual 10 microg dose or with a reduced dose of 5, 2.5 or 1.25 microg of PRP-T at two-monthly intervals. Antibodies were measured prior to the first dose and 4-6 weeks following the third dose. Adverse reactions were similar among all four groups. The only significant difference was a higher rate of irritability (p<0.02) and of temperature elevation >38 degrees C (p<0.009) after doses 1 and 2 in the lowest dose group (1.25 microg PRP-T) compared to the other groups. All participants tested had a 4-fold increase in antibodies against all DTP antigens. In addition, after a fourth booster dose of Hib, 99.6% of infants produced >or=0.15 microg/ml of antibody to Hib-PRP, and 96.4% showed levels >or=1.0 microg/ml after primary immunization, level that correlate with short- and long-term immunity, respectively. Antibody titers to the PRP antigen showed no significant differences among dosage groups with the exception of the 5.0 microg group, which had a significantly higher GMC than the 1.25 microg group (p<0.012). This study demonstrates that primary vaccination with half, one-fourth, or one-eighth of the usual dose of PRP-T, combined with DTP vaccine, produces protective immune responses, and has side effects that are comparable to DTP vaccination alone. In these lower dosages, PRP-T conjugate vaccine can lower vaccine costs to a level that is affordable for infant immunization programs in developing countries.     

Comparative effects of carrier proteins on vaccine-induced immune response

The efficacy of vaccines against major encapsulated bacterial pathogens - Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae type b (Hib) - has been significantly enhanced by conjugating the respective polysaccharides with different carrier proteins: diphtheria toxoid; non-toxic cross-reactive material of diphtheria toxin₁₉₇, tetanus toxoid, N. meningitidis outer membrane protein, and non-typeable H. influenzae-derived protein D. Hib, meningococcal, and pneumococcal conjugate vaccines have shown good safety and immunogenicity profiles regardless of the carrier protein used, although data are conflicting as to which carrier protein is the most immunogenic. Coadministration of conjugate vaccines bearing the same carrier protein has the potential for inducing either positive or negative effects on vaccine immunogenicity (immune interference). Clinical studies on the coadministration of conjugate vaccines reveal conflicting data with respect to immune interference and vaccine efficacy.     

Safety,tolerability and immunogenicity of intramuscular administration of PRP-CRM197 Hib vaccine to healthy Japanese children: An open-label trial

BackgroundJapan licensed the conjugate Haemophilus influenzae type b vaccine, Vaxem™ Hib, based on clinical studies using subcutaneous injection. The present study was performed to ensure this vaccine is suitable for intramuscular injection in Japanese children.MethodsThirty-one healthy 2–6-month-old infants received three doses of Vaxem™ Hib by intramuscular injection at 4-week intervals and a booster dose 1 year later, concomitant with routine infant (DTaP-IPV and pneumococcal) and toddler (measles–rubella) vaccines. Immunogenicity was assessed before and after the primary series and booster dose by enzyme-linked immunosorbent assay for anti-polyribosyl-ribitol-phosphate (PRP) antibodies. Safety was assessed by medical examination and diary cards completed by the subjects’ parents/legal guardians.ResultsThere were no vaccine-related serious adverse events or withdrawals; all children completed the study. Four weeks after the primary series, the geometric mean anti-PRP titer (GMT) was 19.68 μg/mL, and all children had seroprotective titers (≥0.15 μg/mL) that persisted until the booster dose. Proportions of titers indicative of long-term protection (≥1.0 μg/mL) were 100% after the primary series and 77.4% before the booster. Anamnestic responses to the booster had a GMT of 51.33 μg/mL, and 100% had titers ≥1.0 μg/mL. All but one subject reported injection site reactions as resolved within 3 days of vaccination; systemic reactions due to Hib and routine vaccines were also resolved within this period.ConclusionsVaxem™ Hib was generally well tolerated and immunogenic in Japanese children when administered by intramuscular injection in a three-dose primary series and as a booster with concomitant routine vaccines.Clinical trial registry: Registered on Clinical Trials.gov: NCT02074345.     

The impact of administration of conjugate vaccines containing cross reacting material on Haemophilus influenzae type b antibody responses in infants: A systematic review and meta-analysis of randomised controlled trials

BackgroundProtein-polysaccharide conjugate vaccines such as Haemophilus influenzae type b (Hib), meningococcal, and pneumococcal vaccine, induce immunological memory and longer lasting protection than plain polysaccharide vaccines. The most common proteins used as carriers are tetanus toxoid (TT) and cross reacting material-197 (CRM), a mutant form of diphtheria toxoid. CRM conjugate vaccines have been reported to suppress antibody responses to co-administered Hib-TT vaccine.MethodsWe conducted a systematic review and meta-analysis of randomised controlled trials in which infants were randomised to receive meningococcal or pneumococcal conjugate vaccines along with Hib-TT. Trials of licensed vaccines with different carrier proteins were included for group C meningococcal (MenC), quadrivalent ACWY meningococcal (MenACWY), and pneumococcal vaccines.ResultsTwenty-three trials were included in the meta-analyses. Overall, administration of MenC-CRM in a 2 or 3 dose schedule resulted in a 45% reduction in Hib antibody concentrations (GMR 0.55, 95% CI 0.49–0.62). MenACWY-CRM boosted Hib antibody responses by 22% (GMR 1.22, 95% CI 1.06–1.41) whilst pneumococcal CRM conjugate vaccines had no impact on Hib antibody responses (GMR 0.91, 95% CI 0.68–1.22).ConclusionsThe effect of CRM protein-polysaccharide conjugate vaccines on Hib antibody responses varies greatly between vaccines. Co-administration of a CRM conjugate vaccine can produce either positive or negative effects on Hib antibody responses. These inconsistencies suggest that CRM itself may not be the main driver of variability in Hib responses, and challenge current perspectives on this issue.     

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.     

Natural and vaccine-induced immunity against Haemophilus influenzae type b in patients with beta-thalassemia

Natural and vaccine-induced immunity and immunological memory to Haemophilus influenzae type b (Hib) were evaluated in adolescents and adults with beta-thalassemia. At baseline 10/23 (43%) unvaccinated patients had naturally acquired anticapsular antibodies >0.15 microg/ml, the threshold of protection, compared to 9/10 (90%) aged-matched controls. Hib-conjugate vaccine (PRP-T) induced protective immune responses in all subjects and there were no differences in geometric mean concentrations at 1 month (GMC) between patients and controls (69.04 versus 40.5, respectively). Vaccine-induced immunological memory was assessed in 12 subjects with beta-thalassemia who had been vaccinated against Hib in the past. All subjects had retained PRP>1 microg/ml at baseline; PRP-T revaccination induced anamnestic responses which were similar, in terms of post vaccination antibody concentration (P=0.54) and avidity (P=0.08), with primary responses given by previously unvaccinated patients. A single dose of PRP-T induces adequate and long-lasting immunity and should be given in all unvaccinated adolescents and adults with beta-thalassemia.     

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).     

Infant antibody levels following 10-valent pneumococcal-protein D conjugate and DTaP-Hib vaccinations in the first year of life after maternal Tdap vaccination: An open-label,parallel, randomised controlled trial

BackgroundMaternal antibody levels after Tdap vaccination during pregnancy may affect infant primary antibody responses to pertussis, Tetanus toxoid (TT), Diphtheria toxoid (DT) vaccinations and pneumococcal vaccines with diphtheria toxin mutants like CRM197 as carrier protein.MethodsMothers were recruited in an open label randomised parallel controlled trial in 2014–2016 through midwifes. They received Tdap [Boostrix] at 30–32 weeks of pregnancy (n = 58) or within 48 h after delivery (n = 60). Infants received DTaP-IPV-Hib-HepB [Infanrix Hexa] and 10-valent protein D conjugated pneumococcal conjugate vaccine (PHiD-CV10 [Synflorix]) at age 3, 5 and 11 months. We now report on infant specific IgG levels towards DT, TT, Haemophilus influenzae type b polyribosylribitol phosphate (Hib PRP) and PHiD-CV10 before and after primary- and booster vaccination as secondary study endpoints; pertussis antibodies were the primary endpoint of the study. This trial is registered in clinicaltrialsregister.eu (EudraCT 2012–004006-9) and trialregister.nl (NTR number NTR4314).FindingsPost primary vaccinations, antibody levels to DT, but not TT, were significantly lower after Tdap vaccination during pregnancy compared to controls (GMC ratio 0.4, 95% CI 0.3–0.6 and 0.9, 95% CI 0.6–1.2, respectively). Antibodies to serotype 19F were significantly lower in the maternal Tdap group, whereas there were no differences in antibody levels to Hib PRP and the other 9 pneumococcal serotypes. Post booster vaccinations, no significant differences were observed, except for DT.InterpretationMaternal Tdap vaccination results in significant interference with infants responses not only to DT but also to conjugated pneumococcal vaccines containing DT mutants as carrier proteins. These interactions after maternal Tdap vaccination need to be taken into account when designing infants’ national immunization schedules and choice of vaccines.FundingThe Dutch Ministry of Health, Welfare and Sport.     

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.     

Haemophilus influenzae type b carriage in Indigenous children and children attending childcare centers in the Northern Territory, Australia, spanning pre- and post-vaccine eras

This paper investigates Haemophilus influenzae type b (Hib) carriage in Indigenous children and children attending childcare centres in the Northern Territory of Australia, 1992-2005. More than 10 years after the introduction of the Hib conjugate vaccine, Hib carriage persists in Indigenous children (3.4%, 2003-2005) and children attending childcare centres (0.2%, 2004). This is the first Australian study to examine Hib carriage spanning the pre- and post-vaccination eras. Increasing carriage rates contribute to Hib disease resurgence especially in those with higher disease burdens, such as remote Indigenous Australians, ongoing carriage surveillance provides a sentinel warning system for invasive disease.

Background

Following the introduction of H. influenzae type b (Hib) conjugate vaccine to Australia in 1993 as a three dose (2, 4, 12 month) schedule, the incidence of Hib disease decreased dramatically in children, especially in those aged under 5 years. We investigate Hib carriage in Indigenous children and children attending childcare centres from the Northern Territory (NT) of Australia between 1992 and 2005. We report Hib carriage rates in this well vaccinated population, with previously documented high rates of invasive disease.

Methods

Hib carriage was reviewed in nasopharyngeal or nasal swabs collected between 1992 and 2005; from over 2000 children (61% Indigenous) aged 0-6 years enrolled in 7 otitis media or carriage surveillance studies in the NT.

Results

More than 10 years after the introduction of the Hib conjugate vaccine, Hib carriage persists at low levels, but at a higher rate in Indigenous children (3.4%, 2003-2005) than children attending childcare centres (0.2%, 2004), in the NT of Australia.

Conclusions

This is the first Australian study to examine Hib carriage spanning the pre- and post-vaccination eras. Ongoing carriage surveillance provides a sentinel warning system for invasive disease. This notifies public health professionals of potential invasive disease, creating early warning systems for intervention if Australian Indigenous children or children attending childcare centres are to follow current international trends associated with high rates of carriage preceding invasive disease—despite high vaccination rates. Internationally there is growing concern that increasing carriage rates are the driving force behind Hib disease resurgence especially in those with higher disease burdens, such as remote Indigenous Australians. Changes to the vaccination schedule from PRP-OMPC (PedvaxHIB^®), to PRP-T (2, 4, 6, 12 months) from January 2010—may affect carriage and in time, invasive disease rates. This work is important for national and International comparisons as well as feeding back information to vaccine policy makers of the Hib carriage environment throughout this period.     

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 hexavalent diphtheria–tetanus–acellular pertussis–inactivated poliovirus–Haemophilus influenzae b conjugate–hepatitis B vaccine at 2, 3, 4, and 12–14 months of age

Combination vaccines improve parental and provider satisfaction and schedule compliance by decreasing the number of injections. In a Phase 2, randomized, double-blind, multicenter study, we compared four formulations of a liquid, hexavalent diphtheria–tetanus–acellular pertussis–inactivated poliovirus–Haemophilus influenzae b conjugate–hepatitis B virus (DTaP–IPV–Hib–HBV) vaccine in 708 infants immunized at 2, 3, 4, and 12–14 months of age. The formulations contained identical DTaP and IPV components, differing in the contents of Hib polyribosylribitol phosphate (PRP) conjugate component (tetanus-toxoid [PRP-T, 12 μg] or Neisseria meningitidis outer-membrane-protein-complex [PRP-OMPC, 3 μg or 6 μg]), and in hepatitis B surface antigen (HBsAg, 10 μg or 15 μg). A minimum acceptable postdose 3 antibody response rate was defined by the lower limit of the 95% confidence interval exceeding a prespecified target. Rates of adverse events (AEs) were similar among groups, with a trend for increased solicited injection-site reactions (pain, redness, swelling) with increasing PRP-OMPC and HBsAg concentration. Serious AEs reported by eight subjects were not considered to be vaccine related. All PRP-OMPC formulations met prespecified acceptability criteria for postdose 3 immunogenicity for all antigens: PRP, HBsAg, pertussis, diphtheria, tetanus and polio. Apart from the Hib response, the postdose 3 responses obtained with the PRP-T formulation met the acceptability criterion for each antigen. Postdose 4 responses were acceptable for all antigens in all formulations. All vaccine formulations were well tolerated. The three PRP-OMPC formulations met prespecified immunogenicity criteria, and the one with the lowest PRP-OMPC concentration was selected for further optimization of immunogenicity.     

Immunogenicity and safety of a pentavalent acellular pertussis combined vaccine including diphtheria, tetanus, inactivated poliovirus and conjugated Haemophilus Influenzae type b polysaccharide for primary vaccination at 2, 3, 4 or 3, 4, 5 months of age in infants in China

The aim was to demonstrate the immunogenicity and safety of a DTaP-IPV//PRP-T combined vaccine (Pentaxim^®) compared to individual vaccines in infants in the People's Republic of China. Infants (N = 792) were randomly assigned to receive DTaP-IPV//PRP-T at 2, 3 and 4 months of age (Group A) or 3, 4 and 5 months of age (Group B), or DTaP (Wuhan Institute of Biological Products), PRP-T (Act-Hib^®) and IPV (Imovax^® Polio) at 3, 4 and 5 months of age (Group C). Antibody titers were measured pre- and 1 month after the third vaccination; non-inferiority analyses were performed for seroprotection/seroconversion (SP/SC) rates. Safety was assessed 1 month after the primary series. SP/SC rates for the DTaP-IPV//PRP-T vaccine were high and non-inferior to the controls. Reactogenicity was low for each group and no hypotonic hyporesponsive episode or seizure was reported. In conclusion, the DTaP-IPV//PRP-T vaccine was highly immunogenic, non-inferior to the commercially available control vaccines and had a good safety profile for both primary administration schedules.     

Immunogenicity and safety of 7-valent pneumococcal conjugate vaccine (PCV7) in children aged 2–5 years in China

BackgroundThe widespread use of pneumococcal conjugate vaccines (PCVs) has significantly decreased pneumococcal disease worldwide. However, China has not adopted PCVs in their national immunization schedules and had only approved these vaccines for children aged 2–15 months by 2020.MethodsIn an open-label trial, enrolled healthy children aged 2–5 years old were randomized 1:1 and divided into a 7-valent pneumococcal conjugate vaccine (PCV7) group and a Haemophilus influenzae type b conjugate vaccine (Hib) group. Children in the PCV7 group received a single dose of PCV7, and the Hib group received a single dose of Hib vaccine. Blood samples were collected before and 6 months after vaccination. Immunogenicity and safety of PCV7 were assessed at prespecified time points.ResultsSix months after a single dose of PCV7, children in the PCV7 group for all 7 serotypes, IgG mean concentrations (GMCs) and opsonophagocytic geometric mean titres (GMTs) were significantly higher (P < .001) than at baseline, and the proportion of IgG ≥ 0.35 µg/mL ranged from 90.0% to 100%. Although the antibody level increased with age, preexisting antibodies did not induce hyporesponsiveness to PCV7. In the Hib group, the antibody levels were not significantly different or had changed slightly at 6 months. PCV7 was well tolerated in all age groups, and no serious adverse events (AEs) emerged during this study.ConclusionsA single dose of PCV7 was immunogenic and safe for Chinese children aged 2–5 years, and the preexisting antibodies against the PCV7 serotypes did not change the response to vaccination. The findings supported the effectiveness of PCV7 in this age group. PCVs with broader serotype coverage are expected to expand pneumococcal disease protection.