Long-term persistence of protective antibodies in Dutch adolescents following a meningococcal serogroup C tetanus booster vaccination

IntroductionDue to waning immunity, infant vaccination with meningococcal serogroup C conjugated (MenCC) vaccines is insufficient to maintain long-term individual protection. Adolescent booster vaccination is thought to offer direct protection against invasive meningococcal disease (IMD) but also to reduce meningococcal carriage and transmission and in this way establish herd protection in the population. Previously, we studied antibody levels after adolescent MenCC booster vaccination. In the present study, the adolescent vaccinees were revisited after three years to determine antibody persistence and to predict long-term protection.MethodsMeningococcal serogroup C tetanus toxoid conjugated (MenC-TT) vaccine was administered to 10-, 12- and 15-year old participants who had been primed nine years earlier with a single dose of MenC-TT vaccine. Blood samples were collected before, 1 month, 1 year and 3 years after the adolescent booster vaccination. Functional antibody levels were measured with serum bactericidal assay using rabbit complement (rSBA). Meningococcal serogroup C polysaccharide and tetanus toxoid specific antibody levels were measured using fluorescent-bead-based multiplex immunoassay. Long-term protection was estimated using longitudinal multilevel antibody decay modeling.ResultsOf the original 268 participants, 201 (75%) were revisited after 3 years. All participants still had an rSBA titer above the protective threshold of ⩾8 and 98% ⩾128. The 15-year-olds showed the highest antibody titers. Using a bi-exponential decay model, the median time to fall below the protection threshold (rSBA titer <8) was 16.3 years, 45.9 years and around 270 years following the booster for the 10-, 12- and 15-year-olds, respectively.ConclusionsAfter a first steep decline in antibody levels in the first year after the booster, antibody levels slowly declined between one and three years post-booster. A routine MenC-TT booster vaccination for adolescents in the Netherlands will likely provide long-term individual protection and potentially reduce the risk of resurgence of MenC disease in the general population.     

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

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

Seroprevalence of antibodies against serogroup C meningococci in the region of Valencia,Spain: Impact of meningococcal C conjugate vaccination

Background and aimsMeningococcal C conjugate (MCC) vaccination programs provide direct and indirect protection against meningococcal disease. However, a decrease in the antibodies could affect herd immunity. We conducted a seroprevalence study to assess the immunity in subjects 8–12 years after different MCCV vaccination programs were launched and evaluated the impact of vaccination on seroprotection.MethodsSeroepidemiological study conducted from October 2010 to April 2012 in the region of Valencia, Spain. Sample size was not proportional to the population but to the expected seroprotection by age group. Sera from subjects that were ≥ 3 years old were tested using a standardized complement-mediated serum bactericidal antibodies (SBA) assay. Age-stratified proportions of subjects with SBA titers ≥ 8 were considered seroprotected and evaluated. A multivariate logistic regression model was performed to evaluate the impact of vaccination on the seroprotection.ResultsSerum samples from 1880 subjects were collected. In total, 523 (27.8%) of the 1880 subjects and 446 (31.2%) of the 1430 subjects < 30 years (targeted to any vaccination campaign) showed protective SBA titers. The highest percentage of seroprotected subjects (67.8%, 95%CI 56.9–77.4) was observed in those that were vaccinated in a catch-up campaign at 10–13 years of age (20–21 years old at the time of blood sampling). Those scheduled for immunization in infancy at 2, 4 and 6 months of age (7–8 years at blood sample) represented the lowest (7.1%, 95% CI 3.3–13.1) number of seroprotected subjects. Having received one vaccine dose after 12 months of age was associated with increased seroprotection. The present study revealed a positive correlation between the increasing age at vaccination and longer duration of seroprotection.ConclusionOnly one in three subjects who were vaccinated with MCC vaccine was seroprotected after 8–12 years. These findings emphasize that seroprevalence studies are essential to identify susceptible cohorts and to inform vaccine policy.     

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.     

Adolescent meningococcal serogroup A,W and Y immune responses following immunization with quadrivalent meningococcal A,C, W and Y conjugate vaccine: Optimal age for vaccination

BackgroundRecently the incidence of meningococcal serogroup Y (MenY) and in particular serogroup W (MenW) invasive disease has risen in several European countries, including the Netherlands. Adolescents are a target group for primary prevention through vaccination to protect against disease and reduce carriage and induce herd protection in the population. The present study assessed MenA, MenW and MenY antibody levels in adolescents up to one year following primary vaccination with quadrivalent MenACWY-PS conjugated to tetanus toxoid (MenACWY-TT).MethodsIn this phase IV, open-label study, healthy 10-, 12- and 15-year-olds received the MenACWY-TT vaccine. Blood samples were collected before, 1 month and 1 year after the vaccination. Functional antibody levels against MenA, MenW and MenY were measured with serum bactericidal assay using baby rabbit complement (rSBA). MenA-, MenW-, and MenY-PS specific IgG, IgG1 and IgG2 levels were measured using fluorescent-bead-based multiplex immunoassay.ResultsThe quadrivalent MenACWY-TT vaccine elicited robust antibody responses against MenA, MenW and MenY, and the majority (94%) of the participants maintained rSBA titers ≥128 one year after the vaccination against all three serogroups. After one year, higher MenW rSBA GMTs were observed in the 12- and 15-year-olds compared to the 10-year-olds, while rSBA GMTs against MenA and MenY were similar between age groups. Furthermore, those participant who showed SBA titer ≥8 at baseline, also had higher antibody levels one year after vaccination as compared to participants with rSBA titer <8 at baseline.ConclusionThe MenACWY-TT vaccine induces robust protective primary immune responses up to one year after vaccination. Our results suggest that persistence of individual protection increases with the age at which a primary quadrivalent MenACWY-TT vaccination is administered. Our results indicate that 12 or 15 years seems a more optimal age for a primary quadrivalent MenACWY-TT vaccination to protect against the rapid increase of MenW disease.     

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.     

Meningococcal C conjugate age-dependant long-term loss of effectiveness

IntroductionAlthough different epidemiological studies have assessed meningococcal C conjugate vaccine effectiveness within 1 and >1 year since vaccination, none of them evaluated long-term effectiveness. In order to assess if epidemiological data correlates with the findings described in seroprevalence studies we evaluated long-term vaccine effectiveness over time, up to 10 years since vaccination.MethodsCases targeted by vaccination programs and notified to the Spanish Surveillance System between 2001 and 2013 were included in the study. Vaccine effectiveness was estimated using the screening method. Relationship between vaccine effectiveness and time since vaccination was explored using point estimates, simple logistic regression or restricted cubic splines logistic regression model for all and for those vaccinated at <1, 1–11 and at 12–19 years of age.ResultsFrom 345 confirmed cases reported in the period and targeted by vaccination programs, 125 (36.23%) were vaccine failures. Proportion of vaccine failures decreased with age of vaccination: 63.97% at <1 year; 36.84% at 1–11 years; and 3.88% at 12–19 years. Using the best model for each group, vaccine effectiveness decreased from 99.12% to 90.85% (%change = −8.3%) for all; from 99.04% to 48.60% (%change = −50.9%) for those vaccinated at <1 years and from 99.45% to 90.18% (%change = −9.3%) for those vaccinated at 1–11 years after 10 years since vaccination. For those vaccinated at 12–19 years no changes were observed in vaccine effectiveness after 10 years (p = 0.968).ConclusionsAfter 10 years, vaccine effectiveness decreased by 50% in those vaccinated at <1 year, while those vaccinated with one dose at 12–19 years showed no changes. Vaccine failures occurred early after vaccination and more frequently in those vaccinated at younger ages. Vaccination at ≥12 years seems to be related to a low number of vaccine failures and a higher and endurable protection over time.     

Salivary antibody levels in adolescents in response to a meningococcal serogroup C conjugate booster vaccination nine years after priming: systemically induced local immunity and saliva as potential surveillance tool

BackgroundIn several countries large-scale immunization of children and young adults with Meningococcal serogroup C (MenC) conjugate vaccines has induced long-standing herd protection. Salivary antibodies may play an important role in mucosal protection against meningococcal acquisition and carriage.AimTo investigate antibody levels in (pre)adolescents primed 9 years earlier with a single dose of MenC-polysaccharide tetanus toxoid conjugated (MenC-TT) vaccine and the response to a booster vaccination, with special focus on age-related differences and the relation between salivary and serum antibody levels.MethodsNine years after priming, healthy 10- (n = 91), 12- (n = 91) and 15-year-olds (n = 86) received a MenC-TT booster vaccination. Saliva and serum samples were collected prior to and 1 month and 1 year after vaccination. MenC-polysaccharide(MenC-PS)-specific antibody levels were measured using a fluorescent-bead-based multiplex immunoassay.ResultsBefore the booster, MenC-PS-specific IgG and IgA levels in saliva and serum were low and correlated with age at priming. The booster induced a marked increase in salivary MenC-PS-specific IgG (>200-fold), but also in IgA (∼10-fold). One year after the booster, salivary IgG and IgA had remained above pre-booster levels in all age groups (∼20-fold and ∼3-fold, respectively), with persistence of highest levels in the 15-year-olds. MenC-PS-specific IgG and IgA levels in saliva strongly correlated with the levels in serum.ConclusionParenteral MenC-TT booster vaccination induces a clear increase in salivary MenC-PS-specific IgG and IgA levels and persistence of highest levels correlates with age. The strong correlation between serum and salivary antibody levels indicate that saliva may offer an easy and reliable tool for future antibody surveillance.     

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 a booster dose of meningococcal (groups A,C, W,and Y) polysaccharide diphtheria toxoid conjugate vaccine

BackgroundQuadrivalent meningococcal conjugate vaccines (MenACWY) were developed to offer long-term protection against invasive disease caused by serogroups A, C, W, and Y. Reduced MenACWY effectiveness within 5 years after primary vaccination (likely due to declining bactericidal antibody titers) has been described, particularly with respect to C and Y disease in the United States. We evaluated the safety and immunogenicity of a single booster dose of quadrivalent meningococcal polysaccharide diphtheria toxoid conjugate vaccine (MenACWY-D) in adolescents and adults who received a previous dose 4–6 years earlier.MethodsThis phase 2, open-label, multicenter study of 834 persons was conducted in the United States. Participants received a single 0.5-mL booster dose of MenACWY-D. Serogroup-specific bactericidal antibody geometric mean titers (GMTs) were measured with a serum bactericidal antibody assay using human complement (hSBA). Proportions of participants achieving antibody titers of ⩾1:8 for each vaccine serogroup on Days 6 and 28 were determined. Rates of adverse events (AEs), including serious adverse events (SAEs), were also assessed.ResultsBefore booster vaccination, 38.7–68.5% of participants had an hSBA titer ⩾1:8, depending on vaccine serogroup. By Day 6 post-vaccination, 98.2–99.1% of participants had hSBA titers ⩾1:8. By Day 28, >99% of participants achieved this threshold and the primary hypothesis (lower limit of the one-sided 95% confidence limit ⩾85% for each serogroup) was met. The GMT ratios (post-vaccination divided by pre-vaccination) at Day 28 ranged from 47.2 (serogroup A) to 209.1 (serogroup Y). Rates of AEs, including SAEs, were similar to those observed among adolescents and adults who received a primary dose of MenACWY-D in previous studies. There were no study discontinuations due to an AE and no deaths.ConclusionsBooster vaccination with MenACWY-D was safe and induced robust bactericidal antibody responses, consistent with immune memory, among adolescents and adults 4–6 years after primary vaccination.ClinicalTrials.gov registration: NCT01442675.     

Long-term follow-up of Japanese encephalitis chimeric virus vaccine: Immune responses in children

BackgroundA single dose of live attenuated Japanese encephalitis chimeric virus vaccine (JE-CV) was shown to be immunogenic and well tolerated when given either as a booster to formalin-inactivated Japanese encephalitis (JE)-vaccine (mouse brain-derived vaccine [MBDV])-primed 2–5-year-olds, or as a primary vaccination to JE-vaccine-naïve 12–24-month-old toddlers in Thailand. A 5-year follow-up assessment of immune response persistence over time was conducted.MethodsFour additional visits (at 2, 3, 4, and 5 years) for immunologic assessments were added to the original 12-month open-label crossover study, in which 100 healthy children aged 2–5 years with a history of two-dose primary vaccination with MBDV (according to the Thai Expanded Program for Immunization schedule), and 200 healthy JE-vaccine-naïve 12–24-month-old toddlers, were randomized 1:1 to receive JE-CV, containing ⩾4 log₁₀ plaque forming units, 1 month before or after hepatitis A control vaccine.ResultsIn MBDV-primed 2–5-year-olds (n = 78), the immune response to the JE-CV vaccine persisted up to at least 5 years after vaccination with a single dose of JE-CV, with all (n = 78) children seroprotected at the year 5 visit (geometric mean titers [GMT]: 252 1/dil). There was no decrease of seroprotection rate over time (100% at 6 months post-vaccination and 96.8% (90.3–98.9) at 5 years post-vaccination). In JE-vaccine-naïve toddlers, a protective immune response persisted up to at least 5 years in 58.8% (50.9–66.4) after a single-dose administration of JE-CV (GMT 26.7 1/dil; sensitivity analysis).ConclusionsA single-dose of JE-CV as a booster following MBDV administration provided long-lasting immunity. In JE-vaccine-naïve toddlers, despite relatively high seroprotection rates persisting over time, a subsequent booster dose is recommended following a JE-CV primary vaccination for long-term protection.This study was registered on www.clinicaltrials.gov (NCT00621764).     

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     

Hepatitis B vaccine and the need for a booster dose after primary vaccination

ObjectivesProtective antibodies levels, induced by Hepatitis B virus (HBV) vaccine, persist for long-term after primary immunization, but there is evidence that, as the time since vaccination increases, there is a reduced ability to maintain immune memory. The study aim was to determine the prevalence and the duration of persistence of an anti-HBs titer with ≥10 mIU/mL and eventual predictors of reduced seroprotection.MethodsThe study was conducted among students attending medical and healthcare professions schools from January 2014 to June 2016. Data were collected through the review of medical records completed during the medical surveillance visit. All subjects had received HBV vaccine according to the Italian Ministry of Health indications.ResultsThe results are reported for 722 subjects. Positive anti-HBs titer was found in 72.6% (95% CI = 69–76). The mean age of the subjects was 25.5 years. Subjects vaccinated during adolescence and students that had received an adult vaccine dose were significantly more likely to be seroprotected. The longer the time interval since vaccination the lower the probability of being seroprotected; however if the role of time since vaccination was considered after stratification by vaccine dose, a statistically significant association with a lower percentage of seroprotected remains only in the subgroup of subjects who received the pediatric dose. The findings of the multivariate regression analysis partially confirmed those of the univariate analysis.ConclusionsIn conclusion, our findings show that over 25% of HBV vaccine recipients had an antiHBs titer <10 mIU/ml after 18 years of more from the primary vaccination. Furthermore, in the case a booster dose would be needed, our results suggest that the vaccination strategy should prefer administration of a vaccine adult dose during early adolescence, since it might offer longer-term protection through adulthood.     

Effectiveness of different vaccine schedules for heptavalent and 13-valent conjugate vaccines against pneumococcal disease in the Community of Madrid

IntroductionThe heptavalent pneumococcal conjugate vaccine (PCV-7) was added to the childhood routine vaccination program in the Community of Madrid in November of 2006 with 3 + 1 recommended doses and a catch-up for those under 2 years old. In June 2010, PCV-7 was replaced by 13-valent vaccine (PCV-13) with 2 + 1 recommended doses. In July of 2012, the PCV-13 was removed from the funded program and reintroduced again (2 + 1 recommended doses) in December 2014. In between, children were vaccinated privately with 3 + 1 recommended doses of PCV-13. The aim of this study was to evaluate the effectiveness of each vaccination schedule used in the Community of Madrid.MethodsWe included all cases of invasive pneumococcal disease (IPD) reported between 2007 and 2015 to the Notifiable Diseases Surveillance System. Vaccination information was obtained from the Immunization Registry. Vaccine effectiveness (VE) was estimated using the indirect cohort design for cases with serotype information.ResultsA total 779 cases were included in the study. Among them 47.6% of the cases were primo-vaccinated with booster, 20% primo-vaccinated, 15.9% incompletely primo-vaccinated and 16.5% not vaccinated. The VE for ≥1 doses of any PCV was 82% (CI 95%: 67.8–89.9%): 91.9% (CI 95%: 76.5–97.2%) for PCV-7 and 77.2% (48.6–89.9%) for PCV-13. VE in those receiving the full 2 + 1 or 3 + 1 schedules was 100% for both vaccines.ConclusionsA high number of vaccine failures were reported in children before they had the opportunity to receive the booster dose, especially due to PCV-13-non-PCV-7 serotypes. VE was higher for PCV-7 compared to PCV-13, except for those that received the complete schedule with booster that achieved 100% of VE, which shows the relevance of the vaccines and complying with all doses scheduled.     

Immunogenicity of live attenuated Japanese encephalitis SA 14-14-2 vaccine among Sri Lankan children with previous receipt of inactivated JE vaccine

BackgroundThe performance of live attenuated Japanese Encephalitis SA 14-14-2 vaccine (CD-JEV) among children previously given inactivated mouse brain-derived JE vaccine (IMBV) is unknown. We evaluated the safety and immunogenicity of CD-JEV administered to 2- and 5-year-old children in Sri Lanka.MethodsIn this open-label, single arm trial in the Colombo District of Sri Lanka, generally healthy children 2 and 5 years of age who had previously received two and three doses of IMBV, respectively, were administered one dose of CD-JEV subcutaneously. Participants were monitored for adverse events for one year post-vaccination. Serum neutralizing antibody responses were evaluated pre and 28 and 365 days post-vaccination using JE plaque reduction neutralization test and characterized as the proportion of participants seroconverting. Seroconversion was defined as either reaching a titer considered seroprotective (⩾1:10) among participants with a baseline titer <1:10 or achieving at least a 4-fold rise in titer among participants with a baseline titer ⩾1:10.ResultsOf 305 children given CD-JEV, 294 were included in the primary analysis of immunogenicity. Prior to vaccination, 144/147 (98.0%) 2-year-olds and 146/147 (99.3%) 5-year-olds had seroprotective levels. 28 days post-vaccination, 79/147 [53.7% (95% CI, 45.3–62.0)] 2-year olds and of 60/147 [40.8% (95% CI, 32.8–49.2)] 5-year olds achieved seroconversion. Among 2-year-olds, geometric mean titers (GMTs) rose from 697 to 3175 28 days post-vaccination. Among 5-year-olds, GMTs rose from 926 to 2776. Most adverse reactions were mild, and no serious adverse events were related to study vaccination.ConclusionAdministration of CD-JEV to these children with pre-existing neutralizing JE antibody titers was safe and resulted in substantial boosting of antibody levels. These results may inform other countries in Asia considering switching from IMBV to now WHO-prequalified CD-JEV vaccine to combat this disease of public health importance.     

Persistence of bactericidal antibodies following booster vaccination with 4CMenB at 12, 18 or 24 months and immunogenicity of a fifth dose administered at 4 years of age-a phase 3 extension to a randomised controlled trial

Background4CMenB is immunogenic in infants and toddlers. We assessed persistence of human complement serum bactericidal activity (hSBA) following a fourth dose administered at 12, 18 or 24 months and characterised the antibody response to a fifth dose administered at 4 years of age.MethodsA phase 3, open label, multi-centre extension to a randomised controlled trial (ClinicalTrials.gov identifier NCT01717638) conducted in four countries (number of centres): Czech Republic (nineteen), Italy (four), Spain (four) and the United Kingdom (four). Four-year-old children who were either 4CMenB-naïve or had previously received a variety of 3-dose infant priming schedules and a booster vaccine as toddlers (follow-on group) were recruited. Venous blood samples were obtained to determine hSBA against four reference strains; acting as targets to assess immunity to each of the vaccine antigens, NadA (5/99), fHbp (H44/76), PorA (NZ98/254), and NHBA (M10713) at baseline (prior to vaccination, all participants) and one month following a dose of 4CMenB for all vaccine-naïve and follow-on participants primed with the 2, 3, 4 schedule, and a third of follow-on participants primed with a 2, 4, 6 month schedule.ResultsAt baseline (prior to vaccination), the proportion of participants (n = 468) with hSBA titers ⩾ 5 was similar across all followon groups: 89–100% against 5/99; 12–35% for H44/76; 8–12% for NZ98/254 and 53–80% for M10713 compared with 5%, 0%, 0%; and 60% respectively, for the vaccine-naïve controls (n = 206). Following a dose of 4CMenB at 4 years of age, this increased to 100% (5/99), 97–100% (H44/76), 80–95 % (NZ98/254) and 84–100% (M10713) (n = 210), compared with 89%, 70%, 24%, and 76% respectively for vaccine-naïve controls (n = 192).ConclusionWaning of protective antibodies occurred 12–36 months after toddler booster regardless of age at boost. This was least marked against target strains 5/99 and M10713. A robust memory response occurred after a booster dose given at 4 years of age.     

Trends in compliance with two-dose influenza vaccine recommendations in children aged 6 months through 8 years, 2010–2015

BackgroundChildren aged 6 months through 8 years may require two doses of influenza vaccine for adequate immune response against the disease. However, poor two-dose compliance has been reported in the literature.MethodsWe analyzed data for >2.6 million children from six immunization information system (IIS) sentinel sites, and assessed full vaccination coverage and two-dose compliance in the 2010–2015 influenza vaccination seasons. Full vaccination was defined as having received at least the recommended number of influenza vaccine doses (one or two), based on recommendations from the Advisory Committee on Immunization Practices. Two-dose compliance was defined as the percentage of children during each season who received at least two doses of influenza vaccine among those who required two doses and initiated the series.ResultsAcross seasons, ⩾1-dose influenza vaccination coverage was mainly unchanged among 6–23 month olds (range: 60.9–66.6%), 2–4 year olds (range: 44.8–47.4%), and 5–8 year olds (range: 34.5–38.9%). However, full vaccination coverage showed increasing trends from 2010–11 season to 2014–15 season (6–23 months: 43.0–46.5%; 2–4 year olds: 26.3–39.7%; 5–8 year olds, 18.5–33.9%). Across seasons, two-dose compliance remained modest in children 6–23 months (range: 63.3–67.6%) and very low in older children (range: 11.6–18.7% in children 2–4 years and 6.8–13.3% in children 5–8 years). In the 2014–15 season, among children who required and received 2 doses, only half completed the two-dose series before influenza activity peaked.ConclusionsImproved messaging of the two-dose influenza vaccine recommendations is needed for providers and parents. Providers are encouraged to determine a child’s eligibility for two doses of influenza vaccine using the child’s vaccination history, and to vaccinate children early in the season so that two-dose series are completed before influenza peaks.     

Decennial administration in young adults of a reduced-antigen content diphtheria,tetanus, acellular pertussis vaccine containing two different concentrations of aluminium

BackgroundRegular booster vaccination might be necessary throughout life to protect against pertussis infection. Nevertheless the duration of protection after booster vaccination remains unclear. In this study, antibody persistence up to 10 years after previous vaccination of adolescents (N = 478) with combined reduced-antigen-content diphtheria-tetanus-acellular pertussis vaccine (dTpa, Boostrix™, GlaxoSmithKline Belgium) containing 0.5 mg, 0.3 mg or 0.133 mg of aluminium was assessed. The immunogenicity, reactogenicity and safety of a decennial booster dTpa dose were also investigated.MethodsYoung adults vaccinated as adolescents in the initial booster study were invited to participate in an assessment of antibody persistence at years 8.5 and 10, and to receive a dTpa booster dose at year 10 with immunogenicity assessment one month later. Those who originally received the 0.5 mg or 0.3 mg formulations received the same vaccine at year 10. Those in the 0.133 mg group received the 0.5 mg formulation. Reactogenicity and safety endpoints were captured until 30 days after booster vaccination.ResultsPrior to the decennial booster at year 8.5 and year 10, all participants had seroprotective antibodies for diphtheria (ELISA or neutralisation assay) and tetanus. At least 77.8% were seropositive for anti-pertussis toxin (PT) antibodies at year 8.5 and 82.8% at year 10. All participants were seropositive for antibodies for filamentous haemagglutinin and pertactin at both time points. The decennial booster dose induced robust increases in antibody GMCs to all antigens. The post-booster anti-PT geometric mean concentration was 82.5 EL.U/ml (95%CI 67.0–101.6) and 124.0 (103.5–148.5) in the 0.3 mg and 0.5 mg groups, respectively. The reactogenicity and safety profile of the decennial booster dose was consistent with the known safety profile of dTpa. No serious adverse events were reported.ConclusionsDecennial booster vaccination with either of the two licensed formulations of dTpa was highly immunogenic and well tolerated in young adults. Either formulation could be confidently used as a decennial booster.This study is registered at www.clinicaltrials.gov NCT01147900     

The predicted persistence and kinetics of antibody decline 9 years after pre-school booster vaccination in UK children

BackgroundLong term follow-up of vaccine trials is essential to establish the duration of protection. In the context of worldwide concern about rising pertussis incidence, estimates of antibody persistence after vaccination, which do not account for the rise in antibody due to natural boosting or infection, may overestimate the degree of protection afforded by pertussis vaccines.MethodsThis was a 5 year follow up study of a randomised controlled trial of diphtheria, tetanus, pertussis and polio booster vaccines in UK children aged 3.5–5 years. Antibody persistence was measured at 1 month, 1, 3, and 5 years after vaccination and the kinetics of antibody decline were modelled longitudinally. Estimates of predicted antibody persistence 9 years after the pre-school booster were derived from model parameters.ResultsAntibody levels 9 years after vaccination were predicted to be above accepted thresholds for protection for diphtheria, tetanus and polio. Antibody responses to pertussis toxoid were undetectable in 49% of children at the 5 year follow up visit, and responses were predicted to be undetectable in 69% (95% CI 45–88%) of children by the time of their teenage booster at 13–14 years of age.ConclusionsThere is no defined correlate of protection for pertussis. However, the large proportion of participants in this study with undetectable pertussis antibody levels at both measured and predicted timepoints suggests sub-optimal immunity in adolescence. Adding pertussis to the teenage booster for UK children as is done in other countries, would enhance immunity in adolescence.