Sex-Related Differences in the Immune Response to Meningococcal Vaccinations During Adolescence.

Background: Immune responses to pediatric vaccinations have been reported to differ according to sex. Such sex-differential responses may become more pronounced during adolescence due to hormonal differences. We investigated whether the vaccine response following primary vaccination against meningococcal serogroup A (MenA), MenW and MenY and booster vaccination against MenC differed between girls and boys using data from two clinical studies. Methods: Children aged 10, 12, and 15 years, who had been primed with MenC vaccination between 14 months and 6 years of age, received a booster MenC vaccination or MenACWY vaccination. Polysaccharide-specific IgG concentrations and functional antibody titers [determined with the serum bactericidal antibody (SBA) assay] were measured at baseline, 1 month, 1 year, and 3 years (only MenC group) after vaccination. We calculated geometric mean concentrations and titers (GMC and GMT) ratios for girls vs. boys adjusted for age group. Additionally, we compared the proportion protected individuals between girls and boys at all timepoints. Results: This study included 342 girls and 327 boys from two clinical trials. While MenAWY antibody levels did not differ consistently 1 month after vaccination, all GMC- and GMT-ratios were in favor of girls 1 year after vaccination [range: 1.31 (1.02-1.70) for MenA IgG to 1.54 (1.10-2.16) for MenW IgG]. Overall, MenC antibody levels were slightly higher in girls at all postvaccination timepoints (GMC- and GMT-ratios: 1.16/1.17 at 1 month, 1.16/1.22 at 1 year and 1.12/1.15 3 years postvaccination). Higher MenC antibody levels were observed in 12- and 15-year-old girls compared to boys of the same age, whereas 10-year-old boys and girls had similar antibody levels. The percentage of participants protected (SBA titer ≥ 8) was very high (95-100%) at all timepoints, and did not differ significantly between boys and girls. Conclusion: Antibody responses were higher in girls than in boys for all serogroups at most timepoints after primary MenAWY vaccination and booster MenC vaccination. The differences in average titers were however small and the percentage participants with protective titers was very high for both sexes.

[Not to be missed signs of primary amenorrhea]. / Niet te missen signalen van primaire amenorroe.

Primary amenorrhea is defined as the absence of the menarche by the age of 16. Knowledge of the new arrangement of all causes into four pathofysiologic compartments by the NVOG and NVK guideline contributed the diagnostic process. This article present the alarm symptoms of primary amenorrhea in the anamnesis, physical examination and supplementary tests including the interpretation of stages of puberty in relation with length and vaginal examination. In this article, we propose the optimal diagnostic traject for general practitioner, pediatrician and gynaecologist. We describe four cases, one of each compartment, to illustrate the importance of this process.

Different Long-Term Duration of Seroprotection against Neisseria meningitidis in Adolescents and Middle-Aged Adults after a Single Meningococcal ACWY Conjugate Vaccination in The Netherlands.

Neisseria meningitidis is often asymptomatically carried in the nasopharynx but may cause invasive meningococcal disease, leading to morbidity and mortality. Meningococcal conjugate vaccinations induce functional protective antibodies against capsular antigens, but seroprotection wanes over time. We measured functional antibody titers five years after administration of a single dose of the meningococcal ACWY-polysaccharide-specific tetanus toxoid-conjugated (MenACWY-TT) vaccine in adolescents and middle-aged adults in the Netherlands, using the serum bactericidal antibody with baby rabbit complement (rSBA) assay. Protection was defined as rSBA titer ≥8. The meningococcal ACWY-specific serum IgG concentrations were measured with a multiplex immunoassay. Duration of protection was estimated by a bi-exponential decay model. Sufficient protection for MenC, MenW, and MenY was achieved in 94-96% of the adolescents five years postvaccination, but, in middle-aged adults, only in 32% for MenC, 65% for MenW and 71% for MenY. Median duration of protection for MenCWY was 4, 14, and 21 years, respectively, in middle-aged adults, while, in adolescents, it was 32, 98, and 33 years. Our findings suggest that adolescents, primed in early childhood with MenC conjugate vaccination, remain sufficiently protected after a single dose of MenACWY-TT vaccine. Middle-aged adults without priming vaccination show fast waning of antibodies, particularly MenC, for which protection is lost after four years.

Use of saliva to monitor meningococcal vaccine responses: proposing a threshold in saliva as surrogate of protection.

BACKGROUND: Mucosal antibodies against capsular polysaccharides offer protection against acquisition and carriage of encapsulated bacteria like Neisseria meningitidis serogroup C. Measurements of salivary antibodies as replacement for blood testing has important (cost-effective) advantages, particular in studies that assess the impact of large-scale vaccination or in populations in which blood sampling is difficult. This study aimed to estimate a threshold for meningococcal IgG salivary antibody levels to discriminate between unprotected and protected vaccinated individuals. METHODS: MenA-, MenC-, MenW- and MenY-polysaccharide (PS) specific IgG levels in serum and saliva from participants in a meningococcal vaccination study were measured using the fluorescent-bead-based multiplex immunoassay. Functional antibody titers in serum against the four serogroups were measured with serum bactericidal assay using rabbit complement (rSBA). A threshold for salivary IgG was determined by analysis of ROC curves using a serum rSBA titer ≥128 as correlate of protection. The area under the curve (AUC) was calculated to quantify the accuracy of the salivary test and was considered adequate when ≥0.80. The optimal cut-off was considered adequate when salivary IgG cut-off levels provided specificity of ≥90%. True positive rate (sensitivity), positive predictive value, and negative predictive value were calculated to explore the possible use of salivary antibody levels as a surrogate of protection. RESULTS: The best ROC curve (AUC of 0.95) was obtained for MenC, with an estimated minimum threshold of MenC-PS specific salivary IgG ≥3.54 ng/mL as surrogate of protection. An adequate AUC (> 0.80) was also observed for MenW and MenY with an estimated minimal threshold of 2.00 and 1.82 ng/mL, respectively. When applying these thresholds, all (100%) samples collected 1 month and 1 year after the (booster) meningococcal vaccination, that were defined as protective in the saliva test for MenC, MenW and MenY, corresponded with concomitant serum rSBA titer ≥128 for the respective meningococcal serogroups. CONCLUSION: The saliva test offers an alternative screening tool to monitor protective vaccine responses up to one year after meningococcal vaccination against MenC, MenW and MenY. Future (large) longitudinal vaccination studies evaluating also clinical protection against IMD or carriage acquisition are required to validate the currently proposed threshold in saliva.

Safety and immunogenicity of fractional dose intradermal injection of two quadrivalent conjugated meningococcal vaccines.

BACKGROUND: Vaccination with conjugated meningococcal vaccines is the best way to prevent invasive meningococcal disease. Changes in serogroup epidemiology have led to the inclusion of quadrivalent vaccines in the national immunization programs of several countries, but vaccines are frequently in short supply. Intradermal administration has the potential to increase vaccine availability through dose reduction, without sacrificing efficacy. It has never before been investigated for glycoconjugate meningococcal vaccines. METHODS: Different fractional doses of two quadrivalent meningococcal conjugate vaccines (MenACWY-CRM197 (Menveo®) and MenACWY-TT (Nimenrix®)) were administered intradermally to sequential groups of 4 participants, according to an adaptive dose escalation design, starting at 1/10th of the original dose. Booster doses were given after 4-6 months based on interim serology results using a multiplex bead-based assay (MIA). Final analyses were based on serum bactericidal antibody titers (rSBA). RESULTS: A total of 12 subjects were enrolled (average 25 years old, range 19-48). MenACWY-CRM197 became unavailable during the course of the study and was only evaluated for a 1/10th dose. This dose resulted in less than complete seroprotection for serogroup A but complete protection against the other serogroups. MenACWY-TT was evaluated for a 1/10th and 1/5th dose level. Both fractional doses of MenACWY-TT resulted in complete seroprotection against all vaccine serogroups. Geometric mean titers 1 month after vaccination were lower and decayed faster in the MenACWY-CRM197 group. Adverse events were mild and there were no serious adverse events. CONCLUSION: Fractional intradermal vaccination against meningococcal disease with quadrivalent conjugate vaccine appears to be safe and effective in our small dose finding study. Tetanus toxoid conjugated vaccine (Nimenrix®) shows a trend towards higher antibody levels compared to CRM197-conjugated vaccine (Menveo®). The 1/5th fractional dose of MenACWY-TT appears to result in higher antibody levels than does the 1/10th dose. These results can be used for a larger non-inferiority study. This trial was registered in clinicaltrials.gov under NCT01782066.

Induction of salivary antibody levels in Dutch adolescents after immunization with monovalent meningococcal serogroup C or quadrivalent meningococcal serogroup A, C, W and Y conjugate vaccine.

BACKGROUND: Meningococcal infection starts with colonisation of the upper respiratory tract. Mucosal immunity is important for protection against acquisition and subsequent meningococcal carriage. In this study, we assessed salivary antibody levels against meningococcal serogroup A (MenA), W (MenW) and Y (MenY) after vaccination with a quadrivalent MenACWY conjugated vaccine. We also compared salivary meningococcal serogroup C (MenC) antibody levels after monovalent MenC and quadrivalent MenACWY conjugated vaccination. METHODS: Healthy participants, who had received MenC conjugate vaccine between 14 months and 3 years of age, received a (booster) MenC or MenACWY vaccination at age 10-15 years. MenA-, MenC-, MenW- and MenY-polysaccharide (PS) specific IgG and IgA levels in saliva and serum and PS specific secretory component levels in saliva were measured using the fluorescent-bead-based multiplex immunoassay. RESULTS: MenACYW vaccination increased salivary PS-specific IgA (2-fold) and IgG levels(>10-fold) for MenA, MenY, and MenW. After one year, salivary IgA levels had returned to baseline levels. Both vaccines induced an increase in salivary MenC-PS specific IgA (>3-fold) and IgG (>100-fold), with higher levels after MenC as compared to MenACWY vaccination. The antibody decay rate of MenC in saliva between one month and one year was similar for both vaccines. The overall correlation between serum and saliva IgA levels was low (R = 0.39, R = 0.58, R = 0.31, and R = 0.36 for MenA, MenC, MenW and MenY, respectively). Serogroup-PS specific IgG levels between serum and saliva correlated better (R ranged from 0.51 to 0.88). CONCLUSIONS: Both primary (MenA, MenY, and MenW) and booster (MenC) parenteral meningococcal conjugate vaccination induced high salivary antibody levels. The strong correlation for MenC, MenW and MenY between saliva and serum IgG levels indicates that saliva might be used as a reliable tool to measure vaccine responses after both primary and booster meningococcal vaccination.

Lower antibody functionality in middle-aged adults compared to adolescents after primary meningococcal vaccination: Role of IgM.

INTRODUCTION: Successful vaccination of elderly persons is often hampered by immunological ageing, leaving part of the elderly population vulnerable for infectious diseases. As an alternative, timely vaccinations might be administered at middle-age, before reaching old age. Studies evaluating the immunological fitness of middle-aged adults are warranted. In this study we compared the immunogenicity of a primary meningococcal vaccination in Dutch middle-aged adults with that in adolescents, in order to gain knowledge on the early signs of immune ageing. METHODS: In this study, we compared the antibody responses after a primary meningococcal vaccination between middle-aged adults (50-65years of age, N=204) and adolescents (10-15years of age, N=225). Blood samples were taken pre-, as well as 28days and 1year post-vaccination. Functional antibody titers were measured with the serum bactericidal killing assay using baby rabbit complement (rSBA). Meningococcal polysaccharide (PS) specific IgG and IgM concentrations were determined with a fluorescent bead-based multiplex immunoassay. RESULTS: Lower post-vaccination functional antibody titers against meningococcal group W and Y were observed in the middle-aged adults compared to the adolescents. One year post-vaccination, also a significantly higher proportion of the middle-aged adults possessed an rSBA titer below protection level. A large reduction in post-vaccination IgM concentrations was observed in the middle-aged adults, whereas IgG concentrations were only marginally different between the two age groups. Strong correlations between the post-vaccination rSBA titers and IgM concentrations were found both in the middle-aged adults and the adolescents. CONCLUSION: Although protective antibody titers were initiated after primary meningococcal vaccination in middle-aged adults, antibody functionality was significantly lower as compared to that in adolescents. This difference was mainly caused by lower IgM responses. Our results indicate early signs of immune ageing in middle-aged adults, which is important knowledge for the development of future vaccine strategies to better protect elderly persons against infectious diseases.

Enhanced Bordetella pertussis acquisition rate in adolescents during the 2012 epidemic in the Netherlands and evidence for prolonged antibody persistence after infection.

IntroductionIn 2012 a large epidemic of pertussis occurred in the Netherlands. We assessed pertussis toxin (PT) antibody levels in longitudinal serum samples from Dutch 10-18 year-olds, encompassing the epidemic, to investigate pertussis infection incidence. Methods: Blood was sampled in October 2011 (n = 239 adolescents), then 1 year (2012; n = 228) and 3 years (2014; n = 167) later. PT-IgG concentrations were measured by immunoassay and concentrations ≥50 IU/mL (seropositive) assumed indicative of an infection within the preceding year. Results: During the 2012 epidemic, 10% of participants became seropositive, while this was just 3% after the epidemic. The pertussis acquisition rate proved to be sixfold higher during the epidemic (97 per 1,000 person-years) compared with 2012-2014 (16 per 1,000 person-years). In 2012, pertussis notifications among adolescents nationwide were 228/100,000 (0.23%), which is at least 40 times lower than the seropositivity percentage. Remarkably, 17 of the 22 seropositive participants in 2011, were still seropositive in 2012 and nine remained seropositive for at least 3 years. Discussion: Longitudinal studies allow a better estimation of pertussis infections in the population. A PT-IgG concentration ≥50 IU/mL as indication of recent infection may overestimate these numbers in cross-sectional serosurveillance and should be used carefully.

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.

BACKGROUND: Adolescents 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. METHODS: Healthy 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. RESULTS: Of 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. CONCLUSION: Both 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.

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.

BACKGROUND: Recently 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). METHODS: In this phase IV, open-label study, healthy 10-, 12- and 15-year-olds received the MenACWY-TT vaccine. Blood samples were collected before, 1month and 1year 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. RESULTS: The 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. CONCLUSION: The 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 15years seems a more optimal age for a primary quadrivalent MenACWY-TT vaccination to protect against the rapid increase of MenW disease.

Kinetics of Meningococcal Serogroup C-Specific Functional Antibody Levels Up to 15 Years after a Single Immunization with a Meningococcal Serogroup C Conjugate Vaccine during Adolescence.

Adolescent vaccination is now considered the key factor for offering direct protection against meningococcal disease but also for reducing carriage and transmission and, in this way, establishing herd protection. This study estimated age-dependent patterns in functional meningococcal serogroup C (MenC) antibody kinetics after primary MenC conjugate (MenCC) vaccination in adolescents. Serum samples (n = 1,676) were drawn from 2006 to 2011 from individuals aged 9 to 18 years at the time of primary MenCC vaccination in 2002. Functional antibody levels were measured with a serum bactericidal antibody assay (SBA) using rabbit complement. SBA titers gradually declined with time. Up to 9 years after primary vaccination, SBA titers were estimated to be higher in individuals who were aged 13 to 18 years at priming than in those who were aged 9 to 10 years at priming. Based on a linear mixed model, the higher functional antibody levels with age seem to be due to the achievement of higher peak levels upon vaccination rather than to lower rates of decline. It is estimated that 35 to 50% of individuals who received a single primary MenCC vaccination at an age of 9 to 18 years in 2002 will still have sufficient protective antibody levels 15 years later. Using a linear mixed model based on cohort data for a single dated serum sample per person, we were able to estimate the level of protection against MenC up to 15 years after a single vaccination. The current study shows that analysis of antibody kinetics can be done using cross-sectional serology data and is therefore relevant for future serosurveillance studies.

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

INTRODUCTION: Due 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. METHODS: Meningococcal 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, 1month, 1year and 3years 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. RESULTS: Of the original 268 participants, 201 (75%) were revisited after 3years. 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 16.3years, 45.9years and around 270years following the booster for the 10-, 12- and 15-year-olds, respectively. CONCLUSIONS: After 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.