Timing of an Adolescent Booster after Single Primary Meningococcal Serogroup C Conjugate Immunization at Young Age; An Intervention Study among Dutch Teenagers

<div><p>Background</p><p>Meningococcal serogroup C (MenC) specific antibody levels decline rapidly after a single primary MenC conjugate (MenCC) vaccination in preschool children. A second MenCC vaccination during (pre)adolescence might attain longer lasting individual and herd protection. We aimed to establish an appropriate age for a (pre)adolescent MenCC booster vaccination.</p><p>Methods</p><p>A phase-IV trial with healthy 10-year-olds (n = 91), 12-year-olds (n = 91) and 15-year-olds (n = 86) who were primed with a MenCC vaccine nine years earlier. All participants received a booster vaccination with the same vaccine. Serum bactericidal antibody assay titers (SBA, using baby rabbit complement), MenC-polysaccharide (MenC-PS) specific IgG, IgG subclass and avidity and tetanus-specific IgG levels were measured prior to (T0) and 1 month (T1) and 1 year (T2) after the booster. An SBA titer ≥8 was the correlate of protection.</p><p>Results</p><p>258 (96.3%) participants completed all three study visits. At T0, 19% of the 10-year-olds still had an SBA titer ≥8, compared to 34% of the 12-year-olds (P = 0.057) and 45% of the 15-year-olds (P<0.001). All participants developed high SBA titers (GMTs>30,000 in all age groups) and MenC-PS specific IgG levels at T1. IgG levels mainly consisted of IgG1, but the contribution of IgG2 increased with age. At T2, 100% of participants still had an SBA titer ≥8, but the 15-year-olds showed the highest protective antibody levels and the lowest decay.</p><p>Conclusion</p><p>Nine years after primary MenCC vaccination adolescents develop high protective antibody levels in response to a booster and are still sufficiently protected one year later. Our results suggest that persistence of individual - and herd - protection increases with the age at which an adolescent booster is administered.</p><p>Trial Registration</p><p>EU Clinical Trials Database <a href="https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-000375-13" target="_blank">2011-000375-13</a> Dutch Trial Register <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3521" target="_blank">NTR3521</a></p></div

Meningococcal serogroup C PS-specific IgM levels.

<p>Levels of IgM in the pre-MenC introduction era are shown in grey bars, the post-MenC introduction era are shown in black bars. Routine immunization is offered in the post-MenC introduction era at 14 months of age and children and adolescents between 5–21 years of age received a single immunization 4–5 years earlier. Error bars indicate 95% confidence intervals. Age at bloodsampling is indicated in years or as stated otherwise (mo  =  age in months).</p

Correlation between levels of Meningococcal serogroup C PS-specific IgG, IgG1, IgG2 and IgG avidity within immunized or non-immunized cohorts in the post-immunization era.

<p>A) Concentrations of IgG, IgG1, IgG2 and the percentage of persons with a relatively low AI in each cohort. B) Correlation between IgG1 and IgG in the 11 immunized cohorts (15 months to 21 years of age, filled triangles) or in the 4 non-immunized cohorts (22 to 79 years of age, open triangles). C) Correlation between IgG2 and IgG in the 11 immunized cohorts (15 months to 21 years of age, filled circles) or in the 4 non-immunized cohorts (22 to 79 years of age, open circles). D) Correlation between IgG1 and the percentage of individuals with low AI in the 11 immunized cohorts (15 months to 21 years of age, filled triangles) or in the 4 non-immunized cohorts (22 to 79 years of age, open triangles). E) Correlation between IgG2 and the percentage of individuals with low AI in the 11 immunized cohorts (15 months to 21 years of age, filled triangles) or in the 4 non-immunized cohorts (22 to 79 years of age, open triangles). F) Comparison of the AI's of sera with an IgG1/IgG2 ratio >1 and an IgG1/IgG2 ratio <1. * <i>P</i><0.0001.</p

Correlations between levels of IgG, IgG1 or IgG2 and percentages of low or high AI per cohort.

<p>Spearman's rank correlation coefficient (<i>r</i>) with the <i>p</i> values (<i>p</i>) and the number of cohorts tested for each association (<i>n</i>).</p><p>ND, not done; NA, not applicable.</p

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

<div><p>Background</p><p>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.</p><p>Methods</p><p>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.</p><p>Results</p><p>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).</p><p>Conclusions</p><p>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.</p></div

Antibody avidity after HPV infection and vaccination.

<p>Antibody avidity (%) for HPV16 (A) and HPV18 (B) of HPV-specific single-seropositive and multi-seropositive naturally derived antibodies and HPV vaccine-derived antibodies are shown. The dark grey line indicates the mean antibody avidity. *** <i>p</i><0.0001.</p

Geometric Mean Titers (GMTs) of Meningococcal Serogroup C (MenC) Specific Serum Bactericidal Antibody (SBA) and Proportion of Participants with an SBA titer ≥8 and ≥128 prior to (T0) and 1 Month (T1) and 1 Year (T2) after the MenC Conjugate Booster.

<p><b>NOTE</b>: Differences between groups in SBA GMTs at T0 were determined using the Mann-Whitney U test. Differences between groups in SBA GMTs at T1 and T2 were determined with linear regression analyses, adjusting for titers at T0. An SBA titer ≥8 was considered as international correlate of protection. Differences between groups in proportion of participants with an SBA titer ≥8 and ≥128 was determined with χ²-tests.</p><p>* P-values were adjusted for three comparisons with Bonferroni correction. Extensive results of the crude and adjusted linear regression analyses are outlined in supplementary <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100651#pone.0100651.s001" target="_blank">table S1</a>.</p

Correlation between log-transformed Immunoglobulin G (IgG) levels in saliva and serum for meningococcal serogroup A (A), C (B), W (C), and Y (D).

<p>Correlation between log-transformed Immunoglobulin G (IgG) levels in saliva and serum for meningococcal serogroup A (A), C (B), W (C), and Y (D).</p

Meningococcal Serogroup C (MenC) Specific Geometric Mean Titers (GMTs) of Serum Bactericidal Antibody (SBA) and Geometric Mean Concentrations (GMCs) of MenC Polysaccharide (MenC-PS) specific Immunoglobulin G (IgG).

<p>MenC-specific GMTs of SBA (a) and GMCs of MenC-PS specific IgG (b) of different age groups prior to (T0) and 1 month (T1) and 1 year (T2) after the MenC conjugate booster.</p

Avidity of Meningococcal serogroup C PS-specific IgG.

<p>Sera with an avidity indices (AI) of 0–33 are indicated as low AI (in black), sera with an AI of 34–66 are determined to be of intermediate AI (in white) and sera with an AI of 67–100 are assigned to be of high AI (in grey). Age at bloodsampling is indicated in years or as stated otherwise (mo  =  age in months).</p