Rutger M. Schepp

Immunity against Neisseria meningitidis serogroup C in the Dutch population before and after introduction of the meningococcal C conjugate vaccine.

Background In 2002 a Meningococcal serogroup C (MenC) conjugate vaccine, with tetanus toxoid as carrier protein, was introduced in the Netherlands as a single-dose at 14 months of age. A catch-up campaign was performed targeting all individuals aged 14 months to 18 years. We determined the MenC-specific immunity before and after introduction of the MenC conjugate (MenCC) vaccine. Methods and Findings Two cross-sectional population-based serum banks, collected in 1995/1996 (n = 8539) and in 2006/2007 (n = 6386), were used for this study. The main outcome measurements were the levels of MenC polysaccharide(PS)-specific IgG and serum bactericidal antibodies (SBA) after routine immunization, 4–5 years after catch-up immunization or by natural immunity. There was an increasing persistence of PS-specific IgG and SBA with age in the catch-up immunized cohorts 4–5 years after their MenCC immunization (MenC PS-specific IgG, 0.25 µg/ml (95%CI: 0.19–0.31 µg/ml) at age 6 years, gradually increasing to 2.34 µg/ml,(95%CI: 1.70–3.32 µg/ml) at age 21–22 years). A comparable pattern was found for antibodies against the carrier protein in children immunized above 9 years of age. In case of vaccination before the age of 5 years, PS-specific IgG was rapidly lost. For all age-cohorts together, SBA seroprevalence (≥8) increased from 19.7% to 43.0% in the pre- and post-MenC introduction eras, respectively. In non-immunized adults the SBA seroprevalence was not significantly different between the pre- and post-MenC introduction periods, whereas PS-specific IgG was significantly lower in the post-MenC vaccination (GMT, age ≥25 years, 0.10 µg/ml) era compared to the pre-vaccination (GMT, age ≥25 years, 0.43 µg/ml) era. Conclusion MenCC vaccination administered above 5 years of age induced high IgG levels compared to natural exposure, increasing with age. In children below 14 months of age and non-immunized cohorts lower IgG levels were observed compared to the pre-vaccination era, whereas functional levels remained similar in adults. Whether the lower IgG poses individuals at increased risk for MenC disease should be carefully monitored. Large-scale introduction of a MenCC vaccine has led to improved protection in adolescents, but in infants a single-dose schedule may not provide sufficient protection on the long-term and therefore a booster-dose early in adolescence should be considered.

Characteristics of HPV-specific antibody responses induced by infection and vaccination: cross-reactivity, neutralizing activity, avidity and IgG subclasses.

Objectives In order to assess HPV-specific IgG characteristics, we evaluated multiple aspects of the humoral antibody response that will provide insight in the HPV humoral immune response induced by HPV infection and vaccination. Methods Cross-reactivity of HPV-specific antibodies induced by infection or vaccination was assessed with VLP16 or 18 inhibition using a VLP-based multiplex immunoassay (MIA) for HPV16, 18, 31, 33, 45, 52 and 58. HPV16/18 specific IgG1-4 subclasses and avidity were determined with the VLP-MIA in sera after HPV infection and after vaccination. Neutralizing antibodies were determined in a small subset of single-seropositive and multi-seropositive naturally derived antibodies. Results Naturally derived antibodies from single-positive sera were highly genotype-specific as homologue VLP-inhibition percentages varied between 78-94%. In multi-positive sera, cross-reactive antibodies were observed both within and between α7 and α9 species. After vaccination, cross-reactive antibodies were mainly species-specific. Avidity of vaccine-derived HPV-specific antibodies was 3 times higher than that of antibodies induced by HPV infection (p<0.0001). IgG1 and IgG3 were found to be the predominant subclasses observed after HPV infection and vaccination. In the small subset tested, the number of single-positive sera with neutralizing capacity was higher than of multi-positive sera. Conclusion Naturally derived HPV-specific antibodies from single-positive samples showed different characteristics in terms of cross-reactivity and neutralizing capacity compared with antibodies from multi-positive sera. Post-vaccination, HPV antibody avidity was approximately 3 times higher than antibody avidity induced by HPV infection. Therefore, antibody avidity might be a potential surrogate of protection.

Seroprevalence of seven high-risk HPV types in The Netherlands.

BACKGROUND To obtain insight into the age-specific seroprevalence for seven high-risk human papillomavirus (hr-HPV) serotypes (HPV16, 18, 31, 33, 45, 52, and 58) among the general population in the pre-vaccination era in The Netherlands. METHODS From a cross-sectional population-based study (ISRCTN 20164309) performed in 2006/2007 6384 sera of men, women and children were tested for seven hr-HPV specific antibodies using a fluorescent bead-based multiplex immunoassay with virus-like particles of the seven HPV serotypes. RESULTS An increase in seroprevalence was observed in adolescents, especially for the most prevalent HPV type 16 (up to 11.3%). The increase was most pronounced in women, but was less clear for the other six HPV serotypes. Relatively stable seroprevalences were found in the middle aged cohorts and a slight decrease in the elderly. For the age cohorts >14 years, the seroprevalence among women (25.2%) was higher compared with men (20.3%) (p=0.0002). We found that 10.1% of the population was seropositive for multiple HPV serotypes. CONCLUSIONS The HPV vaccination program is targeted at preadolescents as is justified by the results in this study in which a step-up in HPV seroprevalence is observed at ages of sexual debut. Although direct interpretation of seroprevalence data are hampered by cross-reactivity and seroconversion rate, these data are useful as baseline to evaluate long-term population effects of the HPV16/18 vaccination program.

Immunogenicity and safety of the bivalent HPV vaccine in female patients with juvenile idiopathic arthritis: a prospective controlled observational cohort study

Objectives To compare the immunogenicity and safety of the bivalent human papillomavirus (HPV)16/18 vaccine between female patients with juvenile idiopathic arthritis (JIA) and healthy female adolescents. Methods 68 patients and 55 healthy girls aged 12–18 years were included in a prospective controlled observational cohort and were vaccinated at 0, 1 and 6 months. Primary outcomes were immunogenicity expressed as seropositivity rate after three vaccine doses at 7 and 12 months and HPV-specific geometric mean antibody concentrations. Secondary outcomes were HPV16/18-specific memory B cell responses in a subset of participants and safety, defined as adverse events and the effect of vaccination on JIA disease activity. Results All participants were seropositive for HPV16 and HPV18 at 7 months. One patient turned seronegative at 12 months for HPV16/18. No significant differences were found between patients and controls in HPV-specific antibody concentrations; however, antibody concentrations were consistently lower in patients. No effect of methotrexate on HPV16 antibodies (p=0.79) or HPV18 antibodies (p=0.37) was detected. All patients on anti-TNFα treatment were seropositive after vaccination. The kinetics of HPV16/18 memory B cell responses was comparable between patients and controls, but the magnitude of B cell responses at 7 and 12 months appeared lower in patients. No relevant differences in adverse events were found. HPV vaccination did not aggravate JIA disease. Conclusions The bivalent HPV16/18 vaccine is immunogenic and well tolerated in JIA patients. However, HPV-specific antibodies and B cell responses tended to be lower in patients compared with healthy controls. Clinical trial listing NCT00815282

Kinetics of antibody responses after primary immunization with meningococcal serogroup C conjugate vaccine or secondary immunization with either conjugate or polysaccharide vaccine in adults

In the Netherlands the meningococcal serogroup C conjugate (MenCC) vaccine is administered as a single dose at 14 months. We evaluated the kinetics of isotype-specific antibodies in adults (n=21) after primary immunization with MenCC or secondary immunization with MenCC or plain MenC polysaccharide vaccine. Blood samples were collected prior to immunization and at 6 additional time points, from 3 to 25 days post-immunization. Secondary immunization resulted in 5-10-fold higher IgG titers compared to the primary immunization group, 25 days post-immunization. Prior to the secondary immunization, but 5 years after the first immunization, protective bactericidal antibodies and levels of MenC-specific IgG and IgM were still present. Furthermore, IgG antibodies present before secondary immunization were of higher avidity compared to antibodies produced one month after primary immunization. In addition, secondary immunization with nonconjugated MenC polysaccharide seemed to induce a higher IgG2 response compared to MenCC immunization. The kinetics of the observed secondary immune responses were not really faster than the observed primary responses. However, the rate of increase in antibodies seemed faster than the primary responses, representing a booster response. As the course of infection by Neisseria meningitidis can be very rapid, these data support the idea that sustainment of high antibody levels induced by MenCC are important for immediate protection.

Seroepidemiology of high-risk HPV in HIV-negative and HIV-infected MSM: the H2M study

Background: Men who have sex with men (MSM), in particular HIV-infected MSM, are at increased risk for diseases related to human papilloma virus (HPV). Our goal was to assess the effect of HIV status on the presence of type-specific antibodies against seven high-risk HPV types in HPV-unvaccinated MSM. Moreover, we compared determinants of HPV seropositivity between HIV-negative and HIV-infected MSM. Methods: MSM ≥18 years of age were recruited from the Amsterdam Cohort Studies, a sexually transmitted infection clinic, and an HIV-treatment center in Amsterdam, the Netherlands. Participants completed a risk-factor questionnaire; serum samples were analyzed using a fluorescent bead-based multiplex assay. Results: MSM (n = 795) were recruited in 2010 to 2011; 758 MSM were included in this analysis. Median age was 40.1 years (interquartile range 34.8–47.5) and 308 MSM (40.6%) were HIV-infected. Seroprevalence of HPV-16 was 37.1% in HIV-negative and 62.7% in HIV-infected MSM (P < 0.001); seroprevalence of HPV-18 was 29.1% in HIV-negative MSM and 42.5% in HIV-infected MSM (P < 0.001). Similar patterns of seroprevalence were observed for HPV types 31, 33, 45, 52, and 58. In multivariable analyses, HPV seropositivity was associated with HIV infection [adjusted OR = 2.1; 95% confidence interval, 1.6–2.6]. In multivariable analyses stratified by HIV status, increasing age and number of lifetime male sex partners were significantly associated with HPV seropositivity in HIV-negative, but not HIV-infected MSM. Conclusions: Seroprevalence of high-risk HPV types is high among unvaccinated MSM. Impact: HIV infection is a strong and independent determinant for HPV seropositivity, which we hypothesize is because of increased persistence of HPV infection in HIV-infected MSM. Cancer Epidemiol Biomarkers Prev; 22(10); 1698–708. ©2013 AACR.

Simultaneous Detection of Haemophilus influenzae Type b Polysaccharide-Specific Antibodies and Neisseria meningitidis Serogroup A, C, Y, and W-135 Polysaccharide-Specific Antibodies in a Fluorescent-Bead-Based Multiplex Immunoassay

ABSTRACT We expanded the meningococcal serogroup A, C, Y, and W-135 multiplex immunoassay (MIA) to simultaneously detect immunoglobulin type G antibodies directed toward Haemophilus influenzae type b polysaccharide (HibPS). The monoplex HibPS assay was compared to a HibPS-specific competitive enzyme-linked immunosorbent assay and showed a good correlation (R = 0.96). Furthermore, no cross-reactivity between HibPS and the four meningococcal serogroups was detected. This pentaplex meningococcal Hib MIA is a useful tool to investigate serological responses toward different childhood PS vaccines.

Detection of systemic and mucosal HPV-specific IgG and IgA antibodies in adolescent girls one and two years after HPV vaccination.

The bivalent HPV16/18 vaccine induces high antibody concentrations in serum while data about antibody responses in the cervix are limited. In this study, we investigated pre- and post-vaccination antibody responses against seven high-risk HPV types by detection of IgG and IgA HPV-specific antibodies in cervical secretion samples (CVS) and serum. From an HPV vaccine monitoring study CVS and serum samples were available (pre-vaccination (n = 297), one year (n = 211) and two years (n = 141) post-dose-one vaccination) from girls aged 14–16 y. The girls were vaccinated with the bivalent HPV vaccine at months 0, 1 and 6. CVS was self-sampled using a tampon. Samples were tested for HPV-specific antibodies (HPV16/18/31/33/45/52/58) by a VLP-based multiplex immunoassay. Post-vaccination, IgG and IgA antibody levels for HPV16/18 were detectable in CVS and amounted to 2% and 1% of the IgG and IgA antibody levels observed in serum, respectively. The antibody levels remained constant between one and two years after vaccination. The correlation between CVS and serum was similar for IgG and IgA vaccine-derived antibody levels for HPV16 (rs = 0.58, rs = 0.54) and HPV18 (rs = 0.50, rs = 0.55). Vaccine-derived IgG antibody levels against cross-reactive HPV types in CVS and in serum were highest for HPV45. No IgA cross-reactive antibody responses could be detected in CVS. Post-vaccination, HPV16/18 IgG and IgA antibodies are not only detectable in serum but also in CVS. The correlation of HPV16/18 IgG antibody levels between serum and CVS suggests that vaccine induced HPV antibodies transudate and/or exudate from the systemic circulation to the cervical mucosa to provide protection against HPV infections.

Comparison of Different Assays To Assess Human Papillomavirus (HPV) Type 16- and 18-Specific Antibodies after HPV Infection and Vaccination

ABSTRACT We compared the measurement of human papillomavirus (HPV)-specific serum antibody levels with the virus-like-particle multiplex immunoassay (VLP-MIA), competitive Luminex immunoassay (cLIA), and glutathione S-transferase (GST) L1-based MIA. Using a large panel of serum samples, these assays showed mutually good correlations for both naturally induced and vaccine-derived HPV-specific antibody levels. However, an adaptation of the GST L1-based MIA resulted in an improved correlation with both cLIA and VLP-MIA.

Changes in Antibody Seroprevalence of Seven High-Risk HPV Types between Nationwide Surveillance Studies from 1995–96 and 2006–07 in The Netherlands

Objective This study evaluates trends in antibody seroprevalences of seven high-risk human papillomavirus (hr-HPV) serotypes (HPV16, 18, 31, 33, 45, 52, and 58) between the 1995–96 and 2006–07 sero-surveys among the Dutch general population in the pre-vaccination era. Methods Serum samples of men and women (0–79 years of age) from two cross-sectional population-based serosurveillance studies performed in 1995–96 (n = 3303) and 2006–07 (n = 6384) were tested for HPV-specific antibodies in a VLP-based multiplex immunoassay. Results HPV16-specific antibody seroprevalence increased during adolescence and shifted to younger ages in the 2006–07 survey compared to the 1995–96 survey. This step-up in HPV16 seroprevalence was most pronounced in women, while a more gradual increase was observed in men. Also in cohorts older than 49 years, HPV16 seroprevalence was higher in 2006–07 as compared to 1995–96 survey. A higher overall seroprevalence in individuals older than 15 years of age was found for HPV16, 18, 31 and 45 in 2006–07 as compared to 1995–96. For HPV33, 52 and 58 seroprevalences were comparable over this 11-year time period. Seropositivity for one or more HPV types was significantly higher in 2006–07 (23.1%) than in 1995–96 (20.0%) (p = 0.013). Multi-seropositivity increased from 7.1% in 1995–96 up to 10.2% in 2006–07 (p<0.0001). Differences in HPV seropositivity for at least one of the seven HPV types between both surveys could be explained in addition to demographic characteristics (age, sex, urbanization degree and ethnicity), also by changes in sexual behaviour (marital status, age of sexual debut and ever reported an STI). Conclusion The observed increase in particular HPV16 seroprevalence could be due to changes in sexual behaviour over the years, and especially in age of sexual debut. Seroprevalence studies provide insight into the distribution of HPV types and infection dynamics in the general population over time, which is important to assess the impact of HPV-vaccination.