Publications by authors named "Fiona van der Klis"

117 Publications

Associations between measures of social distancing and SARS-CoV-2 seropositivity: a nationwide population-based study in the Netherlands.

Clin Infect Dis 2021 Mar 27. Epub 2021 Mar 27.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Antonie van Leeuwenhoeklaan, MA Bilthoven, the Netherlands.

This large nationwide population-based seroepidemiological study provides evidence on the effectiveness of physical distancing (>1.5m) and indoor group size reductions on SARS-CoV-2 infection. Additionally, young adults may play an important role in viral spread, opposed to children up until 12 years of age with whom close contact is permitted.
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http://dx.doi.org/10.1093/cid/ciab264DOI Listing
March 2021

Development of a Measles and Rubella Multiplex Bead Serological Assay for Assessing Population Immunity.

J Clin Microbiol 2021 Mar 17. Epub 2021 Mar 17.

Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases, Division of Viral Diseases, Viral Vaccine Preventable Diseases Branch, Atlanta, GA, USA.

Serosurveys are important tools for estimating population immunity and providing immunization activity guidance. The measles and rubella multiplex bead assay (MBA) offers multiple advantages over standard serological assays and was validated by comparison with the enzyme-linked immunosorbent assay (ELISA) and the measles plaque reduction neutralization (PRN) assay. Results from a laboratory-produced purified measles whole virus antigen MBA (MeV WVA) correlated better with ELISA and PRN than results from the baculovirus-expressed measles nucleoprotein (N) MBA. Therefore, a commercially produced whole virus antigen (MeV WVA) was evaluated. Serum IgG antibody concentrations correlated significantly with a strong linear relationship between the MeV WVA and MeV WVA MBAs (R=0.962, R=0.926). IgG concentrations from the MeV WVA MBA showed strong correlation with PRN titers (R=0.846) with a linear relationship comparable to values obtained with the MeV WVA MBA and PRN assay (R=0.716 and R=0.768, respectively). Receiver-operating characteristic (ROC) curve analysis of the MeV WVA using PRN titer as the comparator resulted in a seroprotection cutoff of 153 mIU/ml, similar to the established correlate of protection of 120 mIU/ml, with a sensitivity of 98% and a specificity of 84%. IgG concentrations correlated strongly between the rubella WVA MBA and ELISA (R=0.959 and R=0.919). ROC analysis of the rubella MBA using ELISA as the comparator yielded a cutoff of 9.36 IU/ml, similar to the accepted cutoff of 10 IU/ml for seroprotection, with a sensitivity of 99% and a specificity of 100%. These results support use of the MBA for multi-antigen serosurveys assessing measles and rubella population immunity.
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http://dx.doi.org/10.1128/JCM.02716-20DOI Listing
March 2021

Hepcidin-Mediated Hypoferremia Disrupts Immune Responses to Vaccination and Infection.

Med (N Y) 2021 Feb;2(2):164-179.e12

MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.

Background: How specific nutrients influence adaptive immunity is of broad interest. Iron deficiency is the most common micronutrient deficiency worldwide and imparts a significant burden of global disease; however, its effects on immunity remain unclear.

Methods: We used a hepcidin mimetic and several genetic models to examine the effect of low iron availability on T cells and on immune responses to vaccines and viral infection in mice. We examined humoral immunity in human patients with raised hepcidin and low serum iron caused by mutant . We tested the effect of iron supplementation on vaccination-induced humoral immunity in piglets, a natural model of iron deficiency.

Findings: We show that low serum iron (hypoferremia), caused by increased hepcidin, severely impairs effector and memory responses to immunizations. The intensified metabolism of activated lymphocytes requires the support of enhanced iron acquisition, which is facilitated by IRP1/2 and TFRC. Accordingly, providing extra iron improved the response to vaccination in hypoferremic mice and piglets, while conversely, hypoferremic humans with chronically increased hepcidin have reduced concentrations of antibodies specific for certain pathogens. Imposing hypoferremia blunted the T cell, B cell, and neutralizing antibody responses to influenza virus infection in mice, allowing the virus to persist and exacerbating lung inflammation and morbidity.

Conclusions: Hypoferremia, a well-conserved physiological innate response to infection, can counteract the development of adaptive immunity. This nutrient trade-off is relevant for understanding and improving immune responses to infections and vaccines in the globally common contexts of iron deficiency and inflammatory disorders.

Funding: Medical Research Council, UK.
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http://dx.doi.org/10.1016/j.medj.2020.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895906PMC
February 2021

Impact of physical distancing measures against COVID-19 on contacts and mixing patterns: repeated cross-sectional surveys, the Netherlands, 2016-17, April 2020 and June 2020.

Euro Surveill 2021 02;26(8)

Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands.

BackgroundDuring the COVID-19 pandemic, many countries have implemented physical distancing measures to reduce transmission of SARS-CoV-2.AimTo measure the actual reduction of contacts when physical distancing measures are implemented.MethodsA cross-sectional survey was carried out in the Netherlands in 2016-17, in which participants reported the number and age of their contacts the previous day. The survey was repeated among a subsample of the participants in April 2020, after strict physical distancing measures were implemented, and in an extended sample in June 2020, after some measures were relaxed.ResultsThe average number of community contacts per day was reduced from 14.9 (interquartile range (IQR): 4-20) in the 2016-17 survey to 3.5 (IQR: 0-4) after strict physical distancing measures were implemented, and rebounded to 8.8 (IQR: 1-10) after some measures were relaxed. All age groups restricted their community contacts to at most 5, on average, after strict physical distancing measures were implemented. In children, the number of community contacts reverted to baseline levels after measures were eased, while individuals aged 70 years and older had less than half their baseline levels.ConclusionStrict physical distancing measures greatly reduced overall contact numbers, which likely contributed to curbing the first wave of the COVID-19 epidemic in the Netherlands. However, age groups reacted differently when measures were relaxed, with children reverting to normal contact numbers and elderly individuals maintaining restricted contact numbers. These findings offer guidance for age-targeted measures in future waves of the pandemic.
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http://dx.doi.org/10.2807/1560-7917.ES.2021.26.8.2000994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908067PMC
February 2021

Persistence of antibodies to SARS-CoV-2 in relation to symptoms in a nationwide prospective study.

Clin Infect Dis 2021 Feb 24. Epub 2021 Feb 24.

Centre for Immunology of Infectious Diseases and Vaccines , National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.

Background: Assessing the duration of immunity following infection with SARS-CoV-2 is a first priority to gauge the degree of protection following infection. Such knowledge is lacking especially in the general population. Here, we studied changes in Immunoglobulin (Ig) isotype seropositivity and IgG binding strength of SARS-CoV-2-specific serum antibodies up to 7 months following onset of symptoms in a nationwide sample.

Methods: Participants from a prospective representative serological study in the Netherlands were included based on IgG seroconversion to the Spike S1 protein of SARS-CoV-2 (N=353), with up to three consecutive serum samples per seroconverted participant (N=738). IgM, IgA and IgG antibody concentrations to S1, and increase in IgG avidity in relation to time since onset of disease symptoms, were determined.

Results: While SARS-CoV-2-specific IgM and IgA antibodies declined rapidly after the first month post onset of disease, specific IgG was still present in 92% (95% confidence interval, CI, 89-95) of the participants after 7 months. The estimated 2-fold decrease of IgG antibodies was 158 days (95% CI 136-189). Concentrations sustained better in persons reporting significant symptoms compared to asymptomatic persons or those with mild upper respiratory complaints only. Similarly, avidity of IgG antibodies for symptomatic persons showed a steeper increase over time compared with persons with mild or no symptoms (p=0.022).

Conclusion: SARS-CoV-2-specific IgG antibodies persist and show increasing avidity over time, indicative of underlying immune maturation. These data support development of immune memory against SARS-CoV-2 providing insight into protection of the general unvaccinated part of the population.
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http://dx.doi.org/10.1093/cid/ciab172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929058PMC
February 2021

Respiratory syncytial virus in young children: community cohort study integrating serological surveys, questionnaire and electronic health records, Born in Bradford cohort, England, 2008 to 2013.

Euro Surveill 2021 Feb;26(6)

Population, Policy & Practice Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.

BackgroundBronchiolitis caused by respiratory syncytial virus (RSV) is a major cause of mortality and morbidity in infants.AimTo describe RSV epidemiology in children in the community in a high-income setting.MethodsWe used stored blood samples from the United Kingdom Born in Bradford cohort study that had been collected at birth, age 1 and 2 years old, tested for IgG RSV postfusion F antibody and linked to questionnaires and primary and hospital care records. We used finite mixture models to classify children as RSV infected/not infected according to their antibody concentrations at age 1 and 2 years. We assessed risk factors for primary RSV infection at each age using Poisson regression models.ResultsThe study cohort included 700 children with cord blood samples; 490 had additional blood samples taken at both ages 1 and 2 years old. Of these 490 children, 258 (53%; 95% confidence interval (CI): 48-57%) were first infected with RSV at age 1, 99 of whom (38%; 95% CI: 33-43%) had been in contact with healthcare during peak RSV season (November-January). Having older siblings, birth in October-June and attending formal childcare were associated with risk of RSV infection in infancy. By age 2, a further 164 of 490 children (33%; 95% CI: 29-38%) had been infected.ConclusionOver half of children experienced RSV infection in infancy, a further one third had evidence of primary RSV infection by age 2, and one in seven remained seronegative by their second birthday. These findings will inform future analyses to assess the cost-effectiveness of RSV vaccination programmes in high-income settings.
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http://dx.doi.org/10.2807/1560-7917.ES.2021.26.6.2000023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879500PMC
February 2021

Dynamics of the Antibody Response After a Third Dose of Measles-Mumps-Rubella Vaccine Indicate a Slower Decline Compared With a Second Dose.

Open Forum Infect Dis 2020 Nov 20;7(11):ofaa505. Epub 2020 Oct 20.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.

Background: Breakthrough infections of measles and mumps have raised concerns about the duration of vaccine-induced immunity, which might be improved by a third dose of measles-mumps-rubella vaccine (MMR3).

Methods: Here we compared (IgG) antibody levels against measles, mumps, and rubella in blood samples of 9-year-old children and young adults (18-25 years) following MMR2 and MMR3, respectively.

Results: We found that, in addition to antibody boosting for all 3 vaccine components, MMR3 resulted in lower antibody decay rates than MMR2; the declines were most prominent for mumps and rubella.

Conclusions: This study suggests that MMR3 provides long-lasting seroprotection against measles, mumps, and rubella.
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http://dx.doi.org/10.1093/ofid/ofaa505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686655PMC
November 2020

Nationwide seroprevalence of SARS-CoV-2 and identification of risk factors in the general population of the Netherlands during the first epidemic wave.

J Epidemiol Community Health 2020 Nov 28. Epub 2020 Nov 28.

Centre for Infectious Disease Control, RIVM, Bilthoven, Netherlands

Background: We aimed to detect SARS-CoV-2 serum antibodies in the general population of the Netherlands and identify risk factors for seropositivity amidst the first COVID-19 epidemic wave.

Methods: Participants (n=3207, aged 2-90 years), enrolled from a previously established nationwide serosurveillance study, provided a self-collected fingerstick blood sample and completed a questionnaire (median inclusion date 3 April 2020). IgG antibodies targeted against the spike S1-protein of SARS-CoV-2 were quantified using a validated multiplex-immunoassay. Seroprevalence was estimated controlling for survey design, individual pre-pandemic concentration, and test performance. Random-effects logistic regression identified risk factors for seropositivity.

Results: Overall seroprevalence in the Netherlands was 2.8% (95% CI 2.1 to 3.7), with no differences between sexes or ethnic background, and regionally ranging between 1.3 and 4.0%. Estimates were highest among 18-39 year-olds (4.9%), and lowest in children 2-17 years (1.7%). Multivariable analysis revealed that persons taking immunosuppressants and those from the Orthodox-Reformed Protestant community had over four times higher odds of being seropositive compared to others. Anosmia/ageusia was the most discriminative symptom between seropositive (53%) and seronegative persons (4%, p<0.0001). Antibody concentrations in seropositive persons were significantly higher in those with fever or dyspnoea in contrast to those without (p=0.01 and p=0.04, respectively).

Conclusions: In the midst of the first epidemic wave, 2.8% of the Dutch population was estimated to be infected with SARS-CoV-2, that is, 30 times higher than reported. This study identified independent groups with increased odds for seropositivity that may require specific surveillance measures to guide future protective interventions internationally, including vaccination once available.
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http://dx.doi.org/10.1136/jech-2020-215678DOI Listing
November 2020

Safety and immunogenicity of the quadrivalent human papillomavirus vaccine in patients with juvenile dermatomyositis: a real-world multicentre study.

Pediatr Rheumatol Online J 2020 Nov 11;18(1):87. Epub 2020 Nov 11.

Faculdade de Ciências da Saude Dr Paulo Prata (FACISB) e Instituto de Ensino e Pesquisa (IEP), Hospital de Câncer de Barretos, São Paulo, Brazil.

Background: Concerns about the safety and efficacy of vaccines in patients with autoimmune diseases (AID) have led to contradictions and low vaccination coverage in this population, who are at a higher risk of infections, including by human papillomavirus (HPV). Although HPV vaccines have been recommended for immunocompromised patients, there is still a lack of data to support its use for AID patients, such as juvenile dermatomyositis (JDM) patients. The aim of this study was to assess the safety and immunogenicity of the quadrivalent HPV (qHPV) vaccine in a cohort of JDM patients.

Methods: JDM patients aged from 9 to 20 years and healthy controls (HC) were enrolled to receive a 3-dose schedule of qHPV vaccine from March/2014 to March/2016. Study visits were performed before the first dose, 1 month after the second and third doses, and 6 months after the third dose. Participants completed a diary of possible adverse events for 14 days following each dose of vaccination (AEFV). Disease activity and current therapy were analyzed at each visit for JDM patients. In addition, serum samples from all participants were collected to test antibody concentrations against HPV16 and 18 at each visit. Participant recruitment was conducted in ten Brazilian centres. From 47 eligible JDM patients and 41 HC, 42 and 35, respectively, completed the 3-dose schedule of the vaccine, given that five JDM patients and two HC had received doses prior to their inclusion in the study.

Results: The AEFVs presented by the participants were mild and in general did not differ between JDM and HC groups. No severe AEFVs were related to the vaccination. Disease activity was stable, or even improved during the follow-up. One month after the third dose of the vaccine the JDM group presented seropositivity of 100% for HPV16 and 97% for HPV18, similarly to the HC group, who presented 100% for both serotypes (p = 1.000). Six months after the third dose the seropositivity for the patient group was 94% for both HPV types.

Conclusions: The HPV vaccination in this cohort of JDM patients was safe and immunogenic. Since the seropositivity against HPV16 and 18 was very high after the 3-dose schedule, this regimen should be recommended for JDM patients.

Trial Registration: Brazilian Clinical Trials Registry, number: RBR-9ypbtf . Registered 20 March 2018 - Retrospectively registered.
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http://dx.doi.org/10.1186/s12969-020-00479-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659057PMC
November 2020

Susceptibility to SARS-CoV-2 Infection Among Children and Adolescents Compared With Adults: A Systematic Review and Meta-analysis.

JAMA Pediatr 2021 02;175(2):143-156

London School of Hygiene and Tropical Medicine, London, United Kingdom.

Importance: The degree to which children and adolescents are infected by and transmit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unclear. The role of children and adolescents in transmission of SARS-CoV-2 is dependent on susceptibility, symptoms, viral load, social contact patterns, and behavior.

Objective: To systematically review the susceptibility to and transmission of SARS-CoV-2 among children and adolescents compared with adults.

Data Sources: PubMed and medRxiv were searched from database inception to July 28, 2020, and a total of 13 926 studies were identified, with additional studies identified through hand searching of cited references and professional contacts.

Study Selection: Studies that provided data on the prevalence of SARS-CoV-2 in children and adolescents (younger than 20 years) compared with adults (20 years and older) derived from contact tracing or population screening were included. Single-household studies were excluded.

Data Extraction And Synthesis: PRISMA guidelines for abstracting data were followed, which was performed independently by 2 reviewers. Quality was assessed using a critical appraisal checklist for prevalence studies. Random-effects meta-analysis was undertaken.

Main Outcomes And Measures: Secondary infection rate (contact-tracing studies) or prevalence or seroprevalence (population screening studies) among children and adolescents compared with adults.

Results: A total of 32 studies comprising 41 640 children and adolescents and 268 945 adults met inclusion criteria, including 18 contact-tracing studies and 14 population screening studies. The pooled odds ratio of being an infected contact in children compared with adults was 0.56 (95% CI, 0.37-0.85), with substantial heterogeneity (I2 = 94.6%). Three school-based contact-tracing studies found minimal transmission from child or teacher index cases. Findings from population screening studies were heterogenous and were not suitable for meta-analysis. Most studies were consistent with lower seroprevalence in children compared with adults, although seroprevalence in adolescents appeared similar to adults.

Conclusions And Relevance: In this meta-analysis, there is preliminary evidence that children and adolescents have lower susceptibility to SARS-CoV-2, with an odds ratio of 0.56 for being an infected contact compared with adults. There is weak evidence that children and adolescents play a lesser role than adults in transmission of SARS-CoV-2 at a population level. This study provides no information on the infectivity of children.
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http://dx.doi.org/10.1001/jamapediatrics.2020.4573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519436PMC
February 2021

Antibody Responses to Respiratory Syncytial Virus: A Cross-Sectional Serosurveillance Study in the Dutch Population Focusing on Infants Younger Than 2 Years.

J Infect Dis 2020 Sep 23. Epub 2020 Sep 23.

Center for Infectious Disease control, National Institute of Public Health and the Environment, Bilthoven, the Netherlands.

Background: Respiratory syncytial virus (RSV) generally causes mild disease but can cause severe infections in (premature) infants and elderly adults. Here, we studied RSV-specific antibody concentrations throughout life with emphasis on infants and chronic obstructive pulmonary disease (COPD) patients.

Methods: Sera (N = 2655) from 2 nationwide cross-sectional studies in the Netherlands including individuals aged 0-90 years were analyzed for IgG and IgA antibodies to RSV prefusion F, postfusion F, N, Ga, and Gb proteins and for antibody avidity in 42 COPD patients.

Results: Maternal IgG concentrations declined to age 10-12 months. After the first year of life, approximately 40% of children lacked infection-induced IgA antibodies and may therefore be uninfected. All Dutch children showed serological evidence of RSV infection by age 3 years. Antibody concentrations reached a plateau by age 5-9 years and remains constant throughout life. COPD patients had similar levels and avidity of RSV-specific IgG antibodies compared with age-matched healthy controls.

Conclusions: RSV-IgG antibody patterns throughout life can be used to estimate the degree of immunity acquisition to RSV and to identify groups at increased risk of infection. Seroprevalence of IgA could be a proxy to determine RSV infection in children younger than 1 year.
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http://dx.doi.org/10.1093/infdis/jiaa483DOI Listing
September 2020

Changes in HPV Seroprevalence from an Unvaccinated toward a Girls-Only Vaccinated Population in the Netherlands.

Cancer Epidemiol Biomarkers Prev 2020 Nov 20;29(11):2243-2254. Epub 2020 Aug 20.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.

Background: In the Netherlands, bivalent human papillomavirus (HPV) vaccination was included in the National Immunization Program for 12-year-old girls in 2010 (vaccination coverage, 45%-60%). We examined possible changes in HPV seroprevalence in the HPV-unvaccinated Dutch population aged 0-89 years, comparing prevaccination data with data of approximately 6 years after implementation of national vaccination.

Methods: Serum samples of men and women were used from two cross-sectional population-based serosurveillance studies performed before (2006-07, = 6,384) and after (2016-17, = 5,645) implementation of HPV vaccination in the Netherlands. Seven high-risk HPV-specific antibodies (HPV16, 18, 31, 33, 45, 52, and 58) were tested in a virus-like particle-based multiplex immunoassay.

Results: Type-specific HPV seroprevalence increased in women between 2006-07 and 2016-17. Also, a higher seroprevalence for at least one type in women >15 years was found in 2016-17 (31.7%) compared with 2006-07 (25.2%). In men, overall HPV seroprevalence remained similar; however, a lower seroprevalence was found for HPV16 in 2016-17 (7.5%) compared with 2006-07 (10.6%).

Conclusions: Our results indicate an increase in high-risk HPV types in women and a rather stable exposure in men. No clear effects of the strategy of girls-only vaccination were observed in men, probably because of the short time after introduction combined with suboptimal coverage.

Impact: No herd immunity has been observed yet in a population with suboptimal HPV vaccination coverage.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0596DOI Listing
November 2020

Serum Perfluoroalkyl Substances, Vaccine Responses, and Morbidity in a Cohort of Guinea-Bissau Children.

Environ Health Perspect 2020 08 10;128(8):87002. Epub 2020 Aug 10.

Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark.

Background: Perfluoroalkyl substances (PFAS) are a group of widely used persistent chemicals with suspected immunotoxic effects.

Objectives: The present study aimed to examine the association between infant PFAS exposure and antibody responses to measles vaccination as well as morbidity in a low-income country.

Methods: In a randomized controlled trial, children from Guinea-Bissau, West Africa, were followed from inclusion (4-7 months of age) through 2 years of age. Half the children received two measles vaccinations (at inclusion and at 9 months of age), and the other half received only one (at 9 months of age). In a subset of 237 children, six PFAS were quantified in serum at inclusion, and measles antibody concentrations were assessed at inclusion and at approximately 9 months and 2 years of age. At inclusion and at the 9-month visit, mothers were interviewed about infant morbidity.

Results: All but one child had detectable serum concentrations of all six PFAS, although levels were lower than seen elsewhere. A doubling in perfluorooctane sulfonic acid (PFOS) and perfluorodecanoic acid (PFDA) were associated with 21% (95% CI: 2, 37%) and 25% (95% CI: 1, 43%), respectively, lower measles antibody concentrations at the 9-month visit among the children who had received a measles vaccine at inclusion. Elevated serum PFAS concentrations were also associated with reduced prevaccination measles antibody concentrations and increased morbidity.

Discussion: The present study documents that PFAS exposure has reached West Africa and that infants show PFAS-associated increases in morbidity and decreases in measles-specific antibody concentrations before and after vaccination. These findings support the evidence on PFAS immunotoxicity at comparatively low serum concentrations. https://doi.org/10.1289/EHP6517.
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http://dx.doi.org/10.1289/EHP6517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416537PMC
August 2020

SARS-CoV-2-Specific Antibody Detection for Seroepidemiology: A Multiplex Analysis Approach Accounting for Accurate Seroprevalence.

J Infect Dis 2020 10;222(9):1452-1461

Centre for Immunology of Infectious Diseases and Vaccines, National Institute for Public Health and the Environment, Bilthoven, the Netherlands.

Background: The COVID-19 pandemic necessitates better understanding of the kinetics of antibody production induced by infection with SARS-CoV-2. We aimed to develop a high-throughput multiplex assay to detect antibodies to SARS-CoV-2 to assess immunity to the virus in the general population.

Methods: Spike protein subunits S1 and receptor binding domain, and nucleoprotein were coupled to microspheres. Sera collected before emergence of SARS-CoV-2 (n = 224) and of non-SARS-CoV-2 influenza-like illness (n = 184), and laboratory-confirmed cases of SARS-CoV-2 infection (n = 115) with various severities of COVID-19 were tested for SARS-CoV-2-specific IgG concentrations.

Results: Our assay discriminated SARS-CoV-2-induced antibodies and those induced by other viruses. The assay specificity was 95.1%-99.0% with sensitivity 83.6%-95.7%. By merging the test results for all 3 antigens a specificity of 100% was achieved with a sensitivity of at least 90%. Hospitalized COVID-19 patients developed higher IgG concentrations and the rate of IgG production increased faster compared to nonhospitalized cases.

Conclusions: The bead-based serological assay for quantitation of SARS-CoV-2-specific antibodies proved to be robust and can be conducted in many laboratories. We demonstrated that testing of antibodies against multiple antigens increases sensitivity and specificity compared to single-antigen-specific IgG determination.
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http://dx.doi.org/10.1093/infdis/jiaa479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454740PMC
October 2020

Iron Deficiency Anemia at Time of Vaccination Predicts Decreased Vaccine Response and Iron Supplementation at Time of Vaccination Increases Humoral Vaccine Response: A Birth Cohort Study and a Randomized Trial Follow-Up Study in Kenyan Infants.

Front Immunol 2020 13;11:1313. Epub 2020 Jul 13.

Department of Health Sciences and Technology, Institute of Food, Nutrition and Health, Laboratory of Human Nutrition, ETH Zürich, Zurich, Switzerland.

Iron deficiency may impair adaptive immunity and is common among African infants at time of vaccination. Whether iron deficiency impairs vaccine response and whether iron supplementation improves humoral vaccine response is uncertain. We performed two studies in southern coastal Kenya. In a birth cohort study, we followed infants to age 18 mo and assessed whether anemia or iron deficiency at time of vaccination predicted vaccine response to three-valent oral polio, diphtheria-tetanus-whole cell pertussis- type b vaccine, ten-valent pneumococcal-conjugate vaccine and measles vaccine. Primary outcomes were anti-vaccine-IgG and seroconversion at age 24 wk and 18 mo. In a randomized trial cohort follow-up, children received a micronutrient powder (MNP) with 5 mg iron daily or a MNP without iron for 4 mo starting at age 7.5 mo and received measles vaccine at 9 and 18 mo; primary outcomes were anti-measles IgG, seroconversion and avidity at age 11.5 mo and 4.5 y. In the birth cohort study, 573 infants were enrolled and 303 completed the study. Controlling for sex, birthweight, anthropometric indices and maternal antibodies, hemoglobin at time of vaccination was the strongest positive predictor of: (A) anti-diphtheria and anti-pertussis-IgG at 24 wk ( = 0.0071, = 0.0339) and 18 mo ( = 0.0182, = 0.0360); (B) anti-pertussis filamentous hemagglutinin-IgG at 24 wk ( = 0.0423); and (C) anti-pneumococcus 19 IgG at 18 mo ( = 0.0129). Anemia and serum transferrin receptor at time of vaccination were the strongest predictors of seroconversion against diphtheria ( = 0.0484, = 0.0439) and pneumococcus 19 at 18 mo ( = 0.0199, = 0.0327). In the randomized trial, 155 infants were recruited, 127 and 88 were assessed at age 11.5 mo and 4.5 y. Compared to infants that did not receive iron, those who received iron at time of vaccination had higher anti-measles-IgG ( = 0.0415), seroconversion ( = 0.0531) and IgG avidity ( = 0.0425) at 11.5 mo. In Kenyan infants, anemia and iron deficiency at time of vaccination predict decreased response to diphtheria, pertussis and pneumococcal vaccines. Primary response to measles vaccine may be increased by iron supplementation at time of vaccination. These findings argue that correction of iron deficiency during early infancy may improve vaccine response.
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http://dx.doi.org/10.3389/fimmu.2020.01313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369313PMC
July 2020

Lagging Immune Response to Serotype b (Hib) Conjugate Vaccine after the Primary Vaccination with Hib of Infants in The Netherlands.

Vaccines (Basel) 2020 Jun 30;8(3). Epub 2020 Jun 30.

Immunology of Infectious Diseases and Vaccines (IIV), National Institute for Public Health and the Environment, 3721MA Bilthoven, The Netherlands.

In 1993, a serotype b (Hib) conjugate vaccine was introduced in the Dutch national immunization program, resulting in a sharp decrease in invasive Hib disease. We used a population-based set of serum samples collected in the Netherlands in 2006-2007 (Pienter-II, 5696 sera) to assess the concentration of antibodies to the capsular polysaccharide of Hib, and compared the results with those obtained from a similar set collected in 1995-1996 (Pienter-I, 7837 sera). Post-primary vaccination serum samples from children aged 6-11 months from the Pienter-II study contained approximately 4-fold lower anti-Hib antibody concentrations than samples from children from the Pienter-I study. No such difference was found in post-booster samples from children older than 11 months of age. In Pienter-II, the proportion of children aged 6-11 months with anti-Hib antibody concentrations below the putative protective concentration of 0.15 µg/mL was 30%, which is significantly higher than in the Pienter-I study (12%). Fewer children in the Pienter-II group developed antibodies able to kill Hib in a serum bactericidal assay compared to the Pienter-I children. The cause of the lagged response in Pienter-II children remain uncertain, but lack of natural boosting, interference by the acellular pertussis vaccine, combining vaccines and acceleration of the schedule may have contributed.
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http://dx.doi.org/10.3390/vaccines8030347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565023PMC
June 2020

Short- and long-term impact of vaccination against cytomegalovirus: a modeling study.

BMC Med 2020 07 2;18(1):174. Epub 2020 Jul 2.

Center for Infectious Disease Control, National Institute of Public Health and the Environment, Bilthoven, The Netherlands.

Background: Infection with cytomegalovirus (CMV) is highly prevalent worldwide and can cause severe disease in immunocompromised persons and congenitally infected infants. The disease burden caused by congenital CMV infection is high, especially in resource-limited countries. Vaccines are currently under development for various target groups.

Methods: We evaluated the impact of vaccination strategies and hygiene intervention using transmission models. Model parameters were estimated from a cross-sectional serological population study (n=5179) and a retrospective birth cohort (n=31,484), providing information on the age- and sex-specific CMV prevalence and on the birth prevalence of congenital CMV (cCMV).

Results: The analyses show that vertical transmission and infectious reactivation are the main drivers of transmission. Vaccination strategies aimed at reducing transmission from mother to child (vaccinating pregnant women or women of reproductive age) can yield substantial reductions of cCMV in 20 years (31.7-71.4% if 70% of women are effectively vaccinated). Alternatively, hygiene intervention aimed at preventing CMV infection and re-infection of women of reproductive age from young children is expected to reduce cCMV by less than 2%. The effects of large-scale vaccination on CMV prevalence can be substantial, owing to the moderate transmissibility of CMV at the population level. However, as CMV causes lifelong infection, the timescale on which reductions in CMV prevalence are expected is in the order of several decades. Elimination of CMV infection in the long run is only feasible for a vaccine with a long duration of protection and high vaccination coverage.

Conclusions: Vaccination is an effective intervention to reduce the birth prevalence of cCMV. Population-level reductions in CMV prevalence can only be achieved on a long timescale. Our results stress the value of vaccinating pregnant women and women of childbearing age and provide support for the development of CMV vaccines and early planning of vaccination scenarios and rollouts.
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http://dx.doi.org/10.1186/s12916-020-01629-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331215PMC
July 2020

Safety and immunogenicity of the quadrivalent human papillomavirus vaccine in patients with childhood systemic lupus erythematosus: a real-world interventional multi-centre study.

Lupus 2020 Jul 5;29(8):934-942. Epub 2020 Jun 5.

Department of Paediatric Rheumatology, Faculdade de Medicina Barretos (FACISB), Barretos, Brazil.

Objective: This study aimed to assess the safety and immunogenicity of the quadrivalent human papillomavirus (qHPV) vaccination in childhood-onset systemic lupus erythematosus (cSLE) patients.

Methods: Volunteer cSLE patients aged 9-20 years and healthy controls (HC) were enrolled to receive a two- or three-dose qHPV vaccination schedule from March 2014 to March 2016. Study visits were performed before the first dose, one month after the second and third doses and one year after the first dose. In each study visit, disease activity and adverse events following vaccination were analyzed, and a serum sample was collected for testing antibody concentrations. Participant recruitment was conducted in 15 Brazilian paediatric rheumatology units. Of the 256 cSLE patients included, 210 completed the two- or three-dose schedules; 15 had previously received one dose, and 18 had received two doses of the vaccine. The analysis was based on intention-to-treat so that participants who did not complete the entire study protocol were also included.

Results: No severe adverse events were related to the vaccination. Disease activity was generally low and remained stable or even improved. The HC presented 100% seropositivity to HPV16 and HPV18, whereas the two- and three-dose cSLE groups presented 93% and 83% versus 97% and 91%, respectively. One year after the first dose, seropositivity of the three-dose cSLE group was 91% to HPV16 and 84% to HPV18.

Conclusions: HPV vaccination in cSLE patients is safe and immunogenic. Since the seropositivity to HPV16 and HPV18 was higher for the three-dose schedule group, this regimen should be recommended for cSLE patients.
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http://dx.doi.org/10.1177/0961203320928406DOI Listing
July 2020

Immune surveillance for vaccine-preventable diseases.

Expert Rev Vaccines 2020 04 29;19(4):327-339. Epub 2020 Mar 29.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM) , Bilthoven, The Netherlands.

Introduction: Immunesurveillance is an important tool to monitor the protection of the population against vaccine-preventable diseases, which is currently mostly based on the detection of specific serum antibodies. However, the landscape of immune surveillance is changing, driven by emerging and evolving pathogens, changes in the age distribution of the population and scientific understanding of protective immunity, necessitating a comprehensive review.

Areas Covered: To anticipate these changes, reliable and high-throughput detection of antibody levels is desired to enable screening in larger population settings. Antibody levels alone do not always equate with protection and may require additional functional testing of the antibodies or immune cell-based assays. In addition, the location (systemic or locally mucosal) of the infection and whether the antibodies are induced through infection or vaccination have implications for both immune protection and assessing immune status.

Expert Commentary: In order to perform multicenter studies on many samples for multiple antigens, more validated reference materials and wider adoption of high-throughput techniques are needed. The field of serosurveillance will also benefit from better correlates of protection and understanding of (local) mechanisms of protection. Here we give an overview of the current state-of-the-art of serosurveillance and how the field could move forward.
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http://dx.doi.org/10.1080/14760584.2020.1745071DOI Listing
April 2020

Bordetella pertussis induces IFN-γ production by NK cells resulting in chemo-attraction by respiratory epithelial cells.

J Infect Dis 2020 Mar 27. Epub 2020 Mar 27.

Department of Immunology of Infectious Diseases and Vaccination, National Institute of Public Health and the Environment, Bilthoven, The Netherlands.

Background: Whooping cough is caused by infection of the airways with Bordetella pertussis (Bp). As IFN-γ is essential for protective immunity against Bp we investigated how IFN-γ is induced by Bp or the virulence antigens FHA, Prn or PT, and how IFN-γ contributes to local immune responses in humans.

Methods: PBMCs from healthy donors and/or respiratory epithelial cells were stimulated with soluble antigens or inactivated intact Bp and the presence or absence of blocking antibodies or chemokines. Supernatants and cells were analyzed for IFN-γ and chemokine production and lymphocyte migration tested using epithelial supernatants.

Results: The soluble antigens failed to induce IFN-γ production, whereas inactivated Bp induced IFN-γ production. NK cells were the main source of IFN-γ production, which was enhanced by IL-15. Epithelial-PBMC co-cultures showed robust IFN-γ-dependent CXCL9 and CXCL10 production by the epithelial cells following stimulation with IFN-γ and Bp. The epithelial-derived chemokines resulted in CXCR3-dependent recruitment of NK and T cells.

Conclusions: Inactivated Bp, but not antigens, induced potent IFN-γ production by NK cells, resulting in chemo-attraction of lymphocytes towards the respiratory epithelium. These data provide insight into the requirements for IFN-γ production and how IFN-γ enhances local immune responses to prevent Bp-mediated disease.
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http://dx.doi.org/10.1093/infdis/jiaa140DOI Listing
March 2020

HPV infections among young MSM visiting sexual health centers in the Netherlands: Opportunities for targeted HPV vaccination.

Vaccine 2020 04 19;38(17):3321-3329. Epub 2020 Mar 19.

Care and Public Health Research Institute (CAPHRI), Maastricht University Medical Center (MUMC+), 6200 MD Maastricht, the Netherlands; Department of Sexual Health, Infectious Diseases and Environment, South Limburg Public Health Service, 6411 TE Heerlen, the Netherlands.

Introduction: In 2009, girls-only HPV16/18 vaccination was introduced in the Netherlands which has achieved 46-61% uptake. Heterosexual men have benefitted from herd protection, but it is unknown whether men who have sex with men (MSM) also benefit from herd effects of the girls-only HPV16/18 vaccination program. Because MSM bear a high HPV-related disease burden, countries might consider targeted vaccination for MSM. To study possible herd effects and prior HPV exposure at a potential moment of vaccination, we assessed trends in the HPV prevalence and proportions (sero)negative for the various vaccine types among young MSM visiting sexual health centers (SHCs).

Methods: We used data from MSM included in PASSYON study years 2009-2017. In this biennial cross-sectional study among visitors of SHCs aged 16-24 years, MSM provided a penile and anal swab for HPV DNA testing (including vaccine types HPV6/11/16/18/31/33/45/52/58) and blood for HPV antibody testing (HPV16/18/31/33/45/52/58).

Results: In total 575 MSM were included, with a median of 22 years of age and 15 lifetime sex partners and 3.5% HIV positive. Trends in penile or anal HPV prevalence during 2009-2017 were statistically non-significant for all vaccine types. Of the 455 MSM with a penile and anal swab, 360 (79%), 283 (62%) and 242 (53%) were HPV DNA negative at both anatomical sites for HPV16/18, HPV6/11/16/18 and HPV6/11/16/18/31/33/45/52/58 respectively. Among MSM who were HPV16/18 and HPV16/18/31/33/45/52/58 DNA negative and were tested for serology (n = 335 and 279 respectively), 82% and 71% were also seronegative for the respective types.

Discussion: There were no significant declines in the HPV prevalence among MSM up to eight years after introduction of girls-only HPV16/18 vaccination, indicating that MSM are unlikely to benefit largely from herd effects from girls-only vaccination. Most MSM were vaccine-type DNA negative and seronegative, suggesting that vaccination of young MSM visiting SHCs could still be beneficial.
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http://dx.doi.org/10.1016/j.vaccine.2020.03.002DOI Listing
April 2020

High varicella zoster virus susceptibility in Caribbean island populations: Implications for vaccination.

Int J Infect Dis 2020 May 26;94:16-24. Epub 2020 Feb 26.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Antonie van Leeuwenhoeklaan 9, 3720 MA Bilthoven, The Netherlands. Electronic address:

Objectives: Varicella zoster virus (VZV) infection is reported regularly among adolescents and adults in Caribbean island populations. The disease more often runs a severe course among these populations, causing a substantial burden. The aim of this sero-epidemiological study was to obtain an insight into VZV susceptibility and its determinants in island populations of the Caribbean Netherlands (CN).

Methods: Participants from Bonaire, St. Eustatius, and Saba (n = 1829, aged 0-90 years) donated a blood sample and completed a questionnaire. VZV-specific IgG antibodies were determined using a bead-based multiplex immunoassay. Risk factors were analysed using a logistic regression model.

Results: Overall seroprevalence in CN was 78%, being lowest on St. Eustatius (73%) and highest on Bonaire and Saba (79%). Seropositivity increased gradually with age, with 60% and 80% at ages 10 years and 30 years, respectively, and ranging between 80% and 90% thereafter. Higher odds for VZV seronegativity were seen among persons who were born in CN or had resided there since early childhood, and among single-person households.

Conclusions: VZV susceptibility is relatively high among adolescents and adults in CN. In order to reduce the burden of VZV-related disease in these populations, routine varicella vaccination is recommended. As data are scarce, the study findings can serve as a blueprint for the epidemiology in tropical regions.
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http://dx.doi.org/10.1016/j.ijid.2020.02.047DOI Listing
May 2020

High seroprevalence of multiple high-risk human papillomavirus types among the general population of Bonaire, St. Eustatius and Saba, Caribbean Netherlands.

Vaccine 2020 03 19;38(13):2816-2826. Epub 2020 Feb 19.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.

Background: Incidence and mortality of human papillomavirus (HPV)-related cancers differs geographically, with high rates in Caribbean countries. Seroepidemiological data provide information on lifetime cumulative HPV exposure and contributing risk factors, but has not been available yet for Caribbean Netherlands (CN), comprising the islands Bonaire, St. Eustatius and Saba. Therefore, a cross-sectional population-based serosurveillance study was performed in this (recently girls-only HPV-vaccinated) population in 2017.

Methods: Blood samples from participants (n = 1,823, 0-90 years) were tested for seven high-risk (hr)-HPV-specific IgG-antibodies using a VLP-based multiplex-immunoassay. Risk factors for HPV-seropositivity were analysed among persons unvaccinated aged ≥ 15 years who ever had sex (n = 1,080).

Results: Among unvaccinated individuals aged ≥ 15 years, overall seropositivity was high (34%), with over half of them being seropositive for ≥ 2 hr-HPV types, and HPV16 and 52 being most prevalent (13%). Seroprevalence was substantial higher in unvaccinated women (51%) than men (18%), predominantly peaking in women aged 20-59 years, and was highest on St. Eustatius (38%). Besides age and sex, sexual risk factors were associated with HPV-seropositivity.

Conclusions: In accordance with the Caribbean region, seroprevalence of multiple hr-HPV types was high in CN. These data corroborate the decision regarding introduction of a sex-neutral HPV-vaccination program and the relevance for considering a population-based cervical cancer screening program.
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http://dx.doi.org/10.1016/j.vaccine.2020.02.017DOI Listing
March 2020

Is there an association between socioeconomic status and immune response to infant and childhood vaccination in the Netherlands?

Vaccine 2020 04 14;38(18):3480-3488. Epub 2020 Feb 14.

National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.

Introduction: Socioeconomic status (SES) is a well-known determinant of health, but its relation with vaccine-induced immunity is less documented. We explored the association between SES and immunoglobulin G (IgG) levels against vaccine-preventable diseases in vaccinated children in the Dutch National Immunization Programme.

Methods: Data from a population-wide cross-sectional serosurvey in the Netherlands (2006-2007) were used. We compared geometric mean IgG concentrations/titers (GMC/T ratios) against measles, mumps, rubella, Haemophilus influenzae type b (Hib), Neisseria meningococcus type C, diphtheria, tetanus, poliovirus types 1,2,3 and pertussis in children of high versus low SES by linear regression analysis. We included 894 children (0-12 years) at one of two timeframes: 1 month to 1 year, or 1-3 years after vaccination. Mother's educational level and net household income served as binary indicators of SES.

Results: Of 58 possible associations of vaccine-induced antibody responses with educational level and 58 with income, 10 (9%) were statistically significant: 2 favouring (that is, with higher IgG levels at) high educational level (for Hib 1 m-1y after vaccination (GMC/T ratio: 2.99, 95%CI: 1.42-6.30) and polio 2 1 m-1y after the 9-year booster dose (1.14, 1.01-1.27)) and 8 favouring low income (polio 1, 2 and 3 1 m-1y after the 11-month booster (0.74, 0.58-0.94; 0.79, 0.64-0.97; 0.72, 0.55-0.95), polio 3 and pertussis 1-3y after the 11-month booster (0.70, 0.56-0.88; pertussis-prn: 0.60, 0.37-0.98; pertussis-ptx: 0.66, 0.47-0.95), mumps and rubella 1-3y after first vaccination (0.73, 0.55-0.97; 0.70, 0.55-0.90), and rubella 1 m-1y after second vaccination (0.83, 0.55-0.90)). After adjustment for multiple testing, none of the differences remained significant. There was no association between SES and proportion of children with protective IgG levels.

Conclusion: In this explorative study, we found no consistent association between SES and immune response to vaccination in the Netherlands and no association with protective IgG levels. Additional studies in other settings should confirm this finding.
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http://dx.doi.org/10.1016/j.vaccine.2020.01.071DOI Listing
April 2020

Persisting Antibody Response 9 Years After Bivalent Human Papillomavirus (HPV) Vaccination in a Cohort of Dutch Women: Immune Response and the Relation to Genital HPV Infections.

J Infect Dis 2020 05;221(11):1884-1894

Center for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands.

The bivalent human papillomavirus (HPV) vaccine is highly effective and induces robust serological responses. Using a Dutch prospective cohort initiated in 2009, including 744 vaccinated and 294 unvaccinated girls (1993-1994) who provide a vaginal self-swab sample, serum sample, and questionnaire yearly, we report a high, persisting antibody response up to 9 years after vaccination for vaccine types HPV-16 or HPV-18. Antibodies against nonvaccine HPV types 31, 33, 45, 52, and 58 were lower but still significantly higher than in unvaccinated individuals. This was also reflected in the seroprevalence. We compared participant characteristics and antibody levels between vaccinated women with and those without HPV infections 1 year before infection (204 incident and 64 persistent infections), but we observed no consistent difference in type-specific antibody levels. Having a high-risk HPV infection was associated with sexual risk behavior and smoking 1 year before infection. Although high antibody levels are necessary for protection, our study suggests that on the individual level other factors such as HPV exposure or antibody avidity could be important.
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http://dx.doi.org/10.1093/infdis/jiaa007DOI Listing
May 2020

Additional Evidence on Serological Correlates of Protection against Measles: An Observational Cohort Study among Once Vaccinated Children Exposed to Measles.

Vaccines (Basel) 2019 Oct 22;7(4). Epub 2019 Oct 22.

Centre for Infectious Disease Control, Netherlands Institute for Public Health and the Environment (RIVM), Antonie van Leeuwenhoek 9, 3720 MA Bilthoven, The Netherlands.

To assess correlates of protection against measles and against subclinical measles virus (MV) infection, we recruited once-vaccinated children from geographic regions associated with increased MV circulation and/or at schools with low vaccination coverage in the Netherlands. Paired blood samples were collected shortly after onset of the measles outbreak and after the outbreak. A questionnaire was used to document the likelihood of exposure to MV and occurrence of measles-like symptoms. All blood samples were tested for MV-specific antibodies with five different assays. Correlates of protection were assessed by considering the lowest neutralizing antibody levels in children without MV infection, and by ROC analyses. Among 91 participants, two seronegative children (2%) developed measles, and an additional 19 (23%) experienced subclinical MV infection. The correlate of protection against measles was lower than 0.345 IU/mL. We observed a decreasing attack rate of subclinical MV infection with increasing levels of specific antibodies until 2.1 IU/mL, above which no subclinical MV infections were detected. The ROC analyses found a correlate of protection of 1.71 IU/mL (95% CI 1.01-2.11) for subclinical MV infection. Our correlates of protection were consistent with previous estimates. This information supports the analyses of serosurveys to detect immunity gaps that require targeted intervention strategies.
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http://dx.doi.org/10.3390/vaccines7040158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963647PMC
October 2019

Biological sex influences antibody responses to routine vaccinations in the first year of life.

Acta Paediatr 2020 01 10;109(1):147-157. Epub 2019 Oct 10.

Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia.

Aim: We investigated the effect of early-life factors, namely sex, delivery mode, feeding method and antibiotic exposure, on antibody responses to routine vaccinations administered during the first year of life.

Methods: One and seven months after the primary course of routine vaccines and 1 month after routine vaccines at 12 months of age, antibodies against 26 vaccine antigens were measured in 398 healthy infants. The geometric mean concentration (GMC) of antibodies (adjusted for effect modifiers with multiple linear regression) and the seroprotection rate for each vaccine were compared for each early-life factor.

Results: Sex had an influence on GMCs. Antibody concentrations were significantly lower at 7 months of age in females for tetanus and filamentous haemagglutinin and at 13 months of age for pertactin. In contrast, at 13 months of age, antibody concentrations were significantly higher in females for polio type 3, pneumococcal serotype 6A and measles. Sex did not have an influence on seroprotection rates. Delivery mode, feeding method and antibiotic exposure did not exert a substantial influence on vaccine antibody concentrations.

Conclusion: There is a difference between males and females in the humoral response to routine vaccinations in the first year of life.
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http://dx.doi.org/10.1111/apa.14932DOI Listing
January 2020

Seroepidemiology of Measles, Mumps and Rubella on Bonaire, St. Eustatius and Saba: The First Population-Based Serosurveillance Study in Caribbean Netherlands.

Vaccines (Basel) 2019 Oct 1;7(4). Epub 2019 Oct 1.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Antonie van Leeuwenhoeklaan 9, 3720 MA Bilthoven, The Netherlands.

The National Immunization Program (NIP) on Bonaire, St. Eustatius and Saba (i.e., Caribbean Netherlands (CN)) includes the measles-mumps-rubella (MMR) vaccine since 1988/89. Seroepidemiological data is an important tool to evaluate the NIP, hence a cross-sectional representative population-based serosurveillance study was conducted for the first time in CN in mid-2017. Participants ( = 1829, aged 0-90 years) donated a blood sample and completed a health-related questionnaire. MMR-specific IgG antibodies were determined using a bead-based multiplex immunoassay and risk factors were analyzed using logistic regression models. Overall seroprevalence was high for measles (94%), but lower for mumps and rubella (both 85%). In NIP eligibles, including women of childbearing age, rubella seroprevalence (88%) exceeded the threshold for protection (85%); however, for measles (89%) this protective level (95%) was not met. MMR seropositivity was lowest in children who became CN resident at 11-17 years of age (especially for measles (72%)), mostly originating from Latin America and other non-Western countries. Interestingly, rubella seroprevalence was lowest in non-NIP eligible adults from Dutch overseas territories and Suriname (75%). Taken together, MMR immunity is generally good in CN, nonetheless some risk groups were identified. Additionally, we found evidence for a unique island epidemiology. In light of recent regional measles outbreaks, disease monitoring remains of utmost importance.
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http://dx.doi.org/10.3390/vaccines7040137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963433PMC
October 2019

Long-term HPV-specific immune response after one versus two and three doses of bivalent HPV vaccination in Dutch girls.

Vaccine 2019 11 28;37(49):7280-7288. Epub 2019 Sep 28.

Center for Infectious Disease Control, National Institute for Public Health and the Environment, Antonie van Leeuwenhoeklaan 9, 3720 MA Bilthoven, the Netherlands.

Background: In view of further reduction of HPV vaccination schedules, gaining more insight into humoral and cellular immune responses after a single HPV vaccine is of great interest. Therefore, these responses were evaluated after different doses of the bivalent (2v) HPV-vaccine in girls.

Methods: Blood was collected yearly up to seven years post-vaccination with one-, two- or three-doses of the 2vHPV vaccine (N = 890). HPV-type-specific IgG and IgA-antibody levels, IgG-isotypes and avidity indexes were measured by a virus-like-particle-based multiplex-immuno-assay for two vaccine and five non-vaccine HPV types. HPV-type-specific memory B-cell numbers- and T-cell cytokine responses were determined in a subpopulation.

Results: HPV-type-specific antibody concentrations were significantly lower in one- than in two- and three-dose vaccinated girls but remained stable over seven years. The lower antibody response coincided with reduced HPV-type-specific B- and T-cell responses. There were no differences in both the IgG subtypes and the avidity of the HPV16-specific antibodies between the groups.

Conclusions: One-dose of the 2vHPV vaccine is immunogenic, but results in less B- and T-cell memory and considerable lower antibody responses when compared with more doses. Therefore, at least of some of girls receiving the one-dose of the vaccination might be at higher risk for waning immunity to HPV in the long-term.
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http://dx.doi.org/10.1016/j.vaccine.2019.09.066DOI Listing
November 2019

The Effect of Maternal Immunisation During Pregnancy on Infant Vaccine Responses.

EClinicalMedicine 2019 Aug 26;13:21-30. Epub 2019 Jul 26.

Department of Paediatrics, The University of Melbourne, Parkville, Australia.

Introduction: Immunisation during pregnancy to protect infants against tetanus, pertussis and influenza is recommended in many countries. However, maternal antibodies can interfere with infant vaccine responses. We investigated the effect of antenatal diphtheria-tetanus-acellular pertussis (dTpa) and trivalent inactivated influenza (TIV) immunisation on specific and heterologous antibody responses to routine immunisations given in the first year of life.

Methods: In total, 471 healthy infants were included. At 7 and 13 months of age, antibodies to the primary course of routine vaccines given at 6 weeks, 4 and 6 months of age (pertussis (pertussis toxin (PT), filamentous haemagglutinin (FHA), pertactin (PRN)), polio (type 1, 2, 3), type b (Hib), pneumococcus (serotype 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F)) were measured, and at 13 months of age, antibodies to the 12-month routine vaccines (Hib, meningococcus C, measles, mumps and rubella). The seroprotection rates for each vaccine and the geometric mean concentrations (GMC) of antibodies were compared between infants whose mothers did or did not receive dTpa or TIV immunisation during pregnancy.

Results: A total of 369 infants were included in the final analysis. Maternal dTpa immunisation was associated with reduced antibody responses to both specific (diphtheria and pertussis) and heterologous (polio and pneumococcus) vaccine antigens. This effect was stronger for persistence of antibodies at 13 months of age than it was at 7 months of age. At 7 months of age, adjusted average antibody concentrations were significantly lower for diphtheria, pertussis (PT, FHA, PRN) and polio type 2, and at 13 months of age, for diphtheria, pertussis (PT, FHA, PRN), polio type 1-3 and pneumococcal serotypes 1, 4, 5, 6A, 6B, 7F, 18C and 23F. Additionally, at 13 months of age, seroprotection rates for diphtheria, PT, pneumococcal serotype 1, 6A and 6B were significantly lower in infants after maternal dTpa immunisation. In contrast, for Hib, in infants with maternal dTpa immunisation, the adjusted average antibody concentration and the seroprotection rate were higher, particularly at 7 months of age. Maternal TIV immunisation had minimal effect on infant vaccine responses.

Conclusion: Whilst maternal immunisation protects infants in the first few months of life, it might interfere with both specific and heterologous (unrelated) vaccines responses in infants.

Research In Context: Evidence before this study: Maternal immunisation during pregnancy helps to protect infants during the period before they complete their primary immunisations. It has been proven to be safe and beneficial. However, pre-existing maternal antibodies can influence antibody responses following infant immunisation, an effect called 'blunting'. Previous studies have investigated the influence of dTpa but not influenza immunisation during pregnancy on infant vaccine responses. The majority of studies investigated antibody concentrations only to the specific vaccine antigens included in the maternal immunisation, and there is scarce data available on heterologous vaccine responses, particularly pneumococcal responses.Added value of this study: In this study, we have shown that maternal dTpa immunisation during pregnancy is associated with reduced antibody responses to both specific (diphtheria and pertussis) and heterologous (polio and pneumococcus) vaccine antigens. This effect is stronger for persistence of antibodies at 13 months of age than after primary immunisation at 7 months of age. In contrast, for Hib, in infants with maternal dTpa immunisation, antibody concentrations are higher, particularly at 7 months of age. Maternal TIV immunisation has minimal effect on infant vaccine responses.Implications of all the available evidence: Whilst maternal immunisation protects infants in the first few months of life, it might interfere with both specific and heterologous (unrelated) vaccines responses in infants. As most vaccines induce very high antibody responses, small differences in antibody concentrations may not be of clinical significance. However, since maternal immunisation during pregnancy also influences seroprotection rates, strategies, such as additional booster doses in the second year of life, particularly for pertussis and pneumococcus, might need to be considered to address this.
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http://dx.doi.org/10.1016/j.eclinm.2019.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733996PMC
August 2019