Enhanced Bordetella pertussisacquisition 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

No evidence found for an increased risk of long-term fatigue following human papillomavirus vaccination of adolescent girls

METHODS: In this retrospective cohort study conducted in the Integrated Primary Care Information database, we investigated the occurrence of chronic fatigue syndrome (CFS), fatigue ≥6 months and 3-6 months in all girls born in 1991-2000 during the follow-up period January 1st 2007-December 31st 2014 (2007-2008 pre-vaccination and 2009-2014 post-vaccination). Patients with certain fatigue ≥6 m were asked for consent to link their primary care information with vaccination data. Incidence rates per 10,000 person years (PY) for 12-16-year-old girls were compared between pre- and post-HPV-vaccine era. A self-controlled case series (SCCS) analysis was performed using consenting vaccinated cases. A primary high-risk period of 12 months after each dose was defined.CONCLUSIONS: Fatigue ≥6 m and 3-6 m was frequently found among adolescent girls, but CFS was rarely diagnosed. No statistically significant increased incidence rates were found post-vaccination compared to similar age groups of girls pre-vaccination. The SCCS analysis included a low number of cases but revealed no elevated risk of certain fatigue ≥6 m in the high-risk period.RESULTS: The cohort consisted of 69,429 12-16-year-old girls accounting for 2758 PY pre-vaccination and 57,214 PY post-vaccination. Differences between pre- and post-vaccination incidences (CFS: 3.6 (95% CI 0.5-25.7)/10,000 PY and 0.9 (0.4-2.1); certain fatigue ≥6 m: 7.3 (1.8-29.0) and 19.4 (16.1-23.4); certain fatigue 3-6 m: 0.0 and 16.6 (13.6-20.3), respectively) were not statistically significant. SCCS analyses in 16 consenting vaccinated cases resulted in an age-adjusted RR of 0.62 (95%CI 0.07-5.49).INTRODUCTION: In 2013, the Netherlands Pharmacovigilance Center Lareb published an overview of reports of long-lasting fatigue following bivalent HPV-vaccination (2vHPV). After an update of this overview in 2015, concerns regarding the safety of 2vHPV was picked up by the media, which led to further reports of long-lasting fatigue. Therefore, the Dutch National Institute for Public Health and the Environment (RIVM) investigated a possible association between HPV-vaccination and long-term fatigue

Guillain-Barré syndrome and adjuvanted pandemic influenza A (H1N1) 2009 vaccines: A multinational self-controlled case series in Europe

Background: The risk of Guillain-Barré syndrome (GBS) following the United States' 1976 swine flu vaccination campaign in the USA led to enhanced active surveillance during the pandemic influenza (A(H1N1)pdm09) immunization campaign. This study aimed to estimate the risk

Quantifying outcome misclassification in multi-database studies: The case study of pertussis in the ADVANCE project

Background: The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public-private collaboration aiming to develop and test a system for rapid benefit-risk (B/R) monitoring of vaccines using European healthcare databases. Event misclassification can result in biased estimates. Using different algorithms for identifying cases of Bordetella pertussis (BorPer) infection as a test case, we aimed to describe a strategy to quantify event misclassification, when manual chart review is not feasible. Methods: Four participating databases retrieved data from primary care (PC) setting: BIFAP: (Spain), THIN and RCGP RSC (UK) and PEDIANET (Italy); SIDIAP (Spain) retrieved data from both PC and hospital settings. BorPer algorithms were defined by healthcare setting, data domain (diagnoses, drugs, or laboratory tests) and concept sets (specific or unspecified pertussis). Algorithm- and database-specific BorPer incidence rates (IRs) were estimated in children aged 0–14 years enrolled in 2012 and 2014 and followed up until the end of each calendar year and compared with IRs of confirmed pertussis from the ECDC surveillance system (TESSy). Novel formulas were used to approximate validity indices, based on a small set of assumptions. They were applied to approximately estimate positive predictive value (PPV) and sensitivity in SIDIAP. Results: The number of cases and the estimated BorPer IRs per 100,000 person-years in PC, using data representing 3,173,268 person-years, were 0 (IR = 0.0), 21 (IR = 4.3), 21 (IR = 5.1), 79 (IR = 5.7), and 2 (IR = 2.3) in BIFAP, SIDIAP, THIN, RCGP RSC and PEDIANET respectively. The IRs for combined specific/unspecified pertussis were higher than TESSy, suggesting that some false positives had been included. In SIDIAP the estimated IR was 45.0 when discharge diagnoses were included. The sensitivity and PPV of combined PC specific and unspecific diagnoses for BorPer cases in SIDIAP were approximately 85% and 72%, respectively. Conclusion: Retrieving BorPer cases using only specific concepts has low sensitivity in PC databases, while including cases retrieved by unspecified concepts introduces false positives, which were approximately estimated to be 28% in one database. The share of cases that cannot be retrieved from a PC database because they are only seen in hospital was approximately estimated to be 15% in one database. This study demonstrated that quantifying the impact of different event-finding algorithms across databases and benchmarking with disease surveillance data can provide approximate estimates of algorithm validity

Advance system testing: Vaccine benefit studies using multi-country electronic health data – The example of pertussis vaccination

The Accelerated Development of VAccine benefit-risk Collaboration in Europe (ADVANCE), a public-private consortium, implemented and tested a distributed network system for the generation of evidence on the benefits-risks of marketed vaccines in Europe. We tested the system by estimating the incidence rate (IR) of pertussis and pertussis-related complications in children vaccinated with acellular (aP) and whole-cell (wP) pertussis vaccine. Data from seven electronic databases from four countries (Denmark: AUH and SSI, Spain: SIDIAP and BIFAP, UK: THIN and RCGP RSC and Italy: Pedianet) were included in a retrospective cohort analysis. Exposure was defined as any pertussis vaccination (aP or wP). The follow-up time started 14 days after the first dose. Children who had received any pertussis vaccine from January 1990 to December 2015 were included (those w

Narcolepsy and adjuvanted pandemic influenza A (H1N1) 2009 vaccines – Multi-country assessment

Background: In 2010, a safety signal was detected for narcolepsy following vaccination with Pandemrix, an AS03-adjuvanted monovalent pandemic H1N1 influenza (pH1N1) vaccine. To further assess a possible association and inform policy on future use of adjuvants, we conducted a multi-country study of narcolepsy and adjuvanted pH1N1 vaccines. Methods: We used electronic health databases to conduct a dynamic retrospective cohort study to assess narcolepsy incidence rates (IR) before and during pH1N1 virus circulation, and after pH1N1 vaccination campaigns in Canada, Denmark, Spain, Sweden, Taiwan, the Netherlands, and the United Kingdom. Using a case-control study design, we evaluated the risk of narcolepsy following AS03- and MF59-adjuvanted pH1N1 vaccines in Argentina, Canada, Spain, Switzerland, Taiwan, and the Netherlands. In the Netherlands, we also conducted a case-coverage study in children born between 2004 and 2009. Results: No changes in narcolepsy IRs were observed in any periods in single study sites except Sweden and Taiwan; in Taiwan incidence increased after wild-type pH1N1 virus circulation and in Sweden (a previously identified signaling country), incidence increased after the start of pH1N1 vaccination. No association was observed for Arepanrix-AS03 or Focetria-MF59 adjuvanted pH1N1 vaccines and narcolepsy in children or adults in the case-control study nor for children born between 2004 and 2009 in the Netherlands case-coverage study for Pandemrix-AS03. Conclusions: Other than elevated narcolepsy IRs in the period after vaccination campaigns in Sweden, we did not find an association between AS03- or MF59-adjuvanted pH1N1 vaccines and narcolepsy in children or adults in the sites studied, although power to evaluate the AS03-adjuvanted Pandemrix brand vaccine was limited in our study

Vaccine-preventable diseases: evaluation of vaccination programmes and optimisation of surveillance

The Netherlands has a National Immunisation Programme (NIP) and a seasonal influenza vaccination programme. Surveillance enables countries to monitor and assess the impact of these programmes. Dutch surveillance is coordinated by the Centre for Infectious Disease Control and consists of 5 pillars, i.e. assessment of vaccination coverage and safety-, disease-, pathogen- and immune-surveillance. In-depth research can be required to obtain additional data. This thesis contains epidemiological studies on several aspects of vaccine safety and surveillance of vaccine preventable diseases (VPDs) in the Netherlands. Mandatory notification data and information on hospitalisations were used to retrospectively assess trends in pertussis disease in relation to changes in the vaccination schedule. This was used to guide vaccine policy. Through linking of different data sources we studied more severe disease courses and revealed a substantial underreporting of pertussis hospitalisations and death. Unfortunately, linking was hampered by inaccurate linking variables. In a medical record study of infant pertussis hospitalisations, we found an overrepresentation of preterm infants. This group showed a more severe disease course and a lower vaccine-effectiveness. Closer monitoring of preterms is warranted but currently preterms cannot be identified with routine surveillance instruments. In studies on effectiveness and tolerability of an early Measles-Mumps-Rubella vaccination (MMR0), offered to 6-14-month-olds during the 2013-2014 measles outbreak, we used the centralized NIP vaccination registry to invite parents and verify the infant’s vaccination status, which was efficient and increased data reliability. MMR0 proved safe and effective. We also studied the safety of pandemic influenza A(H1N1) vaccination. We demonstrated that this pandemic vaccination was safe not only in combination with prior seasonal influenza vaccination but also when administered during pregnancy. Unfortunately, vaccination status could not be verified. Furthermore, linking questionnaire data of pregnant women to the national Perinatal Registry was challenging. Making use of a large electronic medical record database, we assessed background incidence (IR) of Guillain-Barré Syndrome and Multiple Sclerosis. This is important information to assess possible vaccine safety concerns. It helps to separate legitimate safety concerns from events that are temporally associated but not causally related to the vaccination. Usefulness of those registries can be increased if data become available more real-time and accurate linking to vaccination registries would be possible without great risk of bias. Using data of a nationwide serosurvey (2006-2007), we showed that the general Dutch population is well protected against poliomyelitis. In contrast, Orthodox Protestants are at risk in case poliovirus should be introduced in the area of low vaccination coverage. Likewise, a study on the added value of a bedside test to assess tetanus immunity showed good protection against tetanus with the opportunity to widen the interval of tetanus booster vaccinations. VPD surveillance in the Netherlands has a long track record of high quality data. Due to the need for more detailed and timely results and increased emphasis on privacy, VPD surveillance risks falling short of expectations. Therefore, increased efforts to renew the surveillance systems are very important

Tolerability of Early Measles-Mumps-Rubella Vaccination in Infants Aged 6-14 Months during a Measles Outbreak in the Netherlands in 2013-2014

Background. In 2013–2014, a measles outbreak spread through the Netherlands. To protect young infants, measles-mumps-rubella (MMR) vaccination was offered to those aged 6–14 months in municipalities with routine first-dose MMR vaccine coverage of <90%. We assessed the tolerability of this early administration of MMR vaccine. Methods. After study entry (n = 1866), parents of eligible infants (n = 10 097) completed a questionnaire (n = 1304). For infants who received an early MMR vaccine dose (n = 962), we asked for information about adverse events (AEs) associated with the dose. AE frequencies were compared between infants aged 6–8, 9–11, and 12–14 months. Using multivariable logistic regression, we assessed the association between the risk of AEs and age at early MMR vaccination. Results. The response rate was 13%. Parents of 59 infants (6.1%) and 350 infants (36.4%) who received early MMR vaccination reported local and systemic AEs, respectively. Parents of infants vaccinated at 6–8 months of age reported systemic AEs less frequently (32%) than parents of children vaccinated at 9–11 months (45%) and 12–14 months (43%) of age (P = <.001). For local AEs, there were no differences (5%, 7%, and 10%, respectively; P = .08). Compared with vaccination at 6 months, all older infants except those aged 14 months showed an increased risk for any AE and for systemic AEs starting 5–12 days after vaccination. Conclusions. Early MMR vaccination is well tolerated, with the lowest AE frequencies found in infants aged 6–8 months. It is a safe intervention for protecting young infants against measles

Performance of the Brighton collaboration case definition for hypotonic-hyporesponsive episode (HHE) on reported collapse reactions following infant vaccinations in the Netherlands.

We reviewed collapse (sudden onset of pallor, limpness and hyporesponsiveness) following the first infant (DPTP+Hib) vaccination reported to the enhanced passive surveillance system of the Netherlands in 1994-2003. All 1303 reports identified by the current RIVM (National Institute for Public Health and Environment) case definition were captured by the Brighton Collaboration (BC) case definition, with in 17 (1.3%) reports insufficient information. Over the years the proportion of the highest level of diagnostic certainty (level 1) increased due to more complete data from 70% to over 90%. We checked the BC case definition also on a sample of cases (with pallor or hyporesponsiveness) not meeting RIVM's case definition for collapse at the time. Sixty out of 200 cases were captured by BC but again rejected by RIVM. The sensitivity BC levels 2 and 3 appeared too high. We recommend a more restrict case definition by the Brighton Collaboration with certain exclusion criteria to make it more specific. Furthermore a change in the specifications for levels 2 and 3 will increase specificity and accommodate for the loss of sensitivity