Real-life paediatric immunisation practices and the safety of vaccine co-administrations in children

Introduction: Paediatric immunisation schedules are designed to protect children against vaccine-preventable diseases early in life. Thereby, vaccines are often scheduled for co-administration to facilitate the delivery of a growing number of vaccines. However, it may not always be possible for children to adhere to the immunisation schedule. Thus, vaccinations may be delayed, given too early, or missed. Shifted vaccinations may lead to vaccine co-administrations that aren’t listed in the schedule. Currently, available information about the safety of real-life vaccine co-administrations versus separate vaccinations is limited and inconclusive. This uncertainty about the safety of co-administered vaccines may nourish vaccine hesitancy and consequently negatively affect immunisation rates. We analysed real-life paediatric immunisation patterns and assessed the relative safety of routine paediatric vaccine co-administration to fill the existing knowledge gap. Methods: Our retrospective, dynamic, population-based cohort study included 1’005’827 children between 0 and 18 years, registered with a General Practitioner in England, participating in the Oxford Royal College of General Practitioners’ Research and Surveillance Centre database, between 1 January 2008 and 31 December 2018. We studied 6’257’828 routine childhood vaccinations as recommended in Public Health England’s paediatric immunisation schedules during the study period: DTaP/IPV/Hib/HepB, DTaP/IPV/Hib, DTaP/IPV, dTaP/IPV, Td/IPV, MMR, PCV, MenB, MenC, MenACWY, Hib/MenC, RV, HPV. We analysed the timeliness of these vaccinations, characterised co-administration practices, and compared the differences in relative incidences of adverse events following immunisation between separate vaccination and real-life vaccine co-administration using the self-controlled case series method. Results: Seventy-five percent of first vaccine doses were administered on time, 19% too late and 6% too early. Fifty-one percent of second and 45% of third doses of a series were given timely after the preceding dose, 36% of second and 37% of third doses sooner, and 13% of second and 18% of third doses after a longer time. Socio-economic deprivation was associated with poorer schedule adherence for most vaccines and doses. Seventy-nine percent of all routine paediatric vaccines were co-administered: two vaccines were co-administered in 36%, three in 33%, and four in 9% of co-administrations. Seventy-five percent of vaccine co-administrations were given as recommended in the immunisation schedule, while 4% were never recommended and 21% deviated from the actual schedule (i.e. shifted doses, fewer vaccines, or according to an outdated schedule). Untimely vaccinations were the major determinant for never recommended co-administrations. Seventeen percent of adverse events following immunisation occurred less and 11% more after co-administrations. Five co-administrations of three vaccines led to amplifying interaction effects. After DTaP/IPV/Hib + MenC + PCV there was an increase in fever, rash, gastrointestinal, and respiratory events. After DTaP/IPV/Hib + MenC + RV there was an increase in gastrointestinal events, and after DTaP/IPV/Hib + PCV + RV there was an increase in fever and respiratory events. After MMR + Hib/MenC + PCV there was an increase in gastrointestinal and respiratory events. After MMR + MenC + PCV there was an increase in gastrointestinal events and general symptoms. Among co-administrations of two vaccines, MMR + PCV led to more fever, rash, and neurological events, MMR + MenC to more fever, and DTaP/IPV/Hib + MMR to more musculoskeletal events compared to separate vaccinations. Discussion: The timeliness of routine paediatric vaccinations was suboptimal and decreased for subsequent doses, particularly after the first year of life. Similarly, the proportions of vaccines co-administered as well as the proportions of recommended co-administrations decreased later in life. Assessing the timeliness of vaccinations in addition to coverage rates is likely to optimise protection and decrease co-administrations without recommendation. Families in lower socio-economic status might particularly benefit from adequate monitoring. We detected no interaction effects following vaccine co-administration for most of the adverse events following immunisation. Routine paediatric vaccine co-administrations that were never recommended weren’t less safe than recommended co-administrations according to our analyses of relative incidence ratios. Co-administering two vaccines led to inhibitory interaction effects for more than a quarter of the studied adverse events. Some amplifying interaction effects after co-administering two vaccines were found for adverse events that occurred less after vaccinations than in the control periods, thus making these events less rare after co-administration than after separate vaccinations. Overall, half of the analysed vaccine co-administrations had an increased relative incidence for at least one adverse event, particularly after co-administrations of three vaccines. These previously undetected interaction effects indicate a safety signal for such co-administrations. Adding a fourth vaccine wasn’t associated with further interaction effects for any of the adverse events following immunisation studied. Conclusions: Children are at risk of suboptimal protection against vaccine-preventable disease during specified periods in their childhood due to untimely vaccinations. Poor immunisation schedule adherence also negatively affects vaccine co-administration practices, forgoing the benefits of co-administering vaccines. We found that real-life co-administrations of two vaccines are at least equally safe as giving the same vaccines separately, while adding a third vaccine may increase the relative incidence of adverse events following immunisation. Building on these findings, we propose enhanced surveillance for a continued and comprehensive evaluation of the burden of adverse events following vaccine co-administrations

Safety of routine childhood vaccine coadministration versus separate vaccination

Introduction: As new vaccines are developed more vaccine coadministrations vaccines are being offered to make delivery more practical for health systems and patients. We compared the safety of coadministered vaccines with separate vaccination for 20 coadministrations by considering nine types of adverse events following immunisation (AEFI). Methods: Real-life immunisation and adverse event data for this observational cohort study were extracted from the Oxford-Royal College of General Practitioners Research and Surveillance Centre for children registered in the database between 2008 and 2018. We applied the self-controlled case series method to calculate relative incidence ratios (RIR) for AEFI. These RIRs compare the RI of AEFI following coadministration with the RI following separate administration of the same vaccines. Results: We assessed 3 518 047 adverse events and included 5 993 290 vaccine doses given to 958 591 children. 17% of AEFI occurred less and 11% more frequently following coadministration than would have been expected based on the RIs following separate vaccinations, while there was no significant difference for 72% of AEFI. We found amplifying interaction effects for AEFI after five coadministrations comprising three vaccines: for fever (RIR 1.93 (95% CI 1.63 to 2.29)), rash (RIR 1.49 (95% CI 1.29 to 1.74)), gastrointestinal events (RIR 1.31 (95% CI 1.14 to 1.49)) and respiratory events (RIR 1.27 (1.17–1.38)) following DTaP/IPV/Hib+MenC+ PCV; gastrointestinal events (RIR 1.65 (95% CI 1.35 to 2.02)) following DTaP/IPV/Hib+MenC+ RV; fever (RIR 1.44 (95% CI 1.09 to 1.90)) and respiratory events (RIR 1.40 (95% CI 1.25 to 1.57)) following DTaP/IPV/Hib+PCV+ RV; gastrointestinal (RIR 1.48 (95% CI 1.20 to 1.82)) and respiratory events (RIR 1.43 (95% CI 1.26 to 1.63)) following MMR+Hib/MenC+PCV; gastrointestinal events (RIR 1.68 (95% CI 1.07 to 2.64)) and general symptoms (RIR 11.83 (95% CI 1.28 to 109.01)) following MMR+MenC+PCV. Coadministration of MMR+PCV led to more fever (RIR 1.91 (95% CI 1.83 to 1.99)), neurological events (RIR 2.04 (95% CI 1.67 to 2.49)) and rash (RIR 1.06 (95% CI 1.01 to 1.11)) compared with separate administration, DTaP/IPV/Hib+MMR to more musculoskeletal events (RIR 3.56 (95% CI 1.21 to 10.50)) and MMR+MenC to more fever (RIR 1.58 (95% CI 1.37 to 1.82)). There was no indication that unscheduled coadministrations are less safe than scheduled coadministrations. Conclusion: Real-life RIRs of AEFI justify coadministering routine childhood vaccines according to the immunisation schedule. Further research into the severity of AEFI following coadministration is required for a complete understanding of the burden of these AEFI

In-pandemic development of an application ontology for COVID-19 surveillance in a primary care sentinel network

Background: Creating an ontology for coronavirus disease 2019 (COVID-19) surveillance should help ensure transparency and consistency. Ontologies formalise conceptualisations at either domain or application level. Application ontologies cross domains and are specified through testable use cases. Our use case was extension of the role of the Oxford Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) to monitor the current pandemic and become an in-pandemic research platform. Objective: To develop an application ontology for COVID-19 which can be deployed across the various use case domains of the Oxford- RCGP RSC research and surveillance activities. Methods: We described our domain-specific use case. The actor was the RCGP RSC sentinel network; the system the course of the COVID-19 pandemic; the outcomes the spread and effect of mitigation measures. We used our established three-step method to develop the ontology, separating ontological concept development from code mapping and data extract validation. We developed a coding system–independent COVID-19 case identification algorithm. As there were no gold standard pandemic surveillance ontologies, we conducted a rapid Delphi consensus exercise through the International Medical Informatics Association (IMIA) Primary Health Care Informatics working group and extended networks. Results: Our use case domains included primary care, public health, virology, clinical research and clinical informatics. Our ontology supported: (1) Case identification, microbiological sampling and health outcomes at both an individual practice and national level; (2) Feedback through a dashboard; (3) A national observatory, (4) Regular updates for Public Health England, and (5) Transformation of the sentinel network to be a trial platform. We have identified a total of 8,627 people with a definite COVID-19 status, 4,240 with probable, and 59,147 people with possible COVID-19, within the RCGP RSC network (N=5,056,075). Conclusions: The underpinning structure of our ontological approach has coped with multiple clinical coding challenges. At a time when there is uncertainty about international comparisons, clarity about the basis on which case definitions and outcomes are made from routine data is essential

ADVANCE system testing: Can coverage of pertussis vaccination be estimated in European countries using electronic healthcare databases: An example

Introduction: 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 existing healthcare databases in Europe. The objective of this paper was to assess the feasibility of using electronic healthcare databases to estimate dose-specific acellular pertussis (aP) and whole cell pertussis (wP) vaccine coverage. Methods: Seven electronic healthcare databases in four European countries (Denmark (n = 2), UK (n = 2), Spain (n = 2) and Italy (n = 1)) participated in this study. Children were included from birth and followed up to age six years. Vaccination exposure was obtained from the databases and classified by type (aP or wP), and dose 1, 2 or 3. Coverage was estimated using period prevalence. For the 2006 birth cohort, two estimation methods for pertussis vaccine coverage, period prevalence and cumulative incidence were compared for each database. Results: The majority of the 2,575,576 children included had been vaccinated at the country-specific recommended ages. Overall, the estimated dose 3 coverage was 88–97% in Denmark (birth cohorts from 2003 to 2014), 96–100% in the UK (2003–2014), 95–98% in Spain (2004–2014) and 94% in Italy (2006–2007). The estimated dose 3 coverage per birth cohort in Denmark and the UK differed by 1–6% compared with national estimates, with our estimates mostly higher. The estimated dose 3 coverage in Spain differed by 0–2% with no consistent over- or underestimation. In Italy, the estimates were 3% lower compared with the national estimates. Except for Italy, for which the two coverage estimation methods generated the same results, the estimated cumulative incidence coverages were consistently 1–10% lower than period prevalence estimates. Conclusion: Thi

Immunization in pregnancy clinical research in low- and middle-income countries - Study design, regulatory and safety considerations.

Immunization of pregnant women is a promising public health strategy to reduce morbidity and mortality among both the mothers and their infants. Establishing safety and efficacy of vaccines generally uses a hybrid design between a conventional interventional study and an observational study that requires enrolling thousands of study participants to detect an unknown number of uncommon events. Historically, enrollment of pregnant women in clinical research studies encountered many barriers based on risk aversion, lack of knowledge, and regulatory ambiguity. Conducting research enrolling pregnant women in low- and middle-income countries can have additional factors to address such as limited availability of baseline epidemiologic data on disease burden and maternal and neonatal outcomes during and after pregnancy; challenges in recruiting and retaining pregnant women in research studies, variability in applying and interpreting assessment methods, and variability in locally acceptable and available infrastructure. Some measures to address these challenges include adjustment of study design, tailoring recruitment, consent process, retention strategies, operational and logistical processes, and the use of definitions and data collection methods that will align with efforts globally

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

Guideline for collection, analysis and presentation of safety data in clinical trials of vaccines in pregnant women.

Vaccination during pregnancy is increasingly being used as an effective approach for protecting both young infants and their mothers from serious infections. Drawing conclusions from published studies in this area can be difficult because of the inability to compare vaccine trial results across different studies and settings due to the heterogeneity in the definitions of terms used to assess the safety of vaccines in pregnancy and the data collected in such studies. The guidelines proposed in this document have been developed to harmonize safety data collection in all phases of clinical trials of vaccines in pregnant women and apply to data from the mother, fetus and infant. Guidelines on the prioritization of the data to be collected is also provided to allow applicability in various geographic, cultural and resource settings, including high, middle and low-income countries