Effectiveness of Omicron XBB.1.5 vaccine against infection with SARS-CoV-2 Omicron XBB and JN.1 variants, prospective cohort study, the Netherlands, October 2023 to January 2024.

We estimated vaccine effectiveness (VE) of SARS-CoV-2 Omicron XBB.1.5 vaccination against self-reported infection between 9 October 2023 and 9 January 2024 in 23,895 XBB.1.5 vaccine-eligible adults who had previously received at least one booster. VE was 41% (95% CI: 23-55) in 18-59-year-olds and 50% (95% CI: 44-56) in 60-85-year-olds. Sequencing data suggest lower protection against the BA.2.86 (including JN.1) variant from recent prior infection (OR = 2.8; 95% CI:1.2-6.5) and, not statistically significant, from XBB.1.5 vaccination (OR = 1.5; 95% CI:0.8-2.6).

Assessment of hybrid population immunity to SARS-CoV-2 following breakthrough infections of distinct SARS-CoV-2 variants by the detection of antibodies to nucleoprotein.

Immunity induced by vaccination and infection, referred to as hybrid immunity, provides better protection against SARS-CoV-2 infections compared to immunity induced by vaccinations alone. To assess the development of hybrid immunity we investigated the induction of Nucleoprotein-specific antibodies in PCR-confirmed infections by Delta or Omicron in vaccinated individuals (n = 520). Eighty-two percent of the participants with a breakthrough infection reached N-seropositivity. N-seropositivity was accompanied by Spike S1 antibody boosting, and independent of vaccination status or virus variant. Following the infection relatively more antibodies to the infecting virus variant were detected. In conclusion, these data show that hybrid immunity through breakthrough infections is hallmarked by Nucleoprotein antibodies and broadening of the Spike antibody repertoire. Exposure to future SARS-CoV-2 variants may therefore continue to maintain and broaden vaccine-induced population immunity.

Effects of COVID-19 vaccination and previous infection on Omicron SARS-CoV-2 infection and relation with serology.

An increasing proportion of the population has acquired immunity through COVID-19 vaccination and previous SARS-CoV-2 infection, i.e., hybrid immunity, possibly affecting the risk of new infection. We aim to estimate the protective effect of previous infections and vaccinations on SARS-CoV-2 Omicron infection, using data from 43,257 adult participants in a prospective community-based cohort study in the Netherlands, collected between 10 January 2022 and 1 September 2022. Our results show that, for participants with 2, 3 or 4 prior immunizing events (vaccination or previous infection), hybrid immunity is more protective against infection with SARS-CoV-2 Omicron than vaccine-induced immunity, up to at least 30 weeks after the last immunizing event. Differences in risk of infection are partly explained by differences in anti-Spike RBD (S) antibody concentration, which is associated with risk of infection in a dose-response manner. Among participants with hybrid immunity, with one previous pre-Omicron infection, we do not observe a relevant difference in risk of Omicron infection by sequence of vaccination(s) and infection. Additional immunizing events increase the protection against infection, but not above the level of the first weeks after the previous event.

Vaccine effectiveness of primary and booster COVID-19 vaccinations against SARS-CoV-2 infection in the Netherlands from July 12, 2021 to June 6, 2022: A prospective cohort study.

OBJECTIVES: We estimated vaccine effectiveness (VE) of primary and booster vaccinations against SARS-CoV-2 infection overall and in four risk groups defined by age and medical risk condition during the Delta and Omicron BA.1/BA.2 periods. METHODS: VAccine Study COvid-19 is an ongoing prospective cohort study among Dutch adults. The primary end point was a self-reported positive SARS-CoV-2 test from July 12, 2021 to June 06, 2022. The analyses included only participants without a previous SARS-CoV-2 infection based on a positive test or serology. We used Cox proportional hazard models with vaccination status as the time-varying exposure and adjustment for age, sex, educational level, and medical risk condition. RESULTS: A total of 37,170 participants (mean age 57 years) were included. In the Delta period, VE <6 weeks after the primary vaccination was 80% (95% confidence interval 69-87) and decreased to 71% (65-77) after 6 months. VE increased to 96% (86-99) shortly after the first booster vaccination. In the Omicron period, these estimates were 46% (22-63), 25% (8-39), and 57% (52-62), respectively. For the Omicron period, an interaction term between vaccination status and risk group significantly improved the model (P <0.001), with generally lower VEs for those with a medical risk condition. CONCLUSION: Our results show the benefit of booster vaccinations against infection, also in risk groups; although, the additional protection wanes quite rapidly.

Vaccine Effectiveness Against Severe Acute Respiratory Syndrome Coronavirus 2 Delta and Omicron Infection and Infectiousness Within Households in the Netherlands Between July 2021 and August 2022.

BACKGROUND: We aimed to estimate vaccine effectiveness against infection (VE-infection) and against further transmission (VE-infectiousness) in a household setting during Delta and Omicron. Knowing these effects can aid policy makers in deciding which groups to prioritize for vaccination. METHODS: Participants with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test were asked about coronavirus disease 2019 (COVID-19) vaccination status and SARS-CoV-2 testing of their household members 1 month later. VE-infection and VE-infectiousness were estimated using generalized estimating equation logistic regression adjusting for age, vaccination status, calendar week, and household size. RESULTS: A total of 3399 questionnaires concerning 4105 household members were included. During the Delta period, VE-infection and VE-infectiousness of primary series were 47% (95% confidence interval [CI], -27% to 78%) and 70% (95% CI, 28% to 87%), respectively. During the Omicron period, VE-infection was -36% (95% CI, -88% to 1%) for primary series and -28% (95% CI, -77% to 7%) for booster vaccination. VE-infectiousness was 45% (95% CI, -14% to 74%) for primary series and 64% (95% CI, 31% to 82%) for booster vaccination. CONCLUSIONS: Our study shows that COVID-19 vaccination is effective against infection with SARS-CoV-2 Delta and against infectiousness of SARS-CoV-2 Delta and Omicron. Estimation of VE against infection with SARS-CoV-2 Omicron was limited by several factors. Our results support booster vaccination for those in close contact with vulnerable people to prevent transmission.

Effectiveness of bivalent mRNA booster vaccination against SARS-CoV-2 Omicron infection, the Netherlands, September to December 2022.

We used data of 32,542 prospective cohort study participants who previously received primary and one or two monovalent booster COVID-19 vaccinations. Between 26 September and 19 December 2022, relative effectiveness of bivalent original/Omicron BA.1 vaccination against self-reported Omicron SARS-CoV-2 infection was 31% in 18-59-year-olds and 14% in 60-85-year-olds. Protection of Omicron infection was higher than of bivalent vaccination without prior infection. Although bivalent booster vaccination increases protection against COVID-19 hospitalisations, we found limited added benefit in preventing SARS-CoV-2 infection.

Introduction or Discontinuation of Additional Risk Minimisation Measures During the Life Cycle of Medicines in Europe.

INTRODUCTION: Additional risk minimisation measures (aRMMs) may be required to minimise important risks of medicines. aRMMs may be required at the time of authorisation, but may also be introduced or discontinued during the product life cycle as new safety information arises. The aim of this study is to describe post-authorisation introductions of new aRMMs and discontinuations of existing aRMMs for medicines authorised in the European Union (EU). METHODS: We performed a retrospective cohort study that included all new active substances authorised through the EU centralised procedure between January 1st 2006 and December 31st 2017. Data was extracted from European Public Assessment Reports available on the website of the European Medicines Agency (ema.europa.eu). Medicines were followed up from the date of marketing authorisation (MA) until first introduction or discontinuation of aRMMs, excluding Direct Healthcare Professional Communications (DHPCs), withdrawal/suspension/revocation of the MA, or July 1st 2018, when data extraction took place. Descriptive statistics were used to analyse frequency data, and survival analysis was used to calculate 5- and 10-year probability of introduction or discontinuation of aRMMs. RESULTS: A total of 476 medicines were authorised during the study period. The probability of getting aRMMs after authorisation for products authorised without aRMMs was 3.5% [95% confidence interval (CI) 1.2-5.7] within 5 years after authorisation and 6.9% (95% CI 2.6-11) within 10 years after authorisation. For products authorised with aRMMs, the probability of discontinuation of aRMMs was 0.9% (95% CI 0-2.6) within 5 years and 8.3% (95% CI 0-16.1) within 10 years after authorisation. CONCLUSIONS: We found low probabilities of introduction and discontinuation of aRMMs (excluding DHPCs) during the product life cycle for medicines authorised between 2006 and 2017. The low rate of discontinuation may potentially be due to a lack of robust data on effectiveness of aRMMs. Further research is needed to get more insight into the dynamics of aRMMs during the medicine life cycle.

Dissemination of Direct Healthcare Professional Communications on Medication Errors for Medicinal Products in the EU: An Explorative Study on Relevant Factors.

INTRODUCTION: When serious medication errors (ME) are identified, communication to the field may be necessary. In the EU, communication of serious safety issues, such as medication errors associated with adverse drug reactions, is done through direct healthcare professional communications (DHPCs). We aimed to identify how often DHPCs about medication errors are distributed, and we explored factors associated with these ME DHPCs. METHODS: We performed a descriptive study of all centrally authorised products (CAPs) approved before 1 May 2019 in the EU. All DHPCs issued between 1 January 2001 and 1 May 2019 were reviewed for ME content. Characteristics of CAPs were collected from the website of the European Medicines Agency. A Kaplan-Meier survival analysis was performed to estimate the 5- and 10-year probability of the occurrence of a first ME DHPC. A logistic regression was performed to explore risk factors for ME DHPCs. RESULTS: A total of 678 CAPs were included, of which 35 required an ME DHPC during the study period. The 5-year probability for a CAP to have a first ME DHPC was 2.5% (95% CI 1.1-3.9) and the 10-year probability was 4.4% (95% CI 2.2-6.5). Among products with an ME DHPC, the 5-year probability of a second ME DHPC was 21.3% (95% CI 0.2-38.0). The risk of ME DHPCs was increased for products with multiple pharmaceutical formulations, enteral liquid or parenteral injection preparations, and products classified as nervous system agents or antineoplastic and immunomodulating agents. CONCLUSIONS: The absolute number of ME DHPCs for CAPs is low and does not give rise to immediate concern. We identified potential risk factors for ME DHPCs that should be taken into account during approval procedures or line extensions.

Fatal outcomes following immunization errors as reported to the EudraVigilance: A case series.

BACKGROUND: Serious adverse reactions after immunization are rare but do occur. In very rare instances, cases with fatal outcome have been reported. These reports can have a huge impact and even more so when due to an immunization error. The aim of this study is to systematically review immunization errors with fatal outcomes in EudraVigilance. METHODS: This was a case-series analysis of Individual Case Safety Reports (ICSRs) reporting immunization errors and a fatal outcome. To determine the level of certainty of a causal association between the immunization errors and fatal outcomes two independent reviewers assessed all ICSRs using the WHO tool "Causality assessment of an Adverse Event Following Immunization (AEFI)". In accordance with the tool, the ICSRs were classified as consistent, indeterminate, inconsistent/coincidental, or unclassifiable. In addition, we estimated the contribution of reported errors to the fatal outcomes as large, moderate, small, none, or unclassifiable using a classification developed for this study. RESULTS: A total of 154 ICSRs met the inclusion criteria. Vaccines reported most frequently were pneumococcal (33), rabies (27) and influenza vaccines (24). Most frequently reported errors were non-compliance with recommended schedules of immunization (63). The most frequently reported vaccine-error combination was rabies vaccines and non-compliance with a recommended schedule of immunization (23). Twelve cases were classified as consistent with causal association and had a large error contribution. These cases concerned a cluster of six cases reporting incorrect handling of multi-dose vials containing measles vaccine and six cases reporting administration of live-attenuated vaccines to immunocompromised patients. DISCUSSION: In this study, we showed that fatal outcomes following immunization errors are very rare. Four key issues were the importance of: (1) quality control of multi-dose vaccines, (2) screening patients for immunocompromising factors, (3) education on the importance of adherence, and (4) measures to improve distinction between vaccines and medicines.

Exploratory Study of Signals for Asthma Drugs in Children, Using the EudraVigilance Database of Spontaneous Reports.

INTRODUCTION: As asthma medications are frequently prescribed for children, knowledge of the safety of these drugs in the paediatric population is important. Although spontaneous reports cannot be used to prove causality of adverse events, they are important in the detection of safety signals. OBJECTIVE: Our objective was to provide an overview of adverse drug events associated with asthma medications in children from a spontaneous reports database and to identify new signals. METHODS: Spontaneous reports concerning asthma drugs were obtained from EudraVigilance, the European Medicine Agency's database for suspected adverse drug reactions. For each drug-event combination, we calculated the proportional reporting ratio (PRR) in the study period 2011-2017. Signals in children (aged 0-17 years) were compared with signals in the whole population. Analyses were repeated for different age categories, by sex and by therapeutic area. RESULTS: In total, 372,345 reports in children resulted in 385 different signals concerning asthma therapy. The largest group consisted of psychiatric events (65 signals). Only 30 signals were new, with seven, including herpes viral infections, associated with omalizumab. Stratification by age, sex and therapeutic area provided additional new signals, such as hypertrichoses with budesonide and encephalopathies with theophylline. Of all signals in children, 60 (16%) did not appear in the whole population. CONCLUSIONS: The majority of signals regarding asthma therapy in children were already known, but we also identified new signals. We showed that signals can be masked if age stratification is not conducted. Further exploration is needed to investigate the risk and causality of the newly found signals.

Description of the Risk Management of Medication Errors for Centrally Authorised Products in the European Union.

INTRODUCTION: Medication errors can have serious consequences for patients. To prevent the occurrence of medication errors in clinical practice, safety concerns may be included in the risk management plan and subsequently be addressed with routine and/or additional risk minimisation measures. OBJECTIVE: This study aims to describe safety concerns around medication errors and the risk minimisation measures for centrally authorised products in the European Union. METHODS: All safety concerns included in the risk management plans of originator centrally authorised products, authorised between 1 January, 2010 and 31 December, 2017, were collected from the European Public Assessment Report registry. Medication error safety concerns were categorised by Anatomical Therapeutic Classification code, year of authorisation, type of medication error and type of risk minimisation measure. RESULTS: During the study period, 311 centrally authorised products were approved, of which 84 had at least one medication error safety concern. The proportion of centrally authorised products with medication error safety concerns showed variation between 2010 and 2017 ranging from 15.2% to 36.4%. In total, 95 medication error safety concerns were identified. The type of medication error was highly variable, drug administration error was listed most frequently (n = 17). For 27 out of 95 medication error safety concerns, corresponding to 23 centrally authorised products, additional risk minimisation measures were required. All additional risk minimisation measures consisted of educational material targeted at healthcare professionals (85.2%) and/or patients (51.9%). For 78.3% of centrally authorised products with additional risk minimisation measures for medication errors, studies to evaluate the effectiveness of the additional risk minimisation measures were agreed upon. CONCLUSIONS: Medication error safety concerns were listed for almost a quarter of centrally authorised products approved during the study period. Further research is needed to evaluate the effectiveness and continued need for additional risk minimisation measures for medication errors.

Spontaneous reports of vaccination errors in the European regulatory database EudraVigilance: A descriptive study.

BACKGROUND: Among all post-marketing medication error reports submitted to EudraVigilance, vaccines are the most frequently reported medicinal products. This study aims to describe the characteristics of vaccination errors submitted to Eudravigilance between 2001 and 2016. METHODS: EudraVigilance is a spontaneous reporting database for adverse events maintained by the European Medicines Agency. We extracted Individual Case Safety Reports (ICSRs) submitted to EudraVigilance between 1 January 2001 and 31 December 2016. Reports were included for analysis if a vaccine was reported as interacting or suspect drug and at least one medication error term was listed as an adverse reaction. ICSRs were stratified by age and gender, by year of reporting, region of origin, reporter profession, seriousness of outcome, ATC, and type of error. RESULTS: In total, 7097 ICSRs were included in the study. We observed a yearly increase in the reporting of vaccination errors, with the proportion to all vaccine ICSRs increasing from 0.4% to 4.0% between 2001 and 2016. The majority of reports was classified as serious (4248, 59.9%), but non-serious reports were increasingly reported since 2012. The mean age of patients was 24.1 years. The most frequently reported vaccines were influenza (13.5%), bacterial and viral combined (12.3%), and hepatitis vaccines (11.8%). A total of 8167 medication error terms were reported. The most frequently reported terms were "Inappropriate schedule of drug administration" (27.2%), "Incorrect route of drug administration" (12.5%) and "Drug administered to patient of inappropriate age" (10.0%). For infants and children, the error "Drug administered to patient of inappropriate age" was reported more often than for all other age categories. DISCUSSION: Vaccination errors are increasingly submitted to EudraVigilance. Errors related to the schedule are the most common errors reported with vaccines. However, consequences of vaccination errors appear to be relatively mild.

Is patient exposure preapproval and postapproval a determinant of the timing and frequency of occurrence of safety issues?

BACKGROUND: The amount of drug exposure, pre and post approval, is considered to be a direct determinant of knowledge about the safety of a drug. A larger pre-approval exposed population is supposed to reduce the risk of unanticipated safety issues post-approval. The amount of use in the postapproval population is also expected to influence the occurrence and timing of safety issues. We investigated how the amount of pre and post approval exposure influences the detection of post-approval safety issues. METHODS: A cohort of innovative drugs approved in Europe was followed for the period of 2012-2016. The main outcome of interest was a new safety issue in the period. Post-approval exposure was collected at 6 month intervals, and pre-approval exposure was collected at the moment of authorisation. Other characteristics collected for the included drugs were anatomical therapeutical chemical (ATC) class, biological status, orphan status and type of approval. We used Cox proportional hazards regression to investigate the association between exposure and the hazard of having a first safety issue. RESULTS: The pre-approval exposure was not associated with the risk of safety issues after adjusting for ATC class, biological status, and treatment duration. Higher post-approval exposure was associated with more new safety issues identified (HR = 2.44 (95% CI = 1.12-5.31)) for drugs with more than 1,000 patient-years of cumulative exposure compared to drugs with less than 1,000 patient years of exposure. CONCLUSION: Our results suggest that postapproval exposure influences the detection of safety issues.