Challenges in Assessing COVID-19 Vaccines Safety Signals-The Case of ChAdOx1 nCoV-19 Vaccine and Corneal Graft Rejection.

The rapid and large-scale roll-out of new COVID-19 vaccines has led to unprecedented challenges in assessing vaccine safety. In 2021, the European Medicines Agency (EMA) processed about 1.7 million safety reports related to COVID-19 vaccines in the EudraVigilance (EV) database and identified more than 900 potential signals. Beyond the large amount of information to be processed, the evaluation of safety signals has faced several difficulties and limitations, both in the assessment of case reports and in the investigation of databases. The evaluation of a signal of corneal graft rejection (CGR) with Vaxzevria® was no exception to this. In this commentary, we present the challenges encountered in making regulatory decisions in the context of evolving evidence and knowledge. The pandemic crisis emphasised the importance of quick and proactive communication to address the many questions and, above all, to ensure the transparency of safety data.

Cohort Event Monitoring of Adverse Reactions to COVID-19 Vaccines in Seven European Countries: Pooled Results on First Dose.

INTRODUCTION: COVID-19 vaccines were rapidly authorised, thus requiring intense post-marketing re-evaluation of their benefit-risk profile. A multi-national European collaboration was established with the aim to prospectively monitor safety of the COVID-19 vaccines through web-based survey of vaccinees. METHODS: A prospective cohort event monitoring study was conducted with primary consented data collection in seven European countries. Through the web applications, participants received and completed baseline and up to six follow-up questionnaires on self-reported adverse reactions for at least 6 months following the first dose of COVID-19 vaccine (Netherlands, France, Belgium, UK, Italy) and baseline and up to ten follow-up questionnaires for one year in Germany and Croatia. Rates of adverse reactions have been described by type (solicited, non-solicited; serious/non-serious; and adverse events of special interest) and stratified by vaccine brand. We calculated the frequency of adverse reaction after dose 1 and prior to dose 2 among all vaccinees who completed at least one follow-up questionnaire. RESULTS: Overall, 117,791 participants were included and completed the first questionnaire in addition to the baseline: 88,196 (74.9%) from Germany, 27,588 (23.4%) from Netherlands, 984 (0.8%) from France, 570 (0.5%) from Italy, 326 (0.3%) from Croatia, 89 (0.1%) from the UK and 38 (0.03%) from Belgium. There were 89,377 (75.9%) respondents who had received AstraZeneca vaccines, 14,658 (12.4%) BioNTech/Pfizer, 11,266 (9.6%) Moderna and 2490 (2.1%) Janssen vaccines as a first dose. Median age category was 40-49 years for all vaccines except for Pfizer where median age was 70-79 years. Most vaccinees were female with a female-to-male ratio of 1.34, 1.96 and 2.50 for AstraZeneca, Moderna and Janssen, respectively. BioNtech/Pfizer had slightly more men with a ratio of 0.82. Fatigue and headache were the most commonly reported solicited systemic adverse reactions and injection-site pain was the most common solicited local reaction. The rates of adverse events of special interest (AESIs) were 0.1-0.2% across all vaccine brands. CONCLUSION: This large-scale prospective study of COVID-19 vaccine recipients showed, for all the studied vaccines, a high frequency of systemic reactions, related to the immunogenic response, and local reactions at the injection site, while serious reactions or AESIs were uncommon, consistent with those reported on product labels. This study demonstrated the feasibility of setting up and conducting cohort event monitoring across multiple European countries to collect safety data on novel vaccines that are rolled out at scale in populations which may not have been included in pivotal trials.

Use and misuse of prescription stimulants by university students: a cross-sectional survey in the french-speaking community of Belgium, 2018.

BACKGROUND: Misuse of prescription stimulants (PS) has been reported among students to enhance academic performance in Flanders (Belgium). However, PS misuse among students in the French-speaking community is unknown. The main purpose of the study was to estimate the prevalence of medical use and misuse of PS by university students in the French-speaking community (Belgium), and to investigate the reasons and sources associated with PS misuse. METHODS: A cross-sectional online survey was performed in 2018. All university students 18 years and older were invited to participate and asked about PS use, including medical (i.e., used for therapeutic purposes) and nonmedical reasons and sources of PS. RESULTS: In total, 12 144 students participated in the survey (median age = 21 years, 65.5% female). The estimated prevalence of PS use was 6.9% (ever use) and 5.5% (past-year). Among ever users, 34.7% were classified as medical users and 65.3% as misusers. Lifetime prevalence of misuse was estimated at 4.5%. The most common reason for medical use was treatment of attention disorder (85.9%). Reasons for misuse were mainly to improve concentration (76.1%) or to stay awake and study longer (50.7%). Friends or acquaintances inside the student community and general practitioners were the main sources of PS for misuse (41.5% and 23.5%, respectively). CONCLUSIONS: This study found that rates of misuse of PS in French-speaking universities in Belgium were in line with studies conducted in Flanders and Europe. Academic institutions can use these results to tailor their drug prevention campaigns.

Ongoing measles outbreak in Wallonia, Belgium, December 2016 to March 2017: characteristics and challenges.

We describe characteristics of an ongoing measles outbreak in Wallonia, Belgium, and difficulties in control measures implementation. As at 12 March 2017, 177 measles cases were notified, of which 50% were 15 years and older, 49% female. Atypical clinical presentation and severe complications, mainly among adults, in combination with late notification, low or unknown vaccination coverage of contacts, infected healthcare workers and increased workload due to contact tracing, are the main concerns for outbreak management.

Inferring rubella outbreak risk from seroprevalence data in Belgium.

Rubella is usually a mild disease for which infections often pass by unnoticed. In approximately 50% of the cases, there are no or only few clinical symptoms. However, rubella contracted during early pregnancy could lead to spontaneous abortion, to central nervous system defects, or to one of a range of other serious and debilitating conditions in a newborn such as the congenital rubella syndrome. Before the introduction of mass vaccination, rubella was a common childhood infection occurring all over the world. However, since the introduction of rubella antigen-containing vaccines, the incidence of rubella has declined dramatically in high-income countries. Recent large-scale mumps outbreaks, one of the components in the combined measles-mumps-rubella vaccine, occurring in countries throughout Europe with high vaccination coverage, provide evidence of pathogen-specific waning of vaccine-induced immunity and primary vaccine failure. In addition, recent measles outbreaks affecting populations with suboptimal vaccination coverages stress the importance of maintaining high vaccination coverages. In this paper, we focus on the assessment of rubella outbreak risk using a previously developed method to identify geographic regions of high outbreak potential. The methodology relies on 2006 rubella seroprevalence data and vaccination coverage data from Belgium and information on primary and secondary vaccine failure obtained from extensive literature reviews. We estimated the rubella outbreak risk in Belgium to be low, however maintaining high levels of immunisation and surveillance are of utmost importance to avoid future outbreaks.

Different measles outbreaks in Belgium, January to June 2016 - a challenge for public health.

During the first half of 2016, several outbreaks of measles were reported in the three regions of Belgium. Main challenges for public health were severe complications occurring in adults, nosocomial transmission and infection in healthcare workers. Here, we describe those outbreaks and lessons learnt for public health.

Sustained low rotavirus activity and hospitalisation rates in the post-vaccination era in Belgium, 2007 to 2014.

In 2006, Belgium was the first country in the European Union to recommend rotavirus vaccination in the routine infant vaccination schedule and rapidly achieved high vaccine uptake (86-89% in 2007). We used regional and national data sources up to 7 years post-vaccination to study the impact of vaccination on laboratory-confirmed rotavirus cases and rotavirus-related hospitalisations and deaths. We showed that (i) from 2007 until 2013, vaccination coverage remained at 79-88% for a complete course, (ii) in children 0-2 years, rotavirus cases decreased by 79% (95% confidence intervals (CI): 68--89%) in 2008-2014 compared to the pre-vaccination period (1999--2006) and by 50% (95% CI: 14-82%) in the age group ≥ 10 years, (iii) hospitalisations for rotavirus gastroenteritis decreased by 87% (95% CI: 84-90%) in 2008--2012 compared to the pre-vaccination period (2002--2006), (iv) median age of rotavirus cases increased from 12 months to 17 months and (v) the rotavirus seasonal peak was reduced and delayed in all post-vaccination years. The substantial decline in rotavirus gastroenteritis requiring hospitalisations and in rotavirus activity following introduction of rotavirus vaccination is sustained over time and more pronounced in the target age group, but with evidence of herd immunity.

The resurgence of mumps and pertussis.

Vaccines and extended vaccination programs have had an extensive impact on morbidity and mortality rates due to infectious diseases. Because of the continuous and extensive use of vaccines in industrialized countries, many infectious diseases such as poliomyelitis, diphtheria and measles have been reduced to near-extinction. However, in recent years, many countries including the United States of America, the United Kingdom and Belgium, have been confronted with a resurgence of mumps and pertussis, despite high vaccination coverage for both vaccines. In this commentary, possible causes of this resurgence will be discussed, such as the occurrence of adapted microbes, failure to vaccinate and primary and secondary vaccine failure. Additional research of the immunological mechanisms is clearly needed to support the development of possible new and more immunogenic vaccines against mumps and pertussis. Meanwhile, extensive vaccination campaigns with both vaccines remain necessary.

Varicella paediatric hospitalisations in Belgium: a 1-year national survey.

BACKGROUND: Varicella universal vaccination (UV) has been implemented in many countries for several years. Nevertheless, varicella UV remains debated in Europe and few data are available on the real burden of infection. We assessed the burden of varicella in Belgium through analysis of hospitalised cases during a 1-year period. METHODS: Data on children admitted to hospital with varicella were collected through a national network from November 2011 to October 2012. Inclusion criteria were either acute varicella or related complications up to 3 weeks after the rash. RESULTS: Participation of 101 hospitals was obtained, covering 97.7% of the total paediatric beds in Belgium. 552 children were included with a median age of 2.1 years. Incidence of paediatric varicella hospitalisations reached 29.5/10(5) person-years, with the highest impact among those 0-4 years old (global incidence and odds of hospitalisation: 79/10(5) person-years and 1.6/100 varicella cases, respectively). Only 14% (79/552) of the cohort had an underlying chronic condition. 65% (357/552) of children had ≥1 complication justifying their admission, 49% were bacterial superinfections and 10% neurological disorders. Only a quarter of children (141/552) received acyclovir. Incidence of complicated hospitalised cases was 19/10(5) person-years. Paediatric intensive care unit admission and surgery were required in 4% and 3% of hospitalised cases, respectively. Mortality among Belgian paediatric population was 0.5/10(6) and fatality ratio 0.2% among our cohort. CONCLUSIONS: Varicella demonstrated a substantial burden of disease in Belgian children, especially among the youngest. Our thorough nationwide study, run in a country without varicella UV, offers data to support varicella UV in Belgium.

Performance of acute flaccid paralysis surveillance compared with World Health Organization standards.

AIM: To compare acute flaccid paralysis (AFP) surveillance systems used by members of the International Network of Paediatric Surveillance Units (INoPSU) across the five AFP surveillance performance indicators recommended by the World Health Organization (WHO) for the maintenance of polio-free certification. METHODS: A survey was administered to AFP surveillance co-ordinators in five INoPSU member countries (Australia, Belgium, Canada, New Zealand and Switzerland). Data collected included information on surveillance system processes, WHO-recommended performance indicators, investigative practices and final diagnoses of cases from 2006 to 2010. RESULTS: All countries contacted completed the survey. Each country used similar case definitions and processes for collecting AFP data. All countries used at least one of the WHO indicators for surveillance. No country consistently met the performance indicator for incidence or stool sampling. In all countries, at least one form of neurological testing was used to diagnose cases of AFP. Guillain-Barré syndrome was the most common final diagnosis in all countries for all years examined. CONCLUSIONS: Industrialised countries surveyed do not consistently meet the WHO-recommended AFP surveillance performance indicators. An opportunity exists for INoPSU to suggest a standard way for member countries to collect AFP data in order to examine the potential for strengthening the current systems or introducing additional enterovirus surveillance or alternative/complementary neurological performance measures suitable for countries that have eliminated polio. INoPSU member countries are evaluating these possibilities.

Obstacles in measles elimination: an in-depth description of a measles outbreak in Ghent, Belgium, spring 2011.

BACKGROUND: From Mid-February to April 2011 one of the largest measles-outbreak in Flanders, since the start of the 2-dose vaccination scheme in 1995, took place in Ghent, Belgium. The outbreak started in a day care center, infecting children too young to be vaccinated, after which it spread to anthroposophic schools with a low measles, mumps and rubella vaccination coverage. This report describes the outbreak and evaluates the control measures and interventions. METHODS: Data collection was done through the system of mandatory notification of the public health authority. Vaccination coverage in the schools was assessed by a questionnaire and the electronic immunization database 'Vaccinnet'. A case was defined as anyone with laboratory confirmed measles or with clinical symptoms and an epidemiological link to a laboratory confirmed case. Towards the end of the outbreak we only sought laboratory confirmation for persons with an atypical clinical presentation or without an epidemiological link. In search for an index patient we determined the measles IgG level of infants from the day care center. RESULTS: A total of 65 cases were reported of which 31 were laboratory confirmed. Twenty-five were confirmed by PCR and/or IgM. In 6 infants, too young to be vaccinated, only elevated measles IgG levels were found. Most cases (72%) were young children (0-9 years old). All but two cases were completely unimmunized. In the day care center all the infants who were too young to be vaccinated (N=14) were included as cases. Thirteen of them were laboratory confirmed. Eight of these infants were hospitalized with symptoms suspicious for measles. Vaccination coverage in the affected anthroposophic schools was low, 45-49% of the pupils were unvaccinated. We organized vaccination campaigns in the schools and vaccinated 79 persons (25% of those unvaccinated or incompletely vaccinated). CONCLUSIONS: Clustering of unvaccinated persons, in a day care center and in anthroposophic schools, allows for measles outbreaks and is an important obstacle for the elimination of measles. Isolation measures, a vacation period and an immunization campaign limited the spread of measles within the schools but could not prevent further spread among unvaccinated family members. It was necessary to raise clinicians' awareness of measles since it had become a rare, less known disease and went undiagnosed.

Impact of rotavirus vaccination on laboratory confirmed cases in Belgium.

Rotavirus vaccines were introduced in Belgium in 2006 and recommended in the universal schedule in January 2007. We measured the impact of rotavirus vaccination through an active laboratory-based surveillance system. In 2008, the number of laboratory confirmed rotavirus cases declined by 61.4% (95% CI 60.2-62.6%) compared to the 2005-2006 pre-vaccination period, with the highest decline in children<1 year (80.1%; 95% CI 78.7-81.4%). The rotavirus season was delayed compared to pre-vaccination seasons. Laboratory data provide a crude estimation of vaccination impact, but analysis of in-patient data will be needed to assess the impact on severe disease.

Impact of conjugate 7-valent vaccination in Belgium: addressing methodological challenges.

In Belgium, the 7-valent pneumococcal conjugate vaccine (PCV7) was introduced into the national schedule in 2007. The early impact of PCV7 vaccination on paediatric invasive disease was estimated by comparing pre- and post-vaccination incidence from national surveillance. In children <2 year-olds, vaccine-serotype incidence declined by 96% but non-vaccine-types increased 2-3-fold. Overall invasive disease decreased by 23-46%, depending on adjustment for under-reporting and pre-vaccine trends. Non-vaccine-types 1 and 19A had increased before PCV7 use, suggesting the contribution of other factors. Estimation of PCV7 impact comparing pre- and post-vaccination data should adjust for pre-vaccine trends, and serotype dynamics need further exploration.

Rotavirus vaccines in Belgium: policy and impact.

BACKGROUND: : The current Belgian experience with rotavirus vaccination provides a unique perspective to look at the effect of vaccination. Shortly after introduction, a nation-wide recommendation was issued and despite the fact that both rotavirus vaccines are offered through partial reimbursement, vaccine uptake has already reached a high level (at least 90%). METHODS: : For the purpose of looking at the effectiveness of the Belgian rotavirus vaccination policy, 3 years after introduction, we retrospectively collated the publicly available data on the number of laboratory-confirmed rotavirus cases reported to a national network of sentinel laboratories during 1999 to 2010 and compared them with the available data on hospitalizations due to rotavirus gastroenteritis. RESULTS: : Both data sources (reported laboratory-diagnosed cases to a sentinel network as well as data on hospitalizations due to rotavirus gastroenteritis) show a decrease in the number of rotavirus infections and a 4- to 6-week delay in the onset of disease and the peak of incidence in the postvaccination period. CONCLUSIONS: : Because this decline coincides with the increased vaccine uptake and is sustained during consecutive rotavirus seasons, the effect is mainly attributed to the rotavirus vaccination. The rapid increase in vaccine coverage, despite the partial reimbursement for the vaccines, is remarkable. Continued postlicensure surveillance is necessary to further investigate the effectiveness of the vaccines and to document the public health impact of the vaccination in reducing disease burden.