Validation of the newly proposed Brighton Collaboration case definition for vaccine-induced immune thrombocytopenia and thrombosis.

Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a newly recognized syndrome mediated by anti-platelet factor 4 antibodies induced by Covid-19 adenovirus-vectored vaccines including ChAdOx1 nCoV-19 and Ad26.COV2.S. This study validated a proposed Brighton Collaboration case definition for VITT. A data collection form was developed and used to capture the variations in VITT criteria and assess their level of diagnostic certainty from adjudicated positive VITT case datasheets in Germany (n = 71), UK (n = 220), Australia (n = 203), and Taiwan (n = 56). We observed high prevalence of each component of the proposed VITT definition in positive cases (84%-100%), except for the occurrence of thrombosis or thromboembolism criterion in only 34% of VITT cases in Taiwan. The sensitivity of this proposed definition was 100% for Germany and UK, 92% for Australia, and 89% for Taiwan cases. These findings support the validity of this case definition for VITT.

Thrombosis with thrombocytopenia syndrome (TTS) and vaccine-induced immune thrombocytopenia and thrombosis (VITT): Brighton Collaboration case definitions and guidelines for data collection, analysis, and presentation of immunisation safety data.

This is a revision of the online November 2021 Brighton thrombosis with thrombocytopenia syndrome (TTS) case definition and a new Brighton Collaboration case definition for vaccine-induced immune thrombocytopenia and thrombosis (VITT). These case definitions are intended for use in clinical trials and post-licensure pharmacovigilance activities to facilitate safety data comparability across multiple settings. They are not intended to guide clinical management. The case definitions were developed by a group of subject matter and Brighton Collaboration process experts as part of the Coalition for Epidemic Preparedness Innovations (CEPI)-funded Safety Platform for Evaluation of vACcines (SPEAC). The case definitions, each with defined levels of diagnostic certainty, are based on relevant published evidence and expert consensus and are accompanied by specific guidelines for TTS and VITT data collection and analysis. The document underwent peer review by a reference group of vaccine safety stakeholders and haematology experts to ensure case definition useability, applicability and scientific integrity.

Anosmia: Brighton Collaboration case definition and guidelines for data collection, analysis, and presentation of immunization safety data.

This is a Brighton Collaboration case definition of anosmia to be used in the evaluation of adverse events following immunization, and for epidemiologic studies for the assessment of background incidence or hypothesis testing. The case definition was developed by a group of experts convened by the Coalition for Epidemic Preparedness Innovations (CEPI) in the context of active development of SARS-CoV-2 vaccines. The case definition format of the Brighton Collaboration was followed to develop a consensus definition and defined levels of certainty, after an exhaustive review of the literature and expert consultation. The document underwent peer review by the Brighton Collaboration Network and by two expert reviewers prior to submission.

Anaphylaxis: Revision of the Brighton collaboration case definition.

The Brighton Collaboration (BC) has formulated a number of case definitions which have primarily been applied to adverse events of special interest in the context of vaccine safety surveillance. This is a revision of the 2007 BC case definition for anaphylaxis. Recently, the BC definition has been widely used for evaluating reports of suspected anaphylaxis following COVID-19 vaccination. This has led to debate about the performance of the BC definition in comparison with those from the US National Institute of Allergy and Infectious Disease/Food Allergy Anaphylaxis Network (NIAID/FAAN) and the World Allergy Organization (WAO). BC convened an expert working group to revise the case definition based on their usual process of literature review and expert consensus. This manuscript presents the outcome of this process and proposes a revised case definition for anaphylaxis. Major and minor criteria have been re-evaluated with an emphasis on the reporting of observable clinical signs, rather than subjective symptoms, and a clearer approach to the ascertainment of levels of certainty is provided. The BC case definition has also been aligned with other contemporary and international case definitions for anaphylaxis.

Thrombosis and thromboembolism: Brighton collaboration case definition and guidelines for data collection, analysis, and presentation of immunization safety data.

This is a Brighton Collaboration case definition of thrombosis and thromboembolism to be used in the evaluation of adverse events following immunization, and for epidemiologic studies for the assessment of background incidence or hypothesis testing. The case definition was developed by a group of experts convened by the Coalition for Epidemic Preparedness Innovations (CEPI) in the context of active development of SARS-CoV-2 vaccines. The case definition format of the Brighton Collaboration was followed to develop a consensus definition and defined levels of certainty, after an exhaustive review of the literature and expert consultation. The document underwent peer review by the Brighton Collaboration Network and by selected expert reviewers prior to submission.

The critical role of background rates of possible adverse events in the assessment of COVID-19 vaccine safety.

Beginning in December of 2019, a novel coronavirus, SARS-CoV-2, emerged in China and is now a global pandemic with extensive morbidity and mortality. With the emergence of this threat, an unprecedented effort to develop vaccines against this virus began. As vaccines are now being introduced globally, we face the prospect of millions of people being vaccinated with multiple types of vaccines many of which use new vaccine platforms. Since medical events happen without vaccines, it will be important to know at what rate events occur in the background so that when adverse events are identified one has a frame of reference with which to compare the rates of these events so as to make an initial assessment as to whether there is a potential safety concern or not. Background rates vary over time, by geography, by sex, socioeconomic status and by age group. Here we describe two key steps for post-introduction safety evaluation of COVID-19 vaccines: Defining a dynamic list of Adverse Events of Special Interest (AESI) and establishing background rates for these AESI. We use multiple examples to illustrate use of rates and caveats for their use. In addition we discuss tools available from the Brighton Collaboration that facilitate case evaluation and understanding of AESI.

Vaccine-associated enhanced disease: Case definition and guidelines for data collection, analysis, and presentation of immunization safety data.

This is a Brighton Collaboration Case Definition of the term "Vaccine Associated Enhanced Disease" to be utilized in the evaluation of adverse events following immunization. The Case Definition was developed by a group of experts convened by the Coalition for Epidemic Preparedness Innovations (CEPI) in the context of active development of vaccines for SARS-CoV-2 vaccines and other emerging pathogens. The case definition format of the Brighton Collaboration was followed to develop a consensus definition and defined levels of certainty, after an exhaustive review of the literature and expert consultation. The document underwent peer review by the Brighton Collaboration Network and by selected Expert Reviewers prior to submission.

Quadrivalent human papillomavirus vaccination in girls and the risk of autoimmune disorders: the Ontario Grade 8 HPV Vaccine Cohort Study.

BACKGROUND: Despite demonstrated effectiveness in real-world settings, concerns persist regarding the safety of the quadrivalent human papillomavirus (HPV4) vaccine. We sought to assess the risk of autoimmune disorders following HPV4 vaccination among grade 8 girls eligible for Ontario's school-based HPV vaccination program. METHODS: We undertook a population-based retrospective cohort study using Ontario's administrative health and vaccination databases from 2007 to 2013. The self-controlled case series method was used to compare the rate of a composite end point of autoimmune disorders diagnosed during days 7-60 post-vaccination ("exposed" follow-up) to that at any other time ("unexposed"). The analysis was repeated to assess the effect of a history of immune-mediated diseases and time since vaccination. We also conducted an exploratory analysis of individual autoimmune disorders. Rate ratios and 95% confidence intervals (CIs) were estimated using conditional Poisson regression, adjusted for age, seasonality, concomitant vaccinations and infections. RESULTS: The study cohort consisted of 290 939 girls aged 12-17 years who were eligible for vaccination between 2007 and 2013. There was no significant risk for developing an autoimmune disorder following HPV4 vaccination (n = 681; rate ratio 1.12, 95% CI 0.85-1.47), and the association was unchanged by a history of immune-mediated disorders and time since vaccination. Exploratory analyses of individual autoimmune disorders found no significant risks, including for Bell palsy (n = 65; rate ratio 1.73, 95% CI 0.77-3.89), optic neuritis (n = 67; rate ratio 1.57, 95% CI 0.74-3.33) and Graves disease (n = 47; rate ratio 1.55, 95% CI 0.92-2.63). INTERPRETATION: We did not observe an increased risk of autoimmune disorders following HPV4 vaccination among teenaged girls. These findings should reassure parents and health care providers.

Canada's eight-component vaccine safety system: A primer for health care workers.

Concerns about vaccine safety make some parents hesitant about immunization. Health care providers are pivotal in helping parents understand that Canada is a leader in vaccine safety. The present practice point provides an update on the eight components of Canada's vaccine safety system: (1) an evidence-based pre-license review and approval process; (2) strong regulations for manufacturers; (3) independent evidence-based vaccine use recommendations; (4) immunization competency training and standards for health care providers; (5) pharmacovigilance programs to detect and (6) determine causality of adverse events following immunization (AEFIs); (7) a program for vaccine safety and efficacy signal detection; and (8) the Canadian Immunization Research Network's special immunization clinics for children who have experienced serious AEFIs.

Canada's eight-component vaccine safety system: A primer for health care workers.

Concerns about vaccine safety make some parents hesitant about immunization. Health care providers are pivotal in helping parents understand that Canada is a leader in vaccine safety. The present practice point provides an update on the eight components of Canada's vaccine safety system: (1) an evidence-based pre-license review and approval process; (2) strong regulations for manufacturers; (3) independent evidence-based vaccine use recommendations; (4) immunization competency training and standards for health care providers; (5) pharmacovigilance programs to detect and (6) determine causality of adverse events following immunization (AEFIs); (7) a program for vaccine safety and efficacy signal detection; and (8) the Canadian Immunization Research Network's special immunization clinics for children who have experienced serious AEFIs.

Guillain-BarrÉ Syndrome After Immunization in Canadian Children (1996-2012).

Guillain-Barré syndrome (GBS) cases admitted to Canadian pediatric tertiary care centers were ascertained through active surveillance. From 1996 to 2012, 246 cases were identified, and 24 (10%) had onset ≤30 days after immunization. Annual rate of postimmunization GBS was 2.0 per 100,000 hospitalizations. Postimmunization GBS was an infrequent cause of pediatric hospitalization.

Immunogenicity, safety, and antibody persistence at 3, 5, and 10 years postvaccination in adolescents randomized to booster immunization with a combined tetanus, diphtheria, 5-component acellular pertussis, and inactivated poliomyelitis vaccine administered with a hepatitis B virus vaccine concurrently or 1 month apart.

An understanding of the antibody persistence elicited by a combined tetanus, diphtheria, 5-component acellular pertussis, and inactivated poliovirus vaccine (Tdap-IPV) after adolescent vaccination is important to optimize booster dosing intervals. Our objectives were to compare the safety and immunogenicity of Tdap-IPV coadministered with hepatitis B vaccine (HepB) and sequential administration and evaluate humoral immunity at 3, 5, and 10 years after Tdap-IPV vaccination in adolescents. This phase II randomized, controlled, and open-label study enrolled 280 11- to 14-year-old adolescents with up to 10 years postvaccination follow-up. Group 1 (n = 145) received Tdap-IPV, followed by a HepB dose 1 month later, and group 2 (n = 135) received both vaccines simultaneously. No consistent increases in solicited reactions or unsolicited adverse events occurred with coadministration. All vaccinees attained seroprotective antibody levels at ≥0.01 IU/ml for diphtheria and tetanus, at a ≥1:8 dilution for poliovirus (serotypes 1, 2, and 3), and ≥10 mIU/ml for hepatitis B at 1 month postvaccination. Clinically relevant immunologic interactions did not occur with coadministration. For pertussis, all participants achieved seropositivity levels (at or above the lower limit of quantitation), and 72.7% to 95.8% had 4-fold increases in pertussis antibodies at 1 month postvaccination. At 10 years postvaccination, the remaining participants (62.8% of the original cohort) maintained seroprotective levels of ≥0.01 IU/ml for diphtheria and tetanus, a ≥1:8 dilution for all 3 poliovirus serotypes, and 74.1% to 98.2% maintained pertussis seropositivity levels depending on the antigen tested. There were no differences between the groups. These results support the coadministration of Tdap-IPV and HepB to adolescents and suggest that vaccination with Tdap-IPV can offer protection for 10 years after an adolescent booster vaccination.

Applicability of the Brighton Collaboration Case Definition for seizure after immunization in active and passive surveillance in Canada.

BACKGROUND: The Canadian Adverse Event Following Immunization Surveillance System (CAEFISS) receives reports via active syndromic surveillance for selected serious AEFI from the Canadian Immunization Monitoring Program Active (IMPACT) and via targeted passive surveillance from Federal/Provincial/Territorial health jurisdictions. Post-immunization seizure is a target of active and passive surveillance. Since 2009, the revised national AEFI reporting forms enable capture of terms specific to several Brighton Collaboration Case Definitions (BCCD) including generalized seizure and fever. OBJECTIVE: To evaluate feasibility of applying the BCCD for generalized seizure to adverse event following immunization (AEFI) reports collected by IMPACT and targeted passive surveillance (non-IMPACT). METHODS: Reports to CAEFISS coded as seizure in children <2 years of age (vaccination dates 1998-2011) were reviewed retrospectively. A BCCD level (1-5 or unclassifiable) was assigned. The effects of reporting source (IMPACT versus non-IMPACT), seriousness [serious (e.g., hospitalized) versus non-serious], vaccination year (1998-2008 versus 2009-2011), and data submission method to CAEFISS (electronic versus paper) were assessed by stratified analysis. RESULTS: There were 459 IMPACT and 908 non-IMPACT cases analyzed, of which 99.6% and 27%, respectively, were serious reports. The revised reporting form that captured the BCCD components (2009-2011) was associated with increased proportions of IMPACT and non-IMPACT cases meeting the BCCD for generalized seizure. CONCLUSIONS: Incorporating the BCCD components (level of consciousness, motor manifestations and fever ≥38°C) into the national reporting form and guidelines appeared to improve the feasibility of their use in AEFI surveillance. This effect was more pronounced among active syndromic surveillance compared to targeted passive surveillance reports.

Sustained elevation of systemic oxidative stress and inflammation in exacerbation and remission of asthma.

Oxidative stress has been implicated in the pathogenesis of asthma. We aimed at investigating the biomarkers of oxidative stress, inflammation, and tissue damage in patients with asthma in acute exacerbation and remission. We recruited 18 asthmatics admitted to hospital with acute exacerbation and 18 healthy nonsmoking controls matched for age. We evaluated plasma levels of 8-isoprostane, C-reactive protein (CRP) and total matrix metalloproteinase- (MMP-) 9 by ELISA, and MMP-9 activity by zymographic analysis. Plasma levels of 8-isoprostane and CRP were significantly elevated in acute exacerbation and decreased in remission but remained significantly higher compared to healthy controls. The activities of pro-MMP-9 were also significantly higher in acute exacerbation and decreased in remission but remained significantly higher compared to healthy controls in parallel to plasma levels of total MMP-9. These data suggest that overproduction of MMP-9 along with highly elevated levels of oxidative stress and inflammation is implicated in asthma exacerbation and that measurements of these biomarkers can be a valid index in its management.

Assessment of causality of individual adverse events following immunization (AEFI): a WHO tool for global use.

Serious illnesses or even deaths may rarely occur after childhood vaccinations. Public health programs are faced with great challenges to establish if the events presenting after the administration of a vaccine are due to other conditions, and hence a coincidental presentation, rather than caused by the administered vaccines. Given its priority, the Global Advisory Committee for Vaccine Safety (GACVS) commissioned a group of experts to review the previously published World Health Organization (WHO) Adverse Event Following Immunization (AEFI) causality assessment methodology and aide-memoire, and to develop a standardized and user friendly tool to assist health care personnel in the processing and interpretation of data on individual events, and to assess the causality after AEFIs. We describe a tool developed for causality assessment of individual AEFIs that includes: (a) an eligibility component for the assessment that reviews the diagnosis associated with the event and identifies the administered vaccines; (b) a checklist that systematically guides users to gather available information to feed a decision algorithm; and (c) a decision support algorithm that assists the assessors to come to a classification of the individual AEFI. Final classification generated by the process includes four categories in which the event is either: (1) consistent; (2) inconsistent; or (3) indeterminate with respect of causal association; or (4) unclassifiable. Subcategories are identified to assist assessors in resulting public health decisions that can be used for action. This proposed tool should support the classification of AEFI cases in a standardized, transparent manner and to collect essential information during AEFI investigation. The algorithm should provide countries and health officials at the global level with an instrument to respond to vaccine safety alerts, and support the education, research and policy decisions on immunization safety.

The effect of funded varicella immunization programs on varicella-related hospitalizations in IMPACT centers, Canada, 2000-2008.

BACKGROUND: The 12 Immunization Monitoring Program, Active (IMPACT) centers that represent 90% of pediatric tertiary care beds in Canada conducted active surveillance for varicella-related hospitalizations and complications from 1999 onward, after varicella vaccine was authorized. Publicly funded routine immunization programs at 12 or 15 months of age were introduced by 5 provinces and territories (prov/terr) in 2000 to 2002 (earlier programs, EP) and by 8 prov/terr in 2004 to 2007 (later programs, LP). OBJECTIVE: To determine whether the number of varicella-related hospitalized cases had declined by 2008 at 12 IMPACT centers after the sequential introduction of publicly funded varicella immunization programs in Canada. METHODS: Varicella-related hospitalizations from 2000 to 2008 in the prov/terr with EP were under surveillance by 3 IMPACT centers (Halifax, Edmonton, Calgary), whereas the prov/terr with LP were under surveillance by the remaining 9 centers. The age, gender, underlying health status, varicella complications, and length of stay in hospital and the pediatric intensive care unit were documented. Breakthrough cases were identified and their clinical characteristics described. RESULTS: Between 2000 and 2008, the number of varicella-related hospitalized cases in IMPACT centers declined relatively sooner in prov/terr with EP (by 2002 to 2003), as compared to those with LP (only by 2007 to 2008). In 2008, varicella-related hospitalized cases declined by 88% in the EP centers, and by 81% in the LP centers. In all IMPACT centers, the greatest decline occurred in the 1-4 years age group (90% decline), with smaller declines in both <1 year and 5-9 years age groups (78% and 76% decline, respectively). Breakthrough disease accounted for 39 (2%) cases, with the proportion due to breakthrough increasing from 0.9% in 2000 to 2001, to 2% in 2003 to 2004 and 9.5% in 2007 to 2008. The majority (72%) of breakthrough cases were in immunocompromised children. CONCLUSIONS: Publicly funded varicella vaccination programs have led to a significant decline in varicella-related hospitalizations in Canadian children, as a result of direct effects of the program beginning within 1 to 2 years after the start, as well as probable indirect protection of children outside the vaccinated cohort.

On-time vaccination coverage in premature infants in Ontario, 2002-2009.

OBJECTIVE: Premature children are at increased risk of complications from vaccine-preventable diseases and should be vaccinated with the routinely recommended childhood vaccines at the same chronological age as full-term infants with the exception of the hepatitis B vaccine for infants of HBsAg-positive mothers. We sought to compare on-time vaccination levels in premature children for recommended vaccinations to levels in children born at term. METHODS: Using linked health administrative databases, we compared the proportion of term (37+ wks), near term (33-36 wks), very premature (28-32 wks) and extremely premature (≤27 wks) children who received at least one vaccination during the 2-, 4- and 6-month vaccination visits within the recommended time period in the province of Ontario. RESULTS: When we excluded children who were hospitalized at any time during the vaccination window, we identified that vaccination rates were within 3% of each other in the 4 categories examined. However, when we included infants who may have been hospitalized at any point during the on-time window, we observed substantially lower rates in the extremely premature children at 2 and 4 months and in the very premature children at 2 months. CONCLUSION: Our study identifies the need to confirm whether vaccinations are given while premature children are in hospital during the time of their scheduled vaccinations.

Influenza vaccine effectiveness in the elderly based on administrative databases: change in immunization habit as a marker for bias.

BACKGROUND: Administrative databases provide efficient methods to estimate influenza vaccine effectiveness (IVE) against severe outcomes in the elderly but are prone to intractable bias. This study returns to one of the linked population databases by which IVE against hospitalization and death in the elderly was first assessed. We explore IVE across six more recent influenza seasons, including periods before, during, and after peak activity to identify potential markers for bias. METHODS AND FINDINGS: Acute respiratory hospitalization and all-cause mortality were compared between immunized/non-immunized community-dwelling seniors ≥65 years through administrative databases in Manitoba, Canada between 2000-01 and 2005-06. IVE was compared during pre-season/influenza/post-season periods through logistic regression with multivariable adjustment (age/sex/income/residence/prior influenza or pneumococcal immunization/medical visits/comorbidity), stratification based on prior influenza immunization history, and propensity scores. Analysis during pre-season periods assessed baseline differences between immunized and unimmunized groups. The study population included ∼140,000 seniors, of whom 50-60% were immunized annually. Adjustment for key covariates and use of propensity scores consistently increased IVE. Estimates were paradoxically higher pre-season and for all-cause mortality vs. acute respiratory hospitalization. Stratified analysis showed that those twice consecutively and currently immunized were always at significantly lower hospitalization/mortality risk with odds ratios (OR) of 0.60 [95%CI0.48-0.75] and 0.58 [0.53-0.64] pre-season and 0.77 [0.69-0.86] and 0.71 [0.66-0.77] during influenza circulation, relative to the consistently unimmunized. Conversely, those forgoing immunization when twice previously immunized were always at significantly higher hospitalization/mortality risk with OR of 1.41 [1.14-1.73] and 2.45 [2.21-2.72] pre-season and 1.21 [1.03-1.43] and 1.78 [1.61-1.96] during influenza circulation. CONCLUSIONS: The most pronounced IVE estimates were paradoxically observed pre-season, indicating bias tending to over-estimate vaccine protection. Change in immunization habit from that of the prior two years may be a marker for this bias in administrative data sets; however, no analytic technique explored could adjust for its influence. Improved methods to achieve valid interpretation of protection in the elderly are needed.

The responses of Aboriginal Canadians to adjuvanted pandemic (H1N1) 2009 influenza vaccine.

BACKGROUND: Because many Aboriginal Canadians had severe cases of pandemic (H1N1) 2009 influenza, they were given priority access to vaccine. However, it was not known if the single recommended dose would adequately protect people at high risk, prompting our study to assess responses to the vaccine among Aboriginal Canadians. METHODS: We enrolled First Nations and Métis adults aged 20-59 years in our prospective cohort study. Participants were given one 0.5-mL dose of ASO3-adjuvanted pandemic (H1N1) 2009 vaccine (Arepanrix, GlaxoSmithKline Canada). Blood samples were taken at baseline and 21-28 days after vaccination. Paired sera were tested for hemagglutination-inhibiting antibodies at a reference laboratory. To assess vaccine safety, we monitored the injection site symptoms of each participant for seven days. We also monitored patients for general symptoms within 7 days of vaccination and any use of the health care system for 21-28 days after vaccination. RESULTS: We enrolled 138 participants in the study (95 First Nations, 43 Métis), 137 of whom provided all safety data and 136 of whom provided both blood samples. First Nations and Métis participants had similar characteristics, including high rates of chronic health conditions (74.4%-76.8%). Pre-existing antibody to the virus was detected in 34.3% of the participants, all of whom boosted strongly with vaccination (seroprotection rate [titre ≥ 40] 100%, geometric mean titre 531-667). Participants with no pre-existing antibody also responded well. Fifty-eight of 59 (98.3%) First Nations participants showed seroprotection and a geometric mean titre of 353.6; all 30 Métis participants with no pre-existing antibody showed seroprotection and a geometric mean titre of 376.2. Pain at the injection site and general symptoms frequently occurred but were short-lived and generally not severe, although three participants (2.2%) sought medical attention for general symptoms. INTERPRETATION: First Nations and Métis adults responded robustly to ASO3-adjuvanted pandemic (H1N1) 2009 vaccine. Virtually all participants showed protective titres, including those with chronic health conditions.