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.

Systematic review of spontaneous reports of myocarditis and pericarditis in transplant recipients and immunocompromised patients following COVID-19 mRNA vaccination.

OBJECTIVES: To determine whether spontaneous reporting rates of myocarditis and pericarditis differed in immunocompromised patients compared with the whole population overall, and in terms of demographics, vaccine dose and time-to-onset. DESIGN: Systematic review of spontaneously reported data from the European Union/European Economic Area (EU/EEA), the USA and the UK. DATA SOURCES: EudraVigilance (EU/EEA), Vaccine Adverse Event Reporting System (VAERS; USA) and the Medicines and Healthcare products Regulatory Agency (UK) spontaneous reporting databases were searched from date of vaccine launch to 1 December 2021. ELIGIBILITY CRITERIA: Publicly available spontaneous reporting data for 'myocarditis' and 'pericarditis' from EU/EEA and USA following COVID-19 messenger RNA vaccines. Reports with comorbidities or concurrent medication indicative of transplantation, HIV infection or cancer ('immunocompromised' population) were compared with each overall database population. DATA EXTRACTION AND SYNTHESIS: Two researchers extracted data. Spontaneously reported events of myocarditis and pericarditis were presented for immunocompromised populations for each data source, stratified by age, sex, dose and time-to-onset (where available). Seriousness of each event was determined according to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guideline E2A definition. Proportional reporting ratio (PRR) was calculated. RESULTS: There were 178 reports of myocarditis and pericarditis among immunocompromised individuals overall. Seriousness was comparable between the immunocompromised and overall populations in both databases. No trends in age or sex were observed among immunocompromised individuals. Most reports followed a second vaccine dose and occurred within 14 days. The frequency of reporting was similar to the wider population (PRR=1.36 (95% CI=0.89 to 1.82) for VAERS population). CONCLUSIONS: Myocarditis and pericarditis following COVID-19 vaccination are very rare, and benefits of COVID-19 vaccination continue to outweigh any perceived risks. Reporting rates of myocarditis and pericarditis were similar in immunocompromised individuals, however defining characteristics differed compared with the whole population; therefore, continued monitoring of adverse events following vaccination remains vital to understand differences between population subgroups.

Assessing Case Fatality on Cases of Thrombosis with Concurrent Thrombocytopenia Following COVID-19 Vaccine AstraZeneca (Vaxzevria) in the United Kingdom: A Review of Spontaneously Reported Data.

INTRODUCTION: Thrombotic thrombocytopenia syndrome (TTS) events were reported very rarely following the coronavirus disease 2019 (COVID-19) vaccine AstraZeneca (Vaxzevria). Clinical and demographic characteristics of the affected people, including the outcomes of TTS events, need to be examined using available information to better understand aspects of this association. OBJECTIVE: To analyse clinical and demographic information of TTS events, including calculating the case fatality of reported cases of TTS by age and sex, using spontaneously reported data from the UK's Yellow Card spontaneous reporting system of suspected adverse drug reactions. METHODS: TTS events reported to the Yellow Card scheme were extracted at weekly time points between 12 May 2021 and 25 May 2022. Cumulative numbers of TTS cases and deaths were recorded for each weekly interval, overall and stratified by age, sex, and vaccine dose. RESULTS: To 25 May 2022, 443 cases (81 fatal, 18.28%) had been reported in the UK. Events more frequently occurred following the first vaccine dose. No trends were observed for case fatality overall, or by age or sex. CONCLUSION: In the UK, case fatality of TTS events reported to the Medicines and Health products Regulatory Agency (MHRA) following Vaxzevria has been approximately 17-18% since May 2021. There were no statistical differences in fatality based on age or sex. Most reports followed the first vaccine dose; none have been reported following a third dose to date, although Vaxzervia was not recommended for a third dose of COVID-19 vaccine in the UK. TTS remains very rare, and benefits of vaccination outweigh the risks.

Challenges for Drug Repurposing in the COVID-19 Pandemic Era.

The coronavirus disease (COVID-19) pandemic has affected an estimated 16 million persons and caused 0.6 million deaths worldwide by September 2020. The pandemic has led to a rush to repurpose existing drugs, although the underlying evidence base is of variable quality. The improving knowledge of the virology and clinical presentation of COVID-19 is leading to a broadening pool of potential pharmacological targets. The aim of this review is to describe regulatory and pharmacological aspects of drug repurposing and to identify drugs proposed for repurposing in COVID-19 based on registered clinical trials, discussing the evidence to support their use in the treatment of this disease. The challenges of the correct interpretation of existing pre-clinical/clinical evidence as well as the generation of new evidence concerning drug repurposing in COVID-19 will also be discussed. Clinical Trial Registration: https://clinicaltrials.gov, identifier NCT04321174, NCT04342663, NCT04280705, NCT04244591, NCT04359329, NCT04348695, NCT04304313, NCT043505931.

Postmarketing studies: can they provide a safety net for COVID-19 vaccines in the UK?

In the current era of the COVID-19 pandemic, the world has never been more interested in the process of vaccine development. While researchers across the globe race to find an effective yet safe vaccine to protect populations from the newly emergent SARS-CoV-2 virus, more than one-third of the world has been subjected to either full or partial lockdown measures. With communities having felt the burden of prolonged isolation, finding a safe and efficacious vaccine will yield direct beneficial effects on protecting against COVID-19 morbidity and mortality and help relieve the psychological and economic load on communities living with COVID-19. There is hope that with the extraordinary efforts of scientists a vaccine will become available. However, given the global public health crisis, development of a COVID-19 vaccine will need to be fast tracked through the usual prelicensing development stages and introduced with limited clinical trial data compared with those vaccines that are developed conventionally over more than a decade. In this scenario, surveillance of the vaccine in the real world becomes even more paramount. This responsibility falls to observational researchers who can provide an essential safety net by continuing to monitor the effectiveness and safety of a COVID-19 vaccine after licensing. Postauthorisation observational studies for safety and effectiveness are complementary to prelaunch clinical trials and not a replacement. In this paper, we highlight the importance of postmarketing studies for future newly licensed COVID-19 vaccines and the key epidemiological considerations.

Lopinavir-Ritonavir in the Treatment of COVID-19: A Dynamic Systematic Benefit-Risk Assessment.

INTRODUCTION AND OBJECTIVE: COVID-19 is an ongoing, global public health crisis for which safe and effective treatments need to be identified. The benefit-risk balance for the use of lopinavir-ritonavir in COVID-19 needs to be monitored on an ongoing basis, therefore a systematic benefit-risk assessment was designed and conducted. A key objective of this study was to provide a platform for a dynamic systematic benefit-risk evaluation; although initially this evaluation is likely to contain limited information, it is required because of the urgent unmet public need. Importantly, it allows additional data to be incorporated as they become available, and re-evaluation of the benefit-risk profile. METHODS: A systematic benefit-risk assessment was conducted using the Benefit-Risk Action Team (BRAT) framework. The exposure of interest was lopinavir-ritonavir treatment in severe COVID-19 compared to standard of care, placebo or other treatments. A literature search was conducted in PubMed and Embase to identify peer-reviewed papers reporting clinical outcomes. Two clinicians constructed a value tree and ranked key benefits and risks in order of considered clinical importance. RESULTS: We screened 143 papers from PubMed and 264 papers from Embase for lopinavir-ritonavir; seven papers were included in the final benefit-risk assessment. In comparison to standard of care, data for several key benefits and risks were identified for lopinavir-ritonavir. Time to clinical improvement was not significantly different for lopinavir-ritonavir in comparison to standard of care (hazard ratio 1.31, 95% confidence interval 0.95-1.80). From one study, there were fewer cases of acute respiratory distress syndrome with lopinavir-ritonavir compared with standard of care (13% vs 27%). There also appeared to be fewer serious adverse events with lopinavir-ritonavir (20%) vs standard of care (32%). Limited data were available for comparison of lopinavir-ritonavir to other treatments. CONCLUSIONS: Based on currently available data, there was no clear benefit for the use of lopinavir-ritonavir compared to standard of care in severe COVID-19. Risk data suggested a possible decrease in serious adverse events. There was a reduction in acute respiratory distress syndrome with lopinavir-ritonavir in one study. Overall, the benefit-risk profile for lopinavir-ritonavir in severe COVID-19 cannot be considered positive until further efficacy and effectiveness data become available.

Remdesivir in Treatment of COVID-19: A Systematic Benefit-Risk Assessment.

INTRODUCTION: There is a need to identify effective, safe treatments for COVID-19 (coronavirus disease) rapidly, given the current, ongoing pandemic. A systematic benefit-risk assessment was designed and conducted to examine the benefit-risk profile of remdesivir in COVID-19 patients compared with standard of care, placebo or other treatments. A key objective of this study was to provide a platform for a dynamic systematic benefit-risk evaluation, which starts with inevitably limited information (to meet the urgent unmet public health need worldwide), then update the benefit-risk evaluation as more data become available. METHODS: The Benefit-Risk Action Team (BRAT) framework was used to assess the overall benefit-risk of the use of remdesivir as a treatment for COVID-19 compared with standard of care, placebo or other treatments. We searched PubMed, Google Scholar and government agency websites to identify literature reporting clinical outcomes in patients taking remdesivir for COVID-19. A value tree was constructed and key benefits and risks were ranked by two clinicians in order of considered importance. RESULTS: Using the BRAT method, several key benefits and risks for use of remdesivir in COVID-19 compared with placebo have been identified. In one trial, the benefit of time to clinical improvement was not statistically significant (21 vs 23 days, HR 1.23, 95% CI 0.87-1.75), although the study was underpowered. In another trial, a shorter time to recovery in patients treated with remdesivir was observed (11 vs 15 days), with non-significant reduced mortality risk (8% vs 12%). Risk data were only available from one trial. This trial reported fewer serious adverse events in patients taking remdesivir (18%) compared with the placebo group (26%); however, more patients in the remdesivir group discontinued treatment as a result of an adverse event compared with those patients receiving placebo (12% vs 5%). CONCLUSIONS: Preliminary clinical trial results suggest that there may be a favourable benefit-risk profile for remdesivir compared with placebo in severe COVID-19 infection and further data on benefits would strengthen this evaluation. There is limited safety data for remdesivir, which should be obtained in further studies. The current framework summarises the key anticipated benefits and risks for which further data are needed. Ongoing clinical trial data can be incorporated into the framework when available to provide an updated benefit-risk assessment.