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

Introduction: COVID-19 vaccines were rapidly authorized leaving many questions and the need to monitor safety intensively. Objective(s): Multi-national collaboration was established with the aim to monitor the safety of the COVID-19 vaccines through prospective cohort event monitoring in Europe. Method(s): A prospective cohort event monitoring study was conducted with primary consented data collection in seven countries between December 2020 and November 2021. Participants in Belgium, France, Italy, the Netherlands and United Kingdom registered using the LIM web app and received follow-up questionnaires for six months. Participants from Croatia and Germany registered with the OPeN and SafeVac2.0 apps respectively. Rates of self-reported reactions were described by type (solicited, non-solicited), adverse event of special interest (AESI), seriousness, and stratified by vaccine brand. The rate of self-reported adverse reaction was calculated after dose 1 and prior to dose 2 among all subjects who responded with at least one questionnaire. Result(s): 117,791 participants were included and responded to the first questionnaires after baseline: 88,196 from Germany, 27,588 from the Netherlands, 984 from France, 570 from Italy, 326 from Croatia, 89 from the United Kingdom and 38 from Belgium. 89,377 respondents received AstraZeneca, 14,658 BioNTech/Pfizer, 11,266 Moderna and 2490 Janssen. Reporting included all vaccine brands from all countries, except Germany which only included data on Moderna until May 2021 and AstraZeneca until September 2021. Median time to completion was 8 days for the first questionnaire after dose 1 (Netherlands, Belgium, Italy, France, United Kingdom) and 3 days in Croatia. Median age category was 40-49 for all vaccine exposed groups except for BioNtech/Pfizer where median age was 70-79. Fatigue and headache were the most commonly reported solicited systemic adverse reactions, injection site reactions the most common solicited local reaction. AESIs were very rare (<0.1%) and serious adverse reactions were uncommon (<1%) across all vaccine brands. Conclusion(s): This study that collated self-reported data from more than 100,000 COVID-19 vaccine recipients, demonstrated 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. Different vaccination schedules in countries and different web applications resulted in some heterogeneity. The study confirmed the safety information in the product labels: reactogenic reactions, related to immunogenic response, and local injection site reactions were very common across all vaccines, whereas serious reactions or AESIs were (very) rare.

Oral Presentation: Are COVID-19 Vaccines Safe in Children? Comparative Analysis of European Web-Based Prospective Monitoring vs. Pivotal Trials

Introduction: To date, only two COVID-19 vaccines, Comirnaty and Spikevax, have received an extension of indication of use by European Medicines Agency (EMA) in 5-17 years old children/ adolescents. Due to the small sample size of pivotal trials in pediatrics, real-world evidence on the safety of those vaccines in the pediatric population is urgently required. Objective(s): (i) To investigate the safety of COVID-19 vaccines by measuring frequencies of solicited and serious adverse events following immunization (AEFIs) with the first and the second doses of vaccines through active surveillance and, (ii) to compare the results with the published clinicaltrials in children and adolescents. Method(s): In 5-17 years old vaccinees, and up to April 21, 2022, we explored the COVID-19 vaccine safety using prospectively collected data from the ''Covid Vaccine Monitor'' (CVM) project [1]. CVM comprises several safety assessment approaches amongst which an active surveillance project of COVID-19 vaccines in Europe through web-based baseline + 6 follow-up questionnaires filled by vaccinees (or their parents). We measured the frequency of local/systemic solicited, and serious adverse reactions following COVID-19 vaccination (first and second doses). The results were compared with findings of pivotal trials in children/adolescents. Result(s): Overall, 1,033 children/adolescents (5-11 years old: 32.9%;12-17 years old: 67.1%) who received a first/second dose of vaccine (mostly Comirnaty: 98.2%) were enrolled in the study. Of them, only 658 (63.7 %) filled baseline and at least one follow-up questionnaire and were included in the CVM analysis. Overall, 293 (44.5%) reported at least one AEFI following first dose of COVID-19 vaccine, with injection site pain being the most frequently reported local solicited AEFI (N = 192;29.2%) in both age groups. Fatigue was the most frequently reported systemic solicited AEFIs (N = 106;16.1%) in both age groups, followed by myalgia (N = 90;13.7%) and headache (N = 84;12.8%). Similar trend was observed after administering the second dose of COVID-19 vaccine. Conclusion(s): This study confirmed safety profile of COVID-19 vaccines in the pediatric population as already documented in the pivotal trials, with a high frequency of local solicited adverse events and an extremely low rate of serious adverse events.

Allergic History and Anaphylaxis in COVID-19 Vaccines: A Disproportionality Analysis in the FDA Vaccine Adverse Event Reporting System

Introduction: Many pre- and post-marketing studies on Covid-19 vaccines investigated their safety in the overall population. Little information is available on cohorts with specific comorbidities. Few studies evaluate the safety in allergic subjects, in particular as related to the anaphylaxis risk. Objective(s): To investigate the association between anaphylaxis after Covid-19 vaccines and the history of hypersensitivity reactions to the most common allergens. Method(s): The Vaccine Adverse Event Reporting System (VAERS, January 2020-December 2021) was downloaded and cleaned. We focused on reports of Adverse Events Following Immunization (AEFIs) following COVID-19 vaccination in subjects>12 years old with history of allergy. We performed a descriptive analysis and calculated the Reporting Odds Ratio (ROR) to identify demographic characteristics and allergic histories disproportionally reported with anaphylaxis for each Covid-19 vaccine and the most recorded allergens. Result(s): We retrieved 183,860 AEFI reports recording any allergic history (864 anaphylaxis reports among cases vs 6,162 in Covid-19 reports without history of allergy). They concerned mostly women (81.3%) and adults (74.0%). Almost all reports were submitted in the US (99.7%) and 38.3% of them resulted in hospitalization. Covid-19 vaccines administered were Spikevax (49.3%), Comirnaty (42.1%), and Janssen (8.4%). The antigens most recorded as allergens were penicillins (49,407), sulfa drugs (37,365), opioids (26,398), seafood (12,039), latex (11,442), NSAIDs (11,319), cephalosporins (8,379), quinolones (8,023), macrolides (7,586). Seafood allergy resulted associated with anaphylaxis for Comirnaty (ROR = 2.80;95% CI 2.20-3.56), Spikevax (2.57;1.88-3.51), and Janssen (2.67;1.39-5.11). Latex allergy was associated with anaphylaxis for Comirnaty (ROR = 1.92;95% CI 1.45-2.55). Conclusion(s): We gathered evidence pointing towards a preferential development of anaphylaxis in patients with an history of hypersensitivity to seafood (for all Covid-19 vaccines) or latex (restricted to Comirnaty). Whether confirmed by further studies, this knowledge may drive a more practical anamnesis and a prompt management of anaphylactic reactions.

Cohort Event Monitoring of COVID-19 Vaccine Safety in Special Cohorts in Italy

Introduction: Marketed COVID-19 vaccines showed an overall favourable safety profile in pivotal trials. However, those trials did not include high risk/fragile patient categories;hence, close monitoring of COVID-19 vaccine safety in those special cohorts in real-world setting is needed. The European Medicines Agency-funded "Covid- Vaccine-Monitor" project was set up to prospectively measure the incidence of solicited/unsolicited adverse events following COVID- 19 vaccination in several European Countries as reported by vaccinees through web-based questionnaires. Italy is one of the Countries participating in the project as a large network named "ilmiovaccinocovid19 collaborating group". Objective(s): To measure the incidence of vaccinee-reported adverse events following immunization (AEFIs) with marketed COVID-19 vaccines in pregnant and lactating women, pediatrics, immunocompromised, people with history of allergy and people with prior SARSCoV- 2 infection in Italy. Method(s): We performed a prospective cohort study of the abovementioned categories of vaccinees, who were recruited at multiple vaccination centers within 48 hours from either the first or booster COVID-19 vaccine dose administration. After providing informed consent and get registered into the web-app, vaccinees were asked to fill in an electronic baseline questionnaire and 6 follow-up questionnaires at different time points, within 6-month from vaccine administration, in which information on potential vaccine-related AEFIs were collected. We explored and compared the frequency of local and systemic solicited adverse events following first or booster dose for each special cohort and vaccine brands. Result(s): Overall, 1,331 vaccinees (40.4% first dose and 59.6% booster dose) were included in the analysis. Of these, 8.4% were immunocompromised, 32.0% had history of allergy, 25.5% had prior SARS-CoV-2 infection, 23.4% were children/adolescents, 6.2% were pregnant and 4.6% were lactating women (non-mutually exclusive cohorts). Of subjects belonging to at least one cohort, 52.3% reported at least one AEFI following either the first or booster dose. Among all special cohorts, injection site pain was the most frequently reported solicited local AEFI, after both the first (37.5%) and booster (39.5%) dose. As solicited systemic AEFIs, headache (19.0%) was the most frequently reported after the first dose, while malaise (23.7%) and fatigue (23.7%) after the booster dose. The frequency of severe AEFIs was very low following both first dose (0.8%) and booster dose (0.6%). Conclusion(s): Overall, this study confirmed the favourable safety profile of COVID-19 vaccines also in the above-mentioned special categories who have not (or marginally) been included in pivotal trials.

Safety Profile of Antiviral Therapies for the Early Treatment/ Prevention of COVID-19: Analysis of the International Pharmacovigilance Database VigiBase

Introduction: After many months from the COVID-19 pandemic beginning, several anti-spike monoclonal antibodies (mAbs) and, more recently, other antiviral drugs for COVID-19 treatment in nonhospitalized patients have been marketed. Specifically, those drugs are indicated for SARS-CoV-2 infection early treatment in outpatient adults at high risk of developing severe COVID-19 [1]. Objective(s): To evaluate the post-marketing safety profile of antivirals drugs used for early COVID-19 treatment, using the World Health Organization global spontaneous reporting database (VigiBase). Method(s): From VigiBase we identified all the individual case safety reports (ICSRs) of marketed mAbs (regdanvimab, sotrovimab, casirivimab/imdevimab, bamlanivimab/etesevimab and, specifically for COVID-19 prevention in immunocompromised patients, tixagevimab/ cilgavimab) and other antiviral therapies for COVID-19 early treatment (remdesivir, nirmatrelvir/ritonavir, molnupiravir). We performed a descriptive analysis of ICSRs recorded in VigiBase of patients' demographics (age, sex, continent of origin) type of reporter, adverse drug reactions (ADRs) (Preferred Term level) and the Important Medical Events (IMEs), from their marketing date to May 4, 2022. In addition, we conducted a disproportional analysis using Reporting Odds Ratio (ROR), along with 95% confidence intervals (CIs), by comparing the frequency of ADRs (System Organ Class level) for each drug of interest with distribution of all ADRs from the whole database, excluding vaccines, reported in the same period. Result(s): Overall, up to 4th May,2022, 15,437 ICSRs of anti-spike mAbs (casirivimab/imdevimab: 27.2%;bamlanivimab/etesevimab: 7.3%;sotrovimab 3.3%;tixagevimab/cilgavimab 2.7% regdanvimab: 0.2%) and other antivirals (remdesivir: 54.5%;nirmatrelvir/ritonavir: 4.3%;molnupiravir 0.5%) from VigiBase were retrieved. ICSRs mainly involved females and 45-64 years old. The percentage of ICSRs that included IMEs was 32.4%. Overall, the most frequently reported ADRs were infusion-related reaction for both casirivimab/ imdevimab (20.1%) and bamlanivimab/etesevimab (19.3%), pyrexia for regdanvimab (30.0%) and sotrovimab (8.1%), increased alanine aminotransferase for remdesivir (13.3%), dysgeusia for nirmatrelvir/ ritonavir (39.5%), and diarrhoea for molnupiravir (18.8%). Overall, statistically significant RORs were observed for "Investigations" with remdesivir (N = 3163;ROR: 5.56;95% CI 5.32-5.81), "Gastrointestinal disorders" for molnupiravir (N = 178;ROR: 3.43;95% CI 2.82-4.17) and "Vascular disorders" for sotrovimab (N = 51;ROR: 2.07;95% CI 1.55-2.76). Conclusion(s): This study shows that the safety profile of anti-spike mAbs and other newly marketed antiviral therapies for the early treatment of COVID-19 is overall favourable. The most frequently reported ADRs in VigiBase are in line with those reported in the pivotal trials and Summary of Product Characteristics for all investigated antiviral drugs. The disproportional analysis identified some potential signals requiring further investigation.

Covid-Vaccine-Monitor: a Cohort Event Monitoring Safety Study of COVID-19 Vaccines in Twelve European Countries: An International Journal of Medical Toxicology and Drug Experience

Introduction: Since the WHO declared the COVID-19 global pandemic in March 2020, vaccines to prevent severe SARS-CoV-2 infection have been developed at unprecedented speed. Several vaccines have been conditionally authorized by regulators in December 2020 already. The large-scale vaccination campaigns have undeniably raised the importance of post-authorization evaluations not only through spontaneous reporting but also by cohort event monitoring to obtain more in-depth vaccine safety information, rapidly after launch. Objective: To monitor COVID-19 vaccine safety and estimate the frequency of solicited and non-solicited, non-serious and serious reactions. Methods: We designed a prospective cohort event monitoring (CEM) study as part of the Covid-Vaccine-Monitor (CVM) project. The CEM collects baseline data, adverse reactions (ADRs) of authorized COVID-19 vaccines in the general and special populations (pregnant and lactating women, children, and adolescents, immunocompromised, allergic, and prior COVID-19 infection people) in twelve countries (Germany, Croatia, Netherlands, Belgium, Italy, France, Spain, Portugal, Slovakia, Romania, Switzerland, and UK). The current results comprise data from February 2021-February 2022. Depending on the dose and cohort, two data collection platforms are used: the Lareb-managed Intensive Monitoring (LIM) and the UMC Utrecht Research Online (RO). Germany and Croatia used their national tools. Participants meet local age criteria, have a first vaccination cycle or a booster dose within 48 hours, and are followed up for 6 months. Data are pooled, stratified by special cohorts, and analyzed. Results: We included more than 30,000 general population participants data from Belgium, Croatia, France, Italy, Netherlands, and UK, and more than 520,000 from Germany with the first vaccinations. Across different vaccines, 0.2-0.3% reported at least one serious ADR after receiving the first doses. More than 7,400 special cohorts vaccinees participated. 0.2% and 0.4% reported at least one serious ADR and adverse event of special interest (AESI), respectively, after the first vaccinations. The most-reported ADRs among vaccines were injection site pain, locally, and fatigue, headache, malaise, and myalgia, systemically. Serious ADRs and AESIs were uncommon. More than 11,100 vaccinees from general and special cohorts receiving a booster dose were also included. Among different cohorts, children/adolescents reported the lowest number of ADRs, while lactating women reported the highest. Conclusion: We collected and analyzed COVID-19 vaccines safety evidence in more than 550,000 general and special population persons after the first cycle and booster doses, combining data from twelve countries. Data confirm common ADR rates that are already listed in the summary of product characteristics, and that serious reactions are uncommon. Additional follow-up is ongoing.

Cohort Event Monitoring on Adverse Reactions to COVID-19 Vaccines in Seven European Countries: Pooled Results on First Dose: An International Journal of Medical Toxicology and Drug Experience

Introduction: COVID-19 vaccines were rapidly authorized leaving many questions and the need to monitor safety intensively. Objective: Multi-national collaboration was established with the aim to monitor the safety of the COVID-19 vaccines through prospective cohort event monitoring in Europe. Methods: A prospective cohort event monitoring study was con- ducted with primary consented data collection in seven countries between December 2020 and November 2021. Participants in Bel- gium, France, Italy, the Netherlands and United Kingdom registered using the LIM web app and received follow-up questionnaires for six months. Participants from Croatia and Germany registered with the OPeN and SafeVac2.0 apps respectively. Rates of self-reported reactions were described by type (solicited, non-solicited), adverse event of special interest (AESI), seriousness, and stratified by vaccine brand. The rate of self-reported adverse reaction was calculated after dose 1 and prior to dose 2 among all subjects who responded with at least one questionnaire. Results: 117,791 participants were included and responded to the first questionnaires after baseline: 88,196 from Germany, 27,588 from the Netherlands, 984 from France, 570 from Italy, 326 from Croatia, 89 from the United Kingdom and 38 from Belgium. 89,377 respondents received AstraZeneca, 14,658 BioNTech/Pfizer, 11,266 Moderna and 2490 Janssen. Reporting included all vaccine brands from all coun- tries, except Germany which only included data on Moderna until May 2021 and AstraZeneca until September 2021. Median time to completion was 8 days for the first questionnaire after dose 1 (Netherlands, Belgium, Italy, France, United Kingdom) and 3 days in Croatia. Median age category was 40-49 for all vaccine exposed groups except for BioNtech/Pfizer where median age was 70-79. Fatigue and headache were the most commonly reported solicited systemic adverse reactions, injection site reactions the most common solicited local reaction. AESIs were very rare (< 0.1%) and serious adverse reactions were uncommon (< 1%) across all vaccine brands. Conclusion: This study that collated self-reported data from more than 100,000 COVID-19 vaccine recipients, demonstrated 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. Different vaccination schedules in countries and dif- ferent web applications resulted in some heterogeneity. The study confirmed the safety information in the product labels: reactogenic reactions, related to immunogenic response, and local injection site reactions were very common across all vaccines, whereas serious reactions or AESIs were (very) rare.

Oral Presentation: Are COVID-19 Vaccines Safe in Children? Comparative Analysis of European Web-Based Prospective Monitoring vs. Pivotal Trials: An International Journal of Medical Toxicology and Drug Experience

Introduction: To date, only two COVID-19 vaccines, Comirnaty and Spikevax, have received an extension of indication of use by European Medicines Agency (EMA) in 5-17 years old children/adolescents. Due to the small sample size of pivotal trials in pediatrics, real-world evidence on the safety of those vaccines in the pediatric population is urgently required. Objective: (i) To investigate the safety of COVID-19 vaccines by measuring frequencies of solicited and serious adverse events following immunization (AEFIs) with the first and the second doses of vaccines through active surveillance and, (ii) to compare the results with the published clinicaltrials in children and adolescents. Methods: In 5-17 years old vaccinees, and up to April 21, 2022, we explored the COVID-19 vaccine safety using prospectively collected data from the "Covid Vaccine Monitor" (CVM) project [1]. CVM comprises several safety assessment approaches amongst which an active surveillance project of COVID-19 vaccines in Europe through web-based baseline + 6 follow-up questionnaires filled by vaccinees (or their parents). We measured the frequency of local/systemic solicited, and serious adverse reactions following COVID-19 vaccination (first and second doses). The results were compared with findings of pivotal trials in children/adolescents. Results: Overall, 1,033 children/adolescents (5-11 years old: 32.9%;12-17 years old: 67.1%) who received a first/second dose of vaccine (mostly Comirnaty: 98.2%) were enrolled in the study. Of them, only 658 (63.7 %) filled baseline and at least one follow-up questionnaire and were included in the CVM analysis. Overall, 293 (44.5%) reported at least one AEFI following first dose of COVID-19 vaccine, with injection site pain being the most frequently reported local solicited AEFI (N = 192;29.2%) in both age groups. Fatigue was the most frequently reported systemic solicited AEFIs (N = 106;16.1%) in both age groups, followed by myalgia (N = 90;13.7%) and headache (N = 84;12.8%). Similar trend was observed after administering the second dose of COVID-19 vaccine. Conclusion: This study confirmed safety profile of COVID-19 vaccines in the pediatric population as already documented in the pivotal trials, with a high frequency of local solicited adverse events and an extremely low rate of serious adverse events.

Allergic History and Anaphylaxis in COVID-19 Vaccines: A Disproportionality Analysis in the FDA Vaccine Adverse Event Reporting System: An International Journal of Medical Toxicology and Drug Experience

Introduction: Many pre- and post-marketing studies on Covid-19 vaccines investigated their safety in the overall population. Little information is available on cohorts with specific comorbidities. Few studies evaluate the safety in allergic subjects, in particular as related to the anaphylaxis risk. Objective: To investigate the association between anaphylaxis after Covid-19 vaccines and the history of hypersensitivity reactions to the most common allergens. Methods: The Vaccine Adverse Event Reporting System (VAERS, January 2020-December 2021) was downloaded and cleaned. We focused on reports of Adverse Events Following Immunization (AEFIs) following COVID-19 vaccination in subjects > 12 years old with history of allergy. We performed a descriptive analysis and calculated the Reporting Odds Ratio (ROR) to identify demographic characteristics and allergic histories disproportionally reported with anaphylaxis for each Covid-19 vaccine and the most recorded allergens. Results: We retrieved 183,860 AEFI reports recording any allergic history (864 anaphylaxis reports among cases vs 6,162 in Covid-19 reports without history of allergy). They concerned mostly women (81.3%) and adults (74.0%). Almost all reports were submitted in the US (99.7%) and 38.3% of them resulted in hospitalization. Covid-19 vaccines administered were Spikevax (49.3%), Comirnaty (42.1%), and Janssen (8.4%). The antigens most recorded as allergens were penicillins (49,407), sulfa drugs (37,365), opioids (26,398), seafood (12,039), latex (11,442), NSAIDs (11,319), cephalosporins (8,379), quinolones (8,023), macrolides (7,586). Seafood allergy resulted associated with anaphylaxis for Comirnaty (ROR = 2.80;95% CI 2.20-3.56), Spikevax (2.57;1.88-3.51), and Janssen (2.67;1.39-5.11). Latex allergy was associated with anaphylaxis for Comirnaty (ROR = 1.92;95% CI 1.45-2.55). Conclusion: We gathered evidence pointing towards a preferential development of anaphylaxis in patients with an history of hypersensitivity to seafood (for all Covid-19 vaccines) or latex (restricted to Comirnaty). Whether confirmed by further studies, this knowledge may drive a more practical anamnesis and a prompt management of anaphylactic reactions.

Cohort Event Monitoring of COVID-19 Vaccine Safety in Special Cohorts in Italy: An International Journal of Medical Toxicology and Drug Experience

Introduction: Marketed COVID-19 vaccines showed an overall favourable safety profile in pivotal trials. However, those trials did not include high risk/fragile patient categories;hence, close monitoring of COVID-19 vaccine safety in those special cohorts in real-world setting is needed. The European Medicines Agency-funded "Covid-Vaccine-Monitor" project was set up to prospectively measure the incidence of solicited/unsolicited adverse events following COVID-19 vaccination in several European Countries as reported by vaccinees through web-based questionnaires. Italy is one of the Countries participating in the project as a large network named "ilmiovaccinocovid19 collaborating group". Objective: To measure the incidence of vaccinee-reported adverse events following immunization (AEFIs) with marketed COVID-19 vaccines in pregnant and lactating women, pediatrics, immunocompromised, people with history of allergy and people with prior SARS-CoV- 2 infection in Italy. Methods: We performed a prospective cohort study of the abovementioned categories of vaccinees, who were recruited at multiple vaccination centers within 48 hours from either the first or booster COVID-19 vaccine dose administration. After providing informed consent and get registered into the web-app, vaccinees were asked to fill in an electronic baseline questionnaire and 6 follow-up questionnaires at different time points, within 6-month from vaccine administration, in which information on potential vaccine-related AEFIs were collected. We explored and compared the frequency of local and systemic solicited adverse events following first or booster dose for each special cohort and vaccine brands. Results: Overall, 1,331 vaccinees (40.4% first dose and 59.6% booster dose) were included in the analysis. Of these, 8.4% were immunocompromised, 32.0% had history of allergy, 25.5% had prior SARS-CoV-2 infection, 23.4% were children/adolescents, 6.2% were pregnant and 4.6% were lactating women (non-mutually exclusive cohorts). Of subjects belonging to at least one cohort, 52.3% reported at least one AEFI following either the first or booster dose. Among all special cohorts, injection site pain was the most frequently reported solicited local AEFI, after both the first (37.5%) and booster (39.5%) dose. As solicited systemic AEFIs, headache (19.0%) was the most frequently reported after the first dose, while malaise (23.7%) and fatigue (23.7%) after the booster dose. The frequency of severe AEFIs was very low following both first dose (0.8%) and booster dose (0.6%). Conclusion: Overall, this study confirmed the favourable safety profile of COVID-19 vaccines also in the above-mentioned special categories who have not (or marginally) been included in pivotal trials.

Safety Profile of Antiviral Therapies for the Early Treatment/ Prevention of COVID-19: Analysis of the International Pharmacovigilance Database VigiBase: An International Journal of Medical Toxicology and Drug Experience

Introduction: After many months from the COVID-19 pandemic beginning, several anti-spike monoclonal antibodies (mAbs) and, more recently, other antiviral drugs for COVID-19 treatment in non-hospitalized patients have been marketed. Specifically, those drugs are indicated for SARS-CoV-2 infection early treatment in outpatient adults at high risk of developing severe COVID-19 [1]. Objective: To evaluate the post-marketing safety profile of antivirals drugs used for early COVID-19 treatment, using the World Health Organization global spontaneous reporting database (VigiBase). Methods: From VigiBase we identified all the individual case safety reports (ICSRs) of marketed mAbs (regdanvimab, sotrovimab, casirivimab/imdevimab, bamlanivimab/etesevimab and, specifically for COVID-19 prevention in immunocompromised patients, tixagevimab/cilgavimab) and other antiviral therapies for COVID-19 early treatment (remdesivir, nirmatrelvir/ritonavir, molnupiravir). We performed a descriptive analysis of ICSRs recorded in VigiBase of patients' demographics (age, sex, continent of origin) type of reporter, adverse drug reactions (ADRs) (Preferred Term level) and the Important Medical Events (IMEs), from their marketing date to May 4, 2022. In addition, we conducted a disproportional analysis using Reporting Odds Ratio (ROR), along with 95% confidence intervals (CIs), by comparing the frequency of ADRs (System Organ Class level) for each drug of interest with distribution of all ADRs from the whole database, excluding vaccines, reported in the same period. Results: Overall, up to 4th May,2022, 15,437 ICSRs of anti-spike mAbs (casirivimab/imdevimab: 27.2%;bamlanivimab/etesevimab: 7.3%;sotrovimab 3.3%;tixagevimab/cilgavimab 2.7% regdanvimab: 0.2%) and other antivirals (remdesivir: 54.5%;nirmatrelvir/ritonavir: 4.3%;molnupiravir 0.5%) from VigiBase were retrieved. ICSRs mainly involved females and 45-64 years old. The percentage of ICSRs that included IMEs was 32.4%. Overall, the most frequently reported ADRs were infusion-related reaction for both casirivimab/imdevimab (20.1%) and bamlanivimab/etesevimab (19.3%), pyrexia for regdanvimab (30.0%) and sotrovimab (8.1%), increased alanine aminotransferase for remdesivir (13.3%), dysgeusia for nirmatrelvir/ritonavir (39.5%), and diarrhoea for molnupiravir (18.8%). Overall, statistically significant RORs were observed for "Investigations" with remdesivir (N = 3163;ROR: 5.56;95% CI 5.32-5.81), "Gastrointestinal disorders" for molnupiravir (N = 178;ROR: 3.43;95% CI 2.82-4.17) and "Vascular disorders" for sotrovimab (N = 51;ROR: 2.07;95% CI 1.55-2.76). Conclusion: This study shows that the safety profile of anti-spike mAbs and other newly marketed antiviral therapies for the early treatment of COVID-19 is overall favourable. The most frequently reported ADRs in VigiBase are in line with those reported in the pivotal trials and Summary of Product Characteristics for all investigated antiviral drugs. The disproportional analysis identified some potential signals requiring further investigation.

Risk of COVID-19 hospitalization/mortality in patients with rheumatic disease treated with chloroquine/hydroxychloroquine or other conventional DMARDs in Italy: A large-scale nested casecontrol study

Objective: Chloroquine (CLQ)/hydroxychloroquine (HCQ) are two of the most studied drugs for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. There are very limited data on the effect of treatment of patients affected by rheumatic diseases with HCQ/CLQ and other conventional disease-modifying anti-rheumatic drugs (cDMARDs) on COVID-19. The aim of this study is to investigate the hypothesis that treatment of rheumatic diseases with hydroxychloroquine (HCQ)/chloroquine (CLQ) as compared to other conventional disease-modifying anti-rheumatic drugs (cDMARDs) might decrease the COVID-19-related risk of hospitalization and mortality. Methods: This large-scale case-control study nested within a cohort of cDMARD users was conducted in the Lombardy, Veneto, Tuscany and Lazio regions and Reggio Emilia (Emilia Romagna) Local Health Unit, covering a total of 25.1 million inhabitants. Claims databases were linked to loco-regional COVID-19 surveillance registries from the same catchment area through unique fully-anonymized patient identifiers. Risk of COVID-19-related outcomes was estimated as odds ratios (ORs) along with 95% confidence intervals (CIs), using a multivariate conditional logistic regression analysis, by comparing HCQ/CLQ vs methotrexate (primary comparator) and other cDMARDs (secondary comparator). In addition, the same risk for HCQ/CLQ, methotrexate and other cDMARDs separately vs nonuse of these drugs as well as for presence of rheumatic diseases vs. absence in a non-nested population was investigated. Results: From the cohort of cDMARD users, 1275 cases who were hospitalized due to COVID-19 were identified and matched to 12,734 controls. When compared to recent use of methotrexate, no statistically significant association between recent HCQ/CLQ monotherapy with COVID-19 hospitalization (OR 0.83 [95% CI, 0.69 to 1.00]) or mortality (OR 1.19 [95% CI, 0.85 to 1.67]) was observed. A statistically significant lower risk was found when comparing recent use of HCQ/CLQ to treatment with other cDMARDs and glucocorticoids concomitantly. In the sensitivity analysis in the non-nested population, HCQ/CLQ was not associated with COVID-19 hospitalization as compared with non-use, whereas a mild statistically significant increased risk for recent use of both methotrexate as monotherapy (OR 1.19 [95% CI, 1.05 to 1.34]) or other cDMARDs (OR 1.21 [95% CI, 1.08 to 1.36]) vs non-use was found. Finally, the presence of rheumatoid arthritis or systemic lupus erythematosus was not associated with COVID-19 hospitalization (OR 0.98 [95% CI, 0.89 to 1.07]) or mortality (OR 0.88 [95% CI, 0.74 to 1.05]). Conclusion: Prior exposure to HCQ/CLQ in rheumatic patients was not associated with a protective effect against COVID-19-related hospitalization and mortality. On the contrary, an increased risk in patients receiving other cDMARDs was observed when compared to non-use, especially in those patients concomitantly treated with glucocorticoids. This is likely attributable to a synergistic immunosuppressive effect, leading to increased risk of severe SARS-CoV-2 infection.