Abstract

Plain Language Summary

Key Points

Introduction

Methods

We conducted a retrospective observational pharmacovigilance study by monitoring reports of suspected adverse events following immunization (AEFIs) between January 1, 2021 and December 31, 2021 that occurred in the local health authority Azienda Sanitaria Locale Napoli 3 Sud (Asl Naples 3 South) following administration of COVID-19 disease prophylaxis vaccines. All vaccine doses administered during the reporting period have been counted. We analyzed from the Italian pharmacovigilance network (RNF) all reports of suspected AEFIs, stratifying AEFI reports by patient demographic characteristics (age, sex). In addition, AEFI descriptions by diagnosis and symptoms were coded using the Medical Dictionary for Regulatory Activities (MedDRA) and organized by system organ class (SOC) [24]. AEFI severity was classified according to ‘outcome resolution’ criteria [25] as complete resolution, improvement, worsening, invariant situation, death or not available. For the assessment of the causality of vaccine-related AEFIs, the WHO-specific algorithm was used [26, 27]. This is called vaccinovigilance and encompasses all pharmacovigilance activities related to the collection, evaluation, analysis, and reporting of AEFIs. In broader terms, pharmacovigilance and vaccinovigilance represent a complex set of activities aimed at continuously assessing all information related to the safety of medicinal products and ensuring that the benefit/risk (B/R) ratio remains favorable over time. Thus, vaccinovigilance represents a tool for monitoring the safety of vaccines even after they have been approved and placed on the market. Passive vaccinovigilance is carried out through the collection and analysis of AEFI spontaneous reports (from physicians, health care workers, and vaccinated persons), through which signals may emerge that need further investigation (to be disproved or confirmed and quantified in terms of risk) by conducting pharmacoepidemiology studies. Reports can be made online (through the information technology platform of the National Drug Agency, Aifa), or by sending the completed paper form by mail (or fax/email) to the pharmacovigilance officer of the facility to which the reporter belongs. Reports are collected in the database of the National Pharmacovigilance Network (Rnf). The Rnf ensures not only the collection, management, and analysis of spontaneous reports, but also the rapid dissemination of information issued by Aifa on vaccine safety, through a network involving Aifa, regions and autonomous provinces, local health units, hospitals, scientific research and treatment institutes, and pharmaceutical industries. Aifa evaluates each reported event and forwards reports of serious ones to the European Eudravigilance database (which collects reports of suspected adverse reactions to drugs authorized in the European Economic Area). To learn more, see also the pages on pharmacovigilance data interpretation and adverse reactions [12–14]. National passive pharmacovigilance activities are also enhanced through linkage with Vigibase, the WHO's database for international drug monitoring, which collects reports that currently come from 125 countries around the world. The availability of all these data increases the size of the populations studied and allows specific issues that warrant further investigation to be quickly highlighted, making it possible to assess even very rare AEFIs that cannot be adequately studied using data derived from a limited geographic area or selected sample.

Vaccines used in national immunization programs can be considered among the most controlled and safe pharmaceuticals. Vaccines are administered to healthy people, often children, for the purpose of preventing disease; therefore, a higher standard of safety is expected for them than for drugs used to treat people who are already ill (such as antibiotics), and there tends to be a low tolerance for any adverse reaction. The risks of adverse reactions after vaccination must be compared with the risks associated with the preventable disease and also with the risks of taking treatments to relieve the symptoms of the disease should an unvaccinated person become infected. Vaccines make it possible to prevent thousands of cases of disease and consequently also the complications and deaths associated with them. The frequency of adverse reactions to the vaccine is always much lower than the frequency of complications of the disease being prevented, and the dangers of the diseases always far outweigh the risks associated with vaccines. Therefore, choosing not to vaccinate yourself or your children is not a risk-free choice; it is a choice to accept a different kind of risk.

Surveillance of adverse events arising following vaccination plays a key role in ‘on-the-ground’ knowledge of the effects of vaccines in use and the risk–benefit ratio of strategies implemented. Indeed, it makes it possible to highlight warning signs, such as the possible excess of reactogenicity of a particular batch or the existence of unexpected adverse reactions. The return of surveillance results also improves the work of operators and, consequently, allows them to inform families more adequately.

Results

In the year 2021, 844,548 people have been vaccinated in Asl Naples 3 South, with approximately 1,972,669 doses of COVID-19 vaccines administered (Table ​(Table1).1). In particular, 1,084,968 doses of Comirnaty, 295,900 doses of Vaxzevria, 572,074 doses of Spikevax, and 19,727 doses of Jcovden have been administered (Table ​(Table22).

Asl Naples 3 South (Azienda Sanitaria Locale Napoli 3 Sud) is a local health authority in Naples, Italy

In 2021, Asl Naples 3 South received 1164 reports of suspected adverse events that occurred following the administration of COVID-19 vaccines. Of these, 746 reports have been related to the Comirnaty vaccine (64.1%), 281 to the Vaxzevria vaccine (24.1%), 107 to the Spikevax vaccine (9.2%), and 30 to the Jcovden vaccine (2.6%) (Table ​(Table33).

The distribution of reports by age group shows that 3.1% of reports are related to the age group 12–17 years (n = 36 reports), 81.3% are related to the age group 18–64 years (n = 946 reports), and 15.1% are related to patients aged 65 years and older (n = 176 reports); for the remaining 0.5% of the reported events, age has not been available (n = 6 reports). Regarding sex, 31.8% of the reports referred to males (n = 370 reports), 67.8% to females (n = 789 reports), while the remaining 0.4% of the reports did not report sex information (n = 5 reports) (Table ​(Table44 and Fig. ​Fig.11).

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Fig. 1

Distribution of vaccinated population and AEFIs by age. AEFIs adverse events following immunization

Of all the reports, 89.3% have been classified as not serious (n = 1039 reports) and the remaining 10.7% as serious (n = 125 reports). The severity criterion was reported as “other clinically relevant condition” for 53.6% of the reports (n = 67 reports), “hospitalization or prolongation of hospitalization” for 27.2% (n = 34 reports), “severe or permanent disability” for 11.2% (n = 14 reports), “life-threatening” for 7.2% (n = 9 reports), and death for 0.8% (n = 1 report). In 62.1% of cases, the outcome was complete resolution of the suspected adverse events (n = 723 reports), 20.6% of cases reported improvement (n = 240 reports), for 12.2% of cases the events had not yet resolved at the time of reporting (n = 142 reports), 1.6% of reports showed resolution with sequelae, one report reported a fatal outcome, and for 3.4% of reports the outcome was not available (n = 39 reports) (Table ​(Table55).

The most prevalent reporting source was individual citizens (70%, n = 814 reports), followed by physicians (24.9%, n = 289 reports), other health care providers (3%, n = 35 reports), and pharmacists (2.2%, n = 26 reports). Of the reports, 61% were classified as ‘consistent’ (n = 709 reports), following the application of the WHO algorithm for vaccines to establish the causal link between the reported event and the administered medicinal specialty, 35.9% indeterminate (n = 417 reports), 1.1% unclassifiable (n = 13 reports), and 0.7% indeterminate (n = 8 reports). The outcomes from applying the Naranjo logarithm are shown in Tables ​Tables66 and ​and7.7. In addition, a table is provided to highlight the distribution of AEFIs into severe and non-severe (Table ​(Table88).

In conclusion, vaccine preventability and relative benefit/risk is high and has helped the Asl Naples 3 South population to avoid developing Covid-19 disease and its associated high health risks. The adverse reactions experienced are a small fraction and mostly concern non-serious events. Only 125 serious reactions were reported compared with the total of 1164 in a population of more than one million people with nearly one million vaccinees. This means that the risk from COVID immunization is acceptable compared with the risk from the disease itself. Furthermore, among the serious reactions, the majority were excessive reactogenicity of the vaccine that led to cardiovascular complications in young subjects with an intact and active immune system.

Discussion

In total, 80% of Asl Naples 3 South patients were vaccinated against Sars-Cov-2 in January–December 2021. Of these, 84% received an mRNA vaccine and 16% a viral vector vaccine. In line with the largest number of doses administered, the administration of Comirnaty has seen the highest number of adverse reaction reports (64.1%) compared with the total number of reports received, followed by Vaxzevria (24.1%), Spikevax (9.2%), and Jcovden (2.6%). Reactions and health impacts were reported more frequently in female than in male recipients, and in individuals younger than 65 years old than in older individuals. We found that reported reactions to COVID-19 vaccination were mostly mild in severity and transient in duration, and most reports were non-serious. We received one case of suspected death, in a patient with comorbidity and on drug polypharmacy; this may represent a bias, causation was undefined. We also observed specific severe cases for the following SOCs: cardiac disorders, in particular myocarditis cases with rare frequency, and for Neurologic disorders, Guillain Barré cases, again with very rare reporting frequency. The results of reactogenicity following vaccination with the COVID-19 vaccines examined are similar to those found in the literature [28]. The observed patterns could be explained in part by host characteristics known to influence reactogenicity, including age, sex, and the presence of underlying medical conditions. The rate of AEFI reporting compared with the number of people vaccinated in 2021 is in line with data reported by EMA and large clinical trials [29, 30]. The data collected at the local health authority Asl Naples 3 and described in our study are in line with the most recent vaccine surveillance report published by AIFA at a national level. The reports mainly concern Comirnaty in view of the fact that it was the most widely used vaccine; most of the reported adverse events are classified as non-serious (about 82.7%) and to a lesser extent as serious (1.7%). The most reported adverse events for all vaccines are fever, pain at the injection site, fatigue, headache, muscle/joint pain and chills. Furthermore, our study showed, in line with some recently published research, that vaccination against COVID-19 provides benefits that are significantly greater than the risks of morbidity and mortality that may be expressed after COVID-19 infection and that these benefits involve all types of population groups [31–33]. However, further unknown side effects of these vaccines need to be investigated through the development of further studies that continue to investigate the existence of causality between COVID-19 vaccines and the reported adverse events. Finally, it is noteworthy that the occurrence of cardiac side effects and the reported adverse reactions have been matched by case reports published in the literature [34].

Conclusions

COVID-19 vaccines represent a key weapon in preventing higher numbers of deaths from SARS-CoV-2. Vaccines with mRNA methodology have represented a preventive drug innovation with few precedents in the history of modern medicine, demonstrating an excellent tolerability profile since the first pre-registration clinical trials. In this retrospective observational pharmacovigilance study we have shown that data from more than 844,548 doses of COVID-19 vaccine administered during 2021 in Asl Naples 3 South demonstrated that adverse events have been mild and short in duration, confirming the vaccines’ safety. However, continuous monitoring of the safety profile of COVID-19 vaccines needs to be continued with great care.

Declarations

Contributor Information

Francesco Ferrara, Email: ti.orebil@rfararref, Email: [email protected].

Carolina Mancaniello, Email: [email protected].

Alessia Varriale, Email: [email protected].

Sarah Sorrentino, Email: [email protected].

Andrea Zovi, Email: [email protected].

Eduardo Nava, Email: [email protected].

Ugo Trama, Email: [email protected].

Mariarosaria Boccellino, Email: [email protected].

Antonio Vitiello, Email: ti.liamtoh@olleitiva.

References