Who is responsible for the evaluation and monitoring of vaccines (vaccine safety)?
In Germany, the Paul-Ehrlich-Institut is responsible for the authorisation of vaccines, i.e. the evaluation of quality, safety and efficacy as well as pharmacovigilance (drug safety) after authorisation.
The Standing Commission on Vaccination (Ständige Impfkommission, STIKO), located at the Robert Koch Institute (RKI), prepares vaccination recommendations based on data on the efficacy and safety of the respective approved vaccines so that vaccines can be used optimally. For this purpose, the STIKO incorporates the assessments of the Paul-Ehrlich-Institut on the safety of vaccines.
After a vaccine has been authorised, all reports of suspected adverse reactions or vaccine complications are continuously recorded and evaluated. The monitoring of side effects by the Paul-Ehrlich-Institut on the basis of suspected case reports of side effects and vaccine complications assists in the rapid detection of new risk signals for the use of vaccines and other biomedicines. The Paul-Ehrlich-Institut uses pharmacovigilance measures to not only quickly detect new risk signals, but also to take or initiate measures to reduce risks when needed. This is done both nationally and at European level.
The Paul-Ehrlich-Institut publishes on a regular basis safety reports on reported suspected cases in Germany following vaccination against COVID-19.
Further Information
Safety Reports
Updated: 28.03.2024
How is the efficacy of a COVID-19 vaccine determined?
During the authorisation-related clinical trial of the safety and efficacy of a COVID-19 vaccine candidate, normally phase 3 or 2/3, the study participants are assigned randomly to one of two groups. One group is vaccinated with the vaccine candidate (the “verum group”), while the control group is given a placebo or another vaccine. Care is taken to ensure that both groups have a similar composition (e.g., in terms of age, gender etc.) and that there is a comparable risk of infection with SARS-CoV-2. The occurrence of a laboratory-confirmed symptomatic SARS-CoV-2 infection, i.e., illness with COVID-19, with effect from a specific point in time after vaccination is then recorded in both groups and the frequency is compared. A calculated efficacy of 90% means that the number of COVID-19 cases that occurred in the vaccinated group was reduced by 90% within a certain time compared to a non-vaccinated control group (e.g. n = 10 vs. 100 cases with groups of the same size).
Updated: 27.08.2021
How great is the efficacy of the COVID-19 vaccines?
The efficacy data underlying the conditional authorisation can be found in the product information of the respective COVID-19 vaccines. The product information can be found at http://www.pei.de/covid-19-vaccines in the right-hand column.
The efficacy studies completed in the authorisation process were conducted at a time when the Omicron virus variant was unknown and not yet widespread. Omicron currently dominates the SARS-CoV-2 infection situation in Germany. The previous studies show that the effectiveness of the COVID-19 vaccination is reduced against an infection with the Omicron variant and Omicron-induced COVID-19 compared to previous virus variants. However, it has also been shown that individuals are significantly better protected against illness caused by the Omicron virus variant after booster vaccination than persons after primary vaccination.
The Robert Koch-Institut, which is responsible for epidemiology, regularly provides information in its frequently asked questions (FAQ) about the current state of knowledge on the effectiveness of COVID-19 vaccines against the currently circulating virus variants.
Updated: 01.06.2022
Have any safety steps been omitted during testing in order to speed up marketing authorisation?
For the marketing authorisation of the COVID-19 vaccines, all the tests relevant to an assessment of the safety of the vaccines were carried out. The quality, safety and efficacy of every single vaccine product must be ensured before a vaccine product can receive marketing authorisation.
The current authorisations for the COVID-19 vaccines are conditional marketing authorisations. This means that on certain dates after the marketing authorisation, additional data must be submitted by the marketing authorisation holder. The Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMA) has formulated criteria with regard to which conditions must be met before marketing authorisation can be issued for a COVID-19 vaccine.
Updated: 01.06.2022
Are the COVID-19 vaccines safe, even though they have been developed so quickly?
The short development time for the current COVID-19 vaccine candidates was possible thanks to a number of factors:
- Knowledge of the potentially protective antigen from previous work on vaccines for SARS-CoV in 2002/2003 and MERS-CoV
- Application and further development of new vaccine technologies
- Some otherwise preclinical trials were carried out in parallel to clinical trials
- Performance of overlapping phase 1/2 and phase 2/3 trials
- Regulatory guidance through intensive and in some cases repeated scientific advice
- Rolling review at the Paul-Ehrlich-Institut and at the European Medicines Agency (EMA)
- High level of focus and generous financial support from the German Federal Government, the European Commission and global charitable foundations which also enabled large-scale manufacture to commence prior to marketing authorisation
- Worldwide cooperation, e.g. at the level of the WHO and the International Coalition of Medicines Regulatory Agencies (ICMRA)
- For the marketing authorisation of the COVID-19 vaccines, data was evaluated from between 20,000 and almost 40,000 study participants. This allowed extensive information to be gained on the safety and efficacy of the vaccines.
The follow-up monitoring of the study participants does not end with marketing authorisation. They will be actively monitored over a period of up to two years as part of the ongoing clinical trials tied to the authorisation process. One of the reasons for doing this is to evaluate how long the efficacy of the vaccination will last.
In general, however, it is the case with COVID-19 vaccines, as with all other new vaccines and therapeutic medicinal products, that not all very rare adverse reactions can be recorded at the time of marketing authorisation. For this reason, the safety of vaccines, like that of other newly authorised medicinal products, continues to be checked after marketing authorisation. One element of this follow-up monitoring (surveillance) is, for example, the analysis of spontaneous reports of suspected adverse reactions or vaccination complications. For the pandemic COVID-19 vaccines, other studies are also being carried out, including active safety studies.
Updated: 01.06.2022
Do we need to fear long-term effects of vaccines that occur years after vaccination?
Decades of experience has shown that most vaccine side effects occur within a few hours or a few days after a vaccination. In rare cases, vaccine side effects occur or are recognised only after weeks or a few months.
The first available COVID-19 vaccines in Europe were authorised in late 2020 or early 2021 and have been in general use since. The first clinical trials began several months before authorisation. Since then, the vaccines have been administrated millions or even billions of times. These vaccines and their side effects are now well known - including very rare side effects.
Updated: 01.06.2022
What are long-term effects anyway?
There are two possibilities of what is meant by the term "long-term effects". Something that only occurs after a long time, or something that lasts over a long period of time.
A desirable long-term consequence of vaccination in the sense of a long-lasting effect is protection against infection or serious illness. For some people, this protection even lasts for life - for example, with the measles vaccination. For other vaccinations, such as against influenza - and according to the current status also against COVID-19 - booster vaccinations are necessary. Together, however, the vaccinations lead to continuous protection against the pathogen.
In individual cases, even very rare vaccination complications can last a long time, possibly years. However, this is the absolute exception. An example of such an extremely rare side effect with a long-term effect is the very rare occurrence of narcolepsy after vaccination against swine flu in 2009/2010 and is an absolute exception. Here, too, the first indications of this vaccination complication occurred only a few months after the start of the vaccinations.
Concerned citizens understand long-term consequences - often also called late effects - to mean side effects that occur only after a delay of many months or years after vaccination. These concerns are unjustified. We are not aware of such very late-onset side effects of vaccines.
What is the risk of mRNA vaccines integrating into the genome?
There is no discernible risk of mRNA integrating into the cell genome. The genome, which consists of DNA, is located in the cell nucleus, where vaccine mRNA does not normally reach. RNA itself cannot be integrated into the DNA genome. Therefore, the mRNA would first have to be transcribed into DNA in the cell in order to be integrated into the human genome. Theoretically, an integration of the mRNA into the genome of cells would only be possible in the presence of certain proteins, which could transcribe the vaccine mRNA into DNA, then transport this DNA into the cell nucleus and there in turn integrate it into the genome by means of a virus protein. This is an extremely unlikely and hitherto unobserved sequence of reactions in unmodified cells. Furthermore, the mRNA in the cells of a vaccinated individual is only temporarily present in the cells of the vaccinated person before it is degraded.
Updated: 01.06.2022
Why do the mRNA vaccines authorised contain lipid nanoparticles?
The currently authorised COVID-19 mRNA vaccines – Comirnaty and COVID-19 Vaccine Moderna – contain lipid particles in which the mRNA is encapsulated. On account of their size (< 100 nm), they are also referred to as lipid nanoparticles (LNPs). When using the term “particle”, however, it should be noted that these are not non-degradable solid particles (metals, plastics etc.), but rather fat globules that, like biological cell membranes, are made up of a phospholipid layer. They act as carriers and protect the otherwise unstable mRNA. Above all, however, they ensure that the mRNA is absorbed into the cells after vaccination (especially around the injection site) and is then released within the cell where the mRNA is to be transcribed.
What do we know about the safety of lipid nanoparticles in mRNA vaccines?
Lipid nanoparticles (LNPs) are similar to the liposomes (fat cells) that have been used for over 20 years as delivery mechanisms for medicinal products (e.g. Myocet liposomal, Caelyx pegylated liposomal, DaunoXome, AmBisome). In another authorised medicinal product, therapeutic RNA molecules are encapsulated in very similar LNPs (Onpattro). With these medicinal products, significantly higher amounts of lipids are administered intravenously compared to vaccination. There have also been authorised vaccines with a similar structure, called “virosomal vaccines”, e.g. Epaxal for hepatitis A or Inflexal for influenza. Virosomes are also phospholipid vesicles that carry viral envelope proteins on their surface. We have many years of experience with these vaccines and they have a good safety profile. At present, they are no longer on the market, but this is not the result of safety concerns.
As with biological membranes, the structure of LNPs is formed by phospholipids with cholesterol stored in them. The various LNPs also contain other lipid components that impart special characteristics. As all lipids are identical or very similar to the body’s own lipids, LNPs are considered to be “biodegradable”, i.e. it may be assumed that, similar to dietary lipids, they are broken down in the body enzymatically and are largely incorporated into the body’s own fat metabolism.
The potential toxicity of each of these novel vaccine preparations was tested in preclinical toxicity tests prior to marketing authorisation.
Do the vaccines contain microchips/nanochips?
No. All ingredients are listed in the relevant Summary of Product Characteristics (SmPC).
Updated: 28.03.2024
Is it true that Comirnaty (BioNTech/Pfizer) and Spikevax (Moderna) use excipients that are not allowed in medicines?
No.
The substances ALC-0315 and ALC-0159 in the Comirnaty (BioNTech/Pfizer) vaccine and SM-102 in the Spikevax (Moderna) vaccine are pharmaceutical excipients. Pharmaceutical excipients can be produced by the pharmaceutical manufacturer itself or purchased from other companies. Such substances are sometimes offered as laboratory chemicals for a wide variety of applications. The manufacturer usually provides the product information on these laboratory chemicals with a warning that they are not suitable for use on humans. This can lead to the erroneous assumption that they generally cannot be used in humans.
As soon as such substances are used in medicinal products, their suitability for use in humans must be carefully examined and evaluated by the manufacturer and within the framework of the marketing authorisation, e.g. by the Paul-Ehrlich-Institut. A marketing authorisation application contains corresponding information on quality and production. The above-mentioned testing was also carried out as usual for the approval of mRNA vaccines.
How is the safety of the vaccines monitored after marketing authorisation?
At the time of the first marketing authorisation, our knowledge of the safety of the COVID-19 vaccines is naturally incomplete, because in clinical trials both the duration of the follow-up monitoring and the number of vaccinated persons are limited. It is possible that not all the rare or very rare adverse effects associated with administration of the vaccine have been identified in the clinical trials. They are, however, of great importance for the overall evaluation of a new vaccine. In general, new knowledge about the safety of vaccines, especially with regard to very rare occurrences, can be obtained even a long time after marketing authorisation – as is the case with all vaccines. For this reason, experts in the safety of medicinal products (pharmacovigilance) never stop monitoring the vaccines, even after marketing authorisation.
Routine pharmacovigilance measures after marketing authorisation include the recording and evaluation of reports of suspected vaccination complications or adverse reactions to vaccination. These reports are recorded and evaluated centrally both at the Paul-Ehrlich-Institut and in the EudraVigilance database for the whole of Europe. In this connection, the marketing authorisation holder must regularly prepare safety reports, which are assessed jointly by the various marketing authorisation agencies in the European Union. As part of marketing authorisation, the marketing authorisation holder must submit “risk management plans”, which summarise what is known – and what is not yet known – about the safety of the vaccines. In addition, it must describe precisely the measures that will be used to fill the remaining gaps in knowledge – e.g. further studies after marketing authorisation – and in what timeframe this will be achieved. These gaps in knowledge may, for example, relate to safety in particular groups of people who were not represented sufficiently in the clinical trials.
In the case of the COVID-19 vaccines, the Paul-Ehrlich-Institut is also carrying out additional studies. This includes a study using the SafeVac 2.0 smartphone app, which will be used to further investigate the tolerability of the individual COVID-19 vaccine products. Participation in the app-based study is voluntary.
When does vaccination protection begin with the authorised COVID-19 vaccines?
In the clinical trials for the marketing authorisation of the respective vaccines, complete vaccination protection against COVID-19 was detected seven to fifteen days after the second vaccination or two weeks after the single vaccination with COVID-19 Vaccine Janssen. However, with all the vaccines a certain level of protection against COVID-19 was already evident after the first vaccination.
Should allergy sufferers be vaccinated?
According to current knowledge, allergy sufferers or people who have already experienced a severe allergic reaction (anaphylaxis) can be vaccinated against COVID-19 with all authorised vaccines. There is no increased risk of serious adverse effects. An exception is a pre-existing allergy to an ingredient of the specific COVID-19 vaccine or a severe intolerance reaction to previous administration of the COVID-19 vaccine. In this case, allergological clarification is recommended and it is usually possible to switch to another COVID-19 vaccine.
As a general rule, severe allergic reactions can occur in very rare cases with all vaccines. Therefore, each person should be observed for 15 minutes after vaccination so that they can receive appropriate medical treatment in the event of an allergic reaction. If the person to be vaccinated has a history of anaphylaxis or severe allergic reactions following administration of medication or other vaccines, the observation time will be increased to 30 minutes if necessary.
It is not recommended to take anti-allergic drugs before vaccination, as a possible allergic reaction could be delayed and occur outside the monitoring period of 15 or 30 minutes.
In the rare case of a severe anaphylactic reaction after the first or second dose of vaccine, a further dose should not be administered.
Can COVID-19 mRNA vaccines affect fertility?
There is no evidence from the non-clinical studies of the authorised mRNA-COVID-19 vaccines that vaccination could lead to impairment of female or male fertility (fertility).
As required for any drug approval in the EU, various animal toxicity studies were conducted prior to human use. Potential adverse effects of repeated vaccinations on fertility, pregnancy and embryonic development were each investigated in a special, very large study in female rats conforming to international guidelines (so-called ‘DART(Developmental and Reproductive Toxicity) study’). These studies show no evidence of impairment of female fertility caused by the vaccines. Furthermore, in the toxicity studies with repeated administration of an increased vaccine dose (so-called ‘repeat-dose toxicity study’), no vaccine-related changes in female or male reproductive organs (ovaries or testicles) were observed in the subsequent comprehensive fine-tissue (histopathological) examinations.
With this data situation, the best possible safety for the exclusion of damage to reproductive organs and of an impairment of reproduction in humans is guaranteed within the framework of a drug marketing authorisation.
The studies conducted and their evaluation can be found in the published European public assessment report (EPAR) of the European Medicines Agency (EMA). The EPARs can be found in the right-hand column at http://www.pei.de/covid-19-vaccines. The Robert Koch-Institut reports on further studies in their report (German only): “Does COVID-19 vaccination make men or women infertile?”
Updated: 01.06.2022
Is there a risk that the DNA from vector vaccines can be integrated into the human genome?
The COVID-19 vaccines Vaxzevria from Astra Zeneca and COVID-19 Vaccine Janssen consist of viral vectors from adenoviruses (cold viruses). The genome of the adenovector was modified in such a way that virus propagation in human cells is not possible and, at the same time, the gene with the antigen blueprint (immunoreaction-causing pathogen component) is transferred into the cell. After the adenoviral gene transfer, the optimised surface protein of SARS-Coronavirus-2, the spike protein, is produced in a few body cells and presented to the immune system. Adenoviral vectors are generally considered as non-integrating vectors. This means that they do not integrate their genome into the cell genome. Like the genome of other adenoviruses, the genome of the COVID-19 vector vaccines on the basis of non-replicable adenoviruses will remain outside the human DNA (extrachromosomal) in the cell nucleus.
Also, against the background that the adenoviral vectors – unlike natural cold viruses – cannot replicate in the vaccinated person, due to genetic changes, and are rapidly eliminated in the body, there is – based on the current state of the art – no risk of the adenovirus vector DNA integrating into the human genome.
Updated: 01.06.2022
Can COVID-19 vaccination with an mRNA or a vector vaccine cause damaging cell fusions?
The answer is clearly no.
In the meantime, it is known that the spike protein of Coronavirus SARS-CoV-2, when in contact with human cells, causes the cells to fuse with neighbouring ones and partly die. Such fused cells were found in lungs of patients who had died of COVID-19.
With these findings, the question arose whether vaccines causing the formation of spike proteins might also cause such membrane fusions.
When the COVID-19 vaccines available in Germany (mRNA vaccines or vector vaccines) are used, few body cells receive foreign genetic information at one single time. This information consists of mRNA (mRNA vaccines) or DNA transmitted by harmless cold vaccines (vector vaccines). The genetic information is translated into protein by the cells affected. The cells generate the spike protein of Coronavirus SARS-CoV-2. Since the vaccines do not replicate, unlike the Coronavirus SARS-CoV-2, the amount of spike protein will remain small and local. No clinical effects can be expected, because the number of cells, into which the genetic information for the formation of the spike protein is inserted by the vaccination, is so small.
Clinical studies in tens of thousands of vaccinated study participants have proofed the safety of the vaccines. The regular public safety updates by the Paul-Ehrlich-Institut do not include any evidence of such vaccination complications either.
Membrane fusion is a natural process used by the cells to transport material such as hormones, neurotransmitters, and waste to the desired destination. Viruses also use this process to enter new cells.
What is VAED?
VAED stands for Vaccine-Associated Enhanced Disease. On the one hand, it can be caused by the occurrence of so-called infection-enhancing antibodies (Antibody-Dependent Enhancement, ADE). On the other hand, it can be caused by vaccine-associated hypersensitivity (VAH). These processes involve a shift in the balance between different immune cells, the so-called type 1 and type 2 T helper cells, which in turn has consequences for the release of important messenger substances of the immune system.
VAED arose in context with the development of a vaccine candidate against pneumonia in children caused by the respiratory syncytial virus (RSV) more than 50 years ago (1967). There, increased RSV disease with signs of inflammation in vaccinated individuals was noticed in the clinical trials. The development of the vaccine was stopped early for these reasons.
Is it possible that quality defects in individual batches (production units) could cause adverse events and vaccination complications and would this be detected?
Samples from each vaccine batch are experimentally tested by a European Official Medicines Control Laboratory (OMCL). The Paul-Ehrlich-Institut only grants national batch release for the German market if the samples meet the criteria and specifications stated in the marketing authorisation documentation. This ensures a high level of quality for each batch of the vaccine products. To date, there is no evidence that individual batches were associated with a higher number of adverse events or any specific adverse events.
Where can I find information about the substances contained in vaccines?
The Summary of Product Characteristics (SmPC) is one place where information on the substances contained in a vaccine can be found.
The "Guideline on Summary of Product Characteristics (SmPC)" from the European Medicines Agency (EMA) specifies what must be stated in each medicinal product's SmPC.
Detailed information is listed under the following points:
- Section 2: Qualitative and quantitative composition
The active substance/s are mentioned here. The information is to be provided qualitatively and quantitatively, i.e. in terms of type and amount.
In the case of vaccines, section 2 also includes adjuvants. Adjuvants are by definition excipients (see section 6.1). However, full qualitative and quantitative details for excipients listed in the "Annex to the European Commission guideline on ‘Excipients in the labelling and package leaflet of medicinal products for human use’" must also be provided under section 2 of the Summary of Product Characteristics. - Section 4.3: Contraindications
Circumstances in which the medicinal product should not be given for safety reasons are listed in this section. The list includes a warning for hypersensitivity to the active substance or to any excipients. For example, components that can lead to allergic reactions are mentioned in this section. - Section 6.1: List of excipients
The excipients are listed here. According to the European Pharmacopoeia (Ph. Eur.) 10.7, an excipient is any substance contained in a medicinal product other than an active substance (examples: adjuvants, stabilisers, antimicrobial preservatives, diluents, antioxidants). Adjuvants are listed under section 2 (see above).
Residues from production or impurities need not be reported if they do not pose any identifiable risks.
Residues with which a risk could be associated, such as traces of antibiotics or traces of egg whites, must be reported due to possible anaphylactic reactions (severe immune reactions). These substances must also be mentioned under section 2 (qualitative, not quantitative). For such substances, there is a warning in section 4.4 as a precautionary measure to reduce the risk during use.
Elemental Impurities
Elemental impurities in pharmaceuticals (e.g. metal traces) are considered acceptable up to certain limits. This is regulated in the ICH Q3D Elemental impurities guideline.
Tables A.2.1 and A.2.2 in the document show the PDE values (permitted daily exposure) in micrograms (μg)/day for different elements.
Quantities in excess of these values shall be justified by the applicant in exceptional cases. A level of elemental impurities above the specified PDE value (see Table A.2.1) may be acceptable in certain cases. These cases include intermittent (temporary) administration, short-term administration (i.e. 30 days or less), special indications (e.g. life-threatening diseases, unmet medical needs, rare diseases).
If doses of a vaccine batch (production unit) contain concentrations of elemental impurities that are too high and do not fall under the exceptions mentioned above, the vaccine batch does not receive a federal batch release for Germany from the Paul-Ehrlich-Institut.
Updated: 28.03.2024
Post-Vac Syndrome
The term "Post-Vac Syndrome" is used in connection with certain symptoms observed after COVID-19 vaccination, some of which are similar to Long COVID symptoms.
Currently there is no internationally recognised, standardised case definition for Post-Vac Syndrome. The causes of both Post-Vac Syndrome and Long COVID are unknown.
The recording and categorisation of suspected cases is carried out according to the internationally agreed codes of the "Medical Dictionary for Regulatory Activities" (MedDRA). This creates an electronic, standardised record of all reports corresponding to these codes.
The Paul-Ehrlich-Institut carried out evaluations of international suspected cases from 36 countries using the adverse reaction database (EudraVigilance database) at the European Medicines Agency (EMA). The Paul-Ehrlich-Institut searched for suspected cases of Chronic Fatigue Syndrome, Postural Orthostatic Tachycardia Syndrome, Post-Acute COVID-19 Syndrome and Post-Vaccination Syndrome. In view of the large number of vaccinations that have been carried out, the number of suspected case reports is not unusually high, and a risk signal has not yet emerged on the basis of national and international reports.
Experience with COVID-19 vaccinations, some of which number in the billions, has been gained worldwide in very different healthcare systems (Scandinavia, USA, Asia, Israel, etc.). Therefore, it can be assumed that new risk signals would be detected very quickly. Examples of these are the very rare (<1/10,000) side effects:
- anaphylactic reactions,
- thrombosis with thrombocytopenia syndrome (TTS) after vaccination with adenovirus-based vaccines, in particular in persons under 50 years of age,
- myocarditis, mainly occurring in subjects under 30 years of age after the second dose of mRNA vaccine and
- Guillain-Barré syndrome (GBS) after vaccination with adenovirus-based vaccines.
In addition, there are now studies that suggest that COVID-19 vaccines can protect against Long COVID.
For example, in a study conducted by the Office for National Statistics in the United Kingdom (UK) in which patients were interviewed, the risk of Long COVID was lower in vaccinated individuals who experienced SARS-CoV-2 infection after vaccination than in unvaccinated infected individuals.
In order to scientifically classify and evaluate "Post-Vac Syndrome", further methodologically robust investigations or studies are necessary. Such studies are the only way to gain reliable insights into the possible causes of Long COVID and Post COVID-19 after infection, as well as the reactions currently referred to as Post-Vac Syndrome after COVID-19 vaccination, which has very similar symptoms to Long COVID.
What is the purpose for conducting observed versus expected analyses?
An observed versus expected (OE) analysis is an internationally recognised method for detecting safety signals in pharmacovigilance.
Updated: 04.10.2022
How does an observed versus expected analysis work?
The method used by the Paul-Ehrlich-Institut was published years ago in a peer review journal (by Kries R et al. 2005, https://pubmed.ncbi.nlm.nih.gov/15602672/).
First, the individuals conducting the analysis determine the number of cases of a specific adverse event reported within a plausible time interval after vaccination with a specific vaccine product (observed number: number of suspected cases reported to the Paul-Ehrlich-Institut in which the adverse event was reported as occurring within x days after vaccination with a certain vaccine product). The adverse event analysed could be a medically diagnosed myocarditis, for example.
The number of events based on the background incidence for the adverse event to be analysed (number of cases per 100,000 people per year) within the same time interval of x days in the population immunised with the respective vaccine would then be calculated independently of the given vaccination (expected number). This is the number of vaccination-independent events based on the background incidence of the event, regardless of whether the individuals received the vaccination in question in a comparable population group. The background incidence of an event can be found in publicly valid statistics or peer-reviewed scientific publications.
The observed number is then divided by the expected number (observed versus expected, OE). A 95% confidence interval (Poisson) is calculated for the value thus obtained (point estimator).
A standardized morbidity ratio (SMR) with a lower 95% confidence interval ≥ 1 indicates a safety signal, but this must be further analysed by additional investigations, since the comparison of spontaneous reports with the known incidences from other studies is exploratory due to various methodological limitations.
The OE calculation includes all suspected case reports for a certain event up to and including the day of the evaluation within the selected, plausible time interval between the respective vaccination and the occurrence of the first symptoms of the event (time to onset, TTO).
In addition to the OE analysis, the Paul-Ehrlich-Institut assesses the individual suspected reports according to the World Health Organisation (WHO) recommended evaluation algorithm for causality between vaccination and adverse event (https://www.who.int/publications/i/item/9789241516990). The OE analysis does not take these individual case assessments into account and includes all suspected case reports.
Updated: 04.10.2022
What are some potential limitations of the observed versus expected analysis?
It should be noted that an observed versus expected analysis (OE analysis) can indicate a safety signal, but only further investigations will show whether or not there is actually a risk. An OE analysis is not suitable for confirming a risk. A safety signal indicated by means of a method such as an OE analysis should be further investigated by additional studies (Guideline in good vigilance practices (GVP): Product- or Population-Specific Considerations I: Vaccines for prophylaxis against infectious diseases EMA/488220/2012 Corr*).
The following aspects pose limitations for an OE analysis: variance in the information on background incidence rates in the original sources, lack of information regarding both the time interval between vaccination and start of symptoms as well as the exposure level, reporting delays, and somewhat shorter observation times post-vaccination for the last dose administered. In addition, age stratifications can only be carried out to the extent that data from the literature on the background incidence is available for individual age groups. Therefore, the individual analyses also differ in regards to the age groups presented.
Updated: 16.04.2024
What is the fundamental difference between the suspicion of a vaccine side effect, the side effects listed in the product information and vaccination damage according to the Social Code XIV?
Pharmacovigilance records suspected adverse reactions as part of the spontaneous reporting system. These are spontaneously reported, unconfirmed suspected cases of side effects.
Adverse reactions are identified in clinical trials prior to authorisation or in large post-authorisation studies and their frequency is included in the product information.
Vaccine damage is recognised on the basis of the Social Code XIV (Sozialgesetzbuch XIV, SGB XIV). The vaccine damage assessment is always performed as an individual medical and clinical assessment. Procedures for the recognising vaccine damage involve the assessment of an individual case within the framework of social compensation law.
Updated: 05.08.2024
What are the benefits of recording and evaluating suspected adverse reactions?
The spontaneous reporting system is an essential component in the vaccine safety monitoring. The collection and evaluation of suspected vaccine adverse reactions and vaccine complications reported to the Paul-Ehrlich-Institut serves to identify possible risk signals at an early stage and, if necessary, to take, coordinate or initiate measures to minimise risk.
Suspected case reports are not subject to an individual medical or clinical assessment by the Paul-Ehrlich-Institut.
The data from the spontaneous reports are supplemented by data from the periodic safety update reports (PSURs) specified in the marketing authorisations, which the pharmaceutical companies (marketing authorisation holders) must submit to the committees of the European Medicines Agency (EMA) and thus also to the national drug authorities.
If there is any indication of a new risk signal for an authorised vaccine, the Paul-Ehrlich-Institut will, if necessary, take or initiate measures to minimise the risk or, if necessary, coordinate measures with the sister medicines authorities in the EMA committees and report on them.
Suspected cases of adverse reactions are not identical to adverse reactions as listed in the product information.
Updated: 05.08.2024
What is an adverse vaccination reaction? How and where is it defined?
Section 4 subsection 13 of the German Medicinal Products Act (Arzneimittelgesetz, AMG) distinguishes between "adverse reactions" and "serious adverse reactions".
Adverse reactions are harmful and unintended reactions to a medicinal product.
Serious adverse reactions are adverse reactions that are fatal or life-threatening, require hospitalisation or prolongation of hospitalisation, lead to persistent or significant disability, incapacity, congenital anomalies or birth defects.
For the safety monitoring (pharmacovigilance) of COVID-19 vaccines, further "Adverse Events of Special Interest" (AESI) were classified as "serious" from the outset in accordance with the agreement of the pharmaceutical authorities of the European Economic Area (EEA) in order to recognise their occurrence promptly and to be able to react with risk reduction measures.
Adverse reactions that are identified in clinical trials before authorisation or in large-scale studies after authorisation are listed in Chapter 4.8 "Undesirable effects" in the vaccine product information.
There is a difference between a "severe" vaccination side effect and a "serious" vaccination side effect: Affected persons may experience a reaction such as one that leads to an (even prolonged) incapacity to work as a "severe reaction" to vaccination. However, this is not synonymous with a serious adverse reaction within the meaning of the Medicinal Products Act or an adverse event of special interest (AESI).
Updated: 05.08.2024
How is the frequency of vaccination side effects determined?
The frequency of side effects is determined in clinical trials before or large-scale studies after authorisation. Side effects of vaccine products authorised in Germany and the European Economic Area (EEA) are listed with their frequency determined in corresponding studies in the vaccine's product information product under point 4.8:
- Very common (≥ 1/10),
- Common (≥ 1/100, < 1/10),
- Uncommon (≥ 1/1 000, < 1/100),
- Rare (≥ 1/10 000, < 1/1 000),
- Very rare (< 1/10 000),
- Not known (frequency cannot be estimated based on available data).
The frequency of adverse reactions (confirmed and included in the product information) cannot be inferred from the number of suspected case reports received by the Paul-Ehrlich-Institut as part of the spontaneous reporting system alone, nor from their reporting data.
Updated: 05.08.2024
What is a vaccination damage within the meaning of Social Code XIV?
According to section 24 of the German Social Code XIV (Sozialgesetzbuch, SGB XIV), vaccine damage is defined as a damage to health that goes beyond the usual extent of a reaction to a vaccination.
Section 5 SGB XIV regulates the degree of damage and stipulates that temporary health impairments of up to six months are not considered as damage.
If vaccinated persons or their relatives suspect that they have suffered a vaccine damage following a publicly recommended vaccination, they can submit an application for relief under the Federal War Victims Relief Act (Bundesversorgungsgesetz) in accordance with Section 24 of the German Social Code (SGB) XIV in conjunction with section 4 SGB XIV.
Pursuant to Section 4 subsection 4 of the SGB XIV, the probability of a causal connection is sufficient for the recognition of a health condition as a result of damage.
According to section 113 subsection 5 of the SGB XIV, the application for compensation must be submitted to the Social Welfare Office in the federal state in whose territory the vaccination was carried out. The Paul-Ehrlich-Institut is not responsible for processing applications for recognition of vaccine damage.
Updated: 05.08.2024
Why does the Paul-Ehrlich-Institut publish the number of suspected case reports, but no figures on confirmed suspected cases?
The Paul-Ehrlich-Institut records and evaluates case reports of suspected possible adverse reactions to vaccines and vaccination complications as part of the spontaneous reporting system, an important pillar of medicinal product safety. The spontaneous reporting system has the function of recognising safety signals – indications of a connection between an adverse reaction and the administration of a drug or vaccination – as quickly as possible. Those signals are then followed up by further investigations.
In the case of a safety signal, further investigations are carried out to determine whether the reaction described is actually an adverse reaction caused by the medicinal product. The Paul-Ehrlich-Institut works closely with the EU authorities in the evaluation of safety signals.
No conclusions can be drawn about the frequency of adverse reactions or a causal relationship with the administration of a vaccine or therapeutic on the basis of the suspected case reports submitted to the Paul-Ehrlich-Institut. This is due to the fact that
- adverse reactions can also occur coincidentally after administration of a vaccine or therapeutic and then be reported,
- in the interests of rapid detection of possible new safety signals, it is expressly desired that reactions with a questionable link to vaccination are also reported (low-threshold reporting), and
- reports are often not complete and the assessment of an adverse reaction in an individual case may change with further medical information on a report and/or new scientific findings.
Updated: 05.08.2024
How is a suspected adverse event report evaluated?
A suspected adverse event report is assessed by the Paul-Ehrlich-Institut according to the criteria of the World Health Organization (WHO).
In its user manual for the revised WHO classification, the WHO states the following regarding the assessment of an adverse event following immunisation (AEFI):
"Causality assessment is the systematic review of data about an
AEFI case; it aims to determine the likelihood of a causal association between the event and the vaccine(s) received. For individual cases, one tries to apply the evidence available on the basis of the history and time frame of the event to arrive at a causal likelihood. (...) Causality assessment usually will not prove or disprove an association between an event and the immunization. It is meant to assist in determining the level of certainty of such an association. A definite causal association or absence of association often cannot be established for an individual event."
The evaluation of suspected adverse event reports is therefore not about the final evaluation of the individual reports.
Updated: 05.08.2024
How is the frequency of adverse drug reactions recorded and determined?
The frequency of adverse drug reactions can only be determined in a scientifically reliable manner in controlled clinical studies.
The known, confirmed adverse drug reactions are listed in each medicinal product’s product information (SmPC and package leaflet) in Chapter 4. Information on the frequency of side effects determined in clinical trials can be found in Chapter 4.8 (product information/SmPC).
The current product information (information for healthcare professionals and instructions for use) for vaccines and biomedicines can be accessed via the Paul-Ehrlich-Institut’s website.
Additional Information
Overall, the Paul-Ehrlich-Institut examines the quality, safety and efficacy of vaccines and biomedicines authorised in Germany and the EU within the scope of
- the marketing authorisation for medicinal products,
- post-authorisation batch testing and
- pharmacovigilance (drug safety) by recording suspected cases of adverse reactions.
Medicinal products are only granted marketing authorisation if the risk-benefit ratio is favourable.
Updated: 05.08.2024
Where can I find information and data on vaccine and medicinal product side effects?
Confirmed side effects in the product information (Information for healthcare professionals and package leaflet)
Confirmed possible side effects of a medicinal product, e.g. a vaccine, with information on the frequency can generally be found in the respective product information (Summary of Product Characteristics, SmPC).
The Paul-Ehrlich-Institut provides links to the product information for vaccines and biomedicines at www.pei.de/medicinal-products. After selecting a medicinal product category, you will find the link in the column titled "Further information". This page also links to the European Public Assessment Report (EPAR) for medicinal products that have received a central EU authorisation. The EPAR also contains the product information. For all other medicinal products, you will find the link to the PharmNet.Bund portal, where the SmPCs are stored.
A distinction must be made between confirmed possible side effects listed in the product information and suspected adverse reactions to vaccines and medicinal products. The reporting of a suspected adverse reaction closely following vaccination or the use of a medicinal product does not automatically mean that there is a causal connection.
Suspected adverse reactions – reports from the spontaneous reporting system
The Paul-Ehrlich-Institut publishes a compilation of suspected vaccination reactions and vaccination complications reported in Germany from 2000 onwards on its website in a data protection-compliant manner. The data records include information on the vaccine administered and the age group and gender of the vaccinated persons. They can be searched using the PDF reader search function.
All suspected cases of vaccine and drug side effects reported in Germany are also entered into the EudraVigilance database of the European Medicines Agency (EMA). The EMA publishes this data so that everyone has access to the same information that the European regulatory authorities use when assessing the safety of a medicinal product or active substance. The EudraVigilance database includes suspected case reports from across the European Economic Area (EEA) and other countries worldwide where centrally authorised medicines are used.
In the EMA's EudraVigilance database, you can view reports of suspected adverse reactions sorted by product or substance. Medicinal products that do not have EU authorisation are not available in the EudraVigilance database by product name, only by the name of the active substance.
Expert articles, studies and information letters on pharmacovigilance
If necessary, e.g. if certain suspected adverse drug reaction reports accumulate in connection with a vaccination or the use of a medicinal product, the Paul-Ehrlich-Institut also conducts pharmacovigilance studies to verify causality.
Together with the Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM), the Paul-Ehrlich-Institut regularly publishes information on current aspects of medicinal product risk assessment in the “Bulletin zur Arzneimittelsicherheit”.
In the Newsroom and in the Medicine Safety sections of the Paul-Ehrlich-Institut’s website you will also find announcements, positions, and safety information on aspects relating to medicinal product safety monitoring.
The safety and press newsletters keep subscribers up to date with the latest news in the field of pharmacovigilance.
Further Information
Data on Adverse Drug Reactions
EudraVigilance Database
Pharmacovigilance Studies (German only)
Pharmacovigilance Bulletin
Subscribe to the Newslettters of the Paul-Ehrlich-Institut
Updated: 07.08.2024