Paul-Ehrlich-Institut

Information on the Use of Cookies

In order to operate and optimise our website, we would like to collect and analyse statistical information completely anonymously. Will you accept the temporary use of statistics cookies?

You can revoke your consent at any time in our privacy policy.

OK

Coronavirus and COVID-19

FAQ Coronavirus

Development and Authorisation

How can a COVID-19 vaccine be authorised so quickly and at the same time be safe?

The development of vaccines for new pathogens is a complex and laborious process that usually takes several years.

Before being authorised, a vaccine candidate must successfully complete all the phases of medicinal product development. This begins with the isolation and characterisation of the pathogen and the identification of suitable antigens. Antigens are the components of the pathogen that are intended to bring about the immune protection. This is followed by the development of the vaccine candidate, the preclinical investigations and the clinical trials in phase 1 (immunogenicity), phase 2 (tolerability, dosage) and phase 3 (statistically significant data on safety and efficacy). In order for a vaccine to be authorised, its quality, safety and efficacy must be proven. In addition, its benefits must clearly outweigh the risks. COVID-19 vaccines are also developed and authorised in accordance with this principle.

In Europe, the COVID-19 vaccines are assessed in the centralised marketing authorisation procedure, which is coordinated by the European Medicines Agency (EMA). In the event of a positive assessment, the Committee for Medicinal Products for Human Use (CHMP) at the EMA issues an opinion to the European Commission with a recommendation for authorisation. The European Commission decides on the marketing authorisation of a vaccine product in Europe and thus also in Germany. After being authorised, the vaccine can be marketed in the EU Member States, including the EEA states, and can be made available to all members of the public.

The coronavirus pandemic has presented the modern world with unprecedented challenges – economically, socially and in terms of health. Vaccines are the most effective way to contain the pandemic and to protect ourselves from COVID-19. This understanding motivated all the experts involved in vaccine development to work together more closely and to make processes more efficient, without compromising on due care and diligence. This has also led to significant optimisation of the process flows and time savings in development.

#1 Time savings through scientific advice

Vaccine developers benefit from early and ongoing scientific and regulatory advice from medicines agencies. This scientific advice is initially provided on a national level, and then in the case of advanced development on a European level. It prepares the pharmaceutical company for the regulatory requirements that will need to be observed during development, for the requirements in terms of the content of applications for the approval of clinical trials, for marketing authorisation and for batch release. It makes a smooth submission process possible without undue delays.

#2 Time savings through rolling reviews

A rolling review procedure for marketing authorisation allows the vaccine manufacturer at an early stage – even while the clinical phase 3 trial is still ongoing – to submit individual data packages for a preliminary assessment for marketing authorisation and to answer any questions that arise during the regulatory evaluation of the application. In this way, parts of the application dossier can be checked, improved and assessed before the actual application is submitted. Once all the necessary documents for marketing authorisation have been submitted and the marketing authorisation application has been made, processing will take significantly less time. The assessment process therefore starts much earlier. The rolling review procedure precedes the marketing authorisation application with the submission of the complete data packages.

The Paul-Ehrlich-Institut has also used the rolling review procedure for the approval of clinical trials.

#3 Time savings by combining clinical trial phases

Clinical trials, which generally take place one after the other, have been combined, e.g. phase 1 with phase 2 or phase 2 with phase 3. Organisational processes, for example the recruitment of test subjects for two phases of the clinical trial, can be bundled into one process. In addition, the necessary investigations can be combined.

#4 Time savings through existing research on coronaviruses

In the development of a COVID-19 vaccine, scientists were able to build on preparatory research work that had already taken place into other coronaviruses and corresponding vaccine developments, e.g. the SARS coronavirus in 2003 and the MERS coronaviruses. These coronaviruses, which are similar to SARS-CoV-2, triggered the SARS epidemic in 2002/2003 and the MERS (Middle East Respiratory Syndrome) epidemic in 2012.

Updated: 01.09.2022

Can individual phases of the vaccine development be omitted?

No.

The development and manufacture of safe and efficacious vaccines is highly complex. In the EU, and thus also in Germany, we already had three effective and safe vaccines against COVID-19 one year after the outbreak after the pandemic – this was previously unthinkable. All these vaccines underwent the regular course of marketing authorisations for vaccines in a short period of time without skipping important phases of development – very central to this is the clinical testing for safety and efficacy. Extensive tests are all important – after all, vaccines are administered to healthy persons.

The Paul-Ehrlich-Institut supports the complex development of a vaccine along the entire chain of procedures. It offers the opportunity, to all pharmaceutical companies and founders of start-ups alike to inform themselves on the requirements for medicines with regard to quality, safety, and efficacy in scientific advice meetings. Besides, the Paul-Ehrlich-Institut provides information on the prerequisites for the authorisation of clinical trials and further steps on the road to a marketing authorisation. At the Paul-Ehrlich-Institut, it is the Innovation Office, which focuses on such scientific advice.

Before a clinical trial is authorised, a number of data must be available and prerequisites must be fulfilled, which include a manufacturing authorisation for the investigational medicinal product as well as the production in compliance with good manufacturing practice (GMP). The hurdles are set deliberately high, since the aim is to ensure the maximum possible safety for the study participants.

Further Information

Official Duties of the Paul-Ehrlich-Institut
The regular course to an authorised vaccine in our gallery "Official duties of the Paul-Ehrlich-Institut on the road to a vaccine”

Updated: 01.09.2022

What accelerated authorisation procedures are available in the EU?

In the EU, there are three standardised procedures, each of which permits early marketing authorisation under certain conditions:

  • accelerated assessment
  • conditional marketing authorisation
  • authorisation under exceptional circumstances.

In addition to these procedures, medicine developers can participate in a voluntary programme for accelerating the marketing authorisation process, the PRIME scheme of the European Medicines Agency (EMA).

In order to accelerate the authorisation of COVID-19 vaccines as much as possible, the rolling review procedure has been used. This procedure was established for precisely this type of pandemic health situation.

Updated: 01.09.2022

What is an accelerated assessment?

In the accelerated assessment procedure, the timeframe for regulatory assessment is reduced from 210 days to 150 days. The prerequisite is that the European Medicines Agency (EMA) must approve the medicine developer’s request for an accelerated assessment.

This procedure is possible for medicinal products that are of major interest for public health, e.g. because they target a disease for which there is currently no treatment option or address an unmet medical need.

Updated: 01.09.2022

What is a conditional marketing authorisation?

A conditional marketing authorisation is a marketing authorisation that is linked to certain conditions. It can be granted for a medicine in the interest of public health,

  • if the benefit of immediate availability of the medicinal product outweighs the risk of less comprehensive data than normally required.
  • if the medicinal product aims to treat or prevent a life-threatening illness. This also includes orphan medicines,
  • if the CHMP finds that all the following requirements are met:

    • A positive benefit-risk balance of the product, i.e. the benefit to public health of the medicinal product’s immediate availability on the market outweighs the risks due to the need to submit further data.
    • The applicant will provide comprehensive data at a later date.
    • An unmet medical need will be fulfilled.

Conditional marketing authorisations are valid for one year and can be renewed annually. They can be converted into a full marketing authorisation.

The marketing authorisation holder is required to fulfil specific obligations (ongoing or new studies, and in some cases additional activities) in the specified timeframe with a view to providing comprehensive data that confirms that the benefit-risk balance continues to be positive.

Once all obligations have been conclusively fulfilled and, as a result, more comprehensive data on the medicinal product has been obtained, the marketing authorisation is converted into a normal authorisation with unlimited validity that is not subject to any specific obligations. Initially, this will be valid for five years, but can be extended for an unlimited validity.

Updated: 01.09.2022

What is a marketing authorisation under exceptional circumstances (generally medicinal products for rare diseases)?

In very rare cases, a marketing authorisation under exceptional circumstances can be granted. In such cases, the European Medicines Agency (EMA) and the European Commission, as the authorising body, understand that the comprehensive clinical data that is usually required cannot be provided, but that there is a reasonable assumption that a medicinal product can help patients in the event of a high medical need.

If the usually required clinical data cannot be produced for a particular treatment option or a particular medicinal product, it would not be in the interests of the patients concerned to formally insist on compliance with this requirement. This may be the case if a disease is very rare (orphan disease) or if there are ethical concerns about specific studies in the therapeutic situation.

This form of marketing authorisation is linked to particularly strict conditions: the authorisation is reviewed annually and is generally not converted into a standard marketing authorisation. Almost all the medicinal products concerned are for rare diseases (orphan drugs).

Updated: 01.09.2022

How does a conditional marketing authorisation differ from a marketing authorisation under exceptional circumstances?

A conditional marketing authorisation is granted with the requirement that the applicant will provide the required comprehensive data within an agreed timeframe.

A marketing authorisation in exceptional circumstances is granted if it is unlikely that the normally required comprehensive data can be collected. This applies, for example, to very rare disorders (orphan diseases). This approval route does not generally lead to a standard marketing authorisation.

Updated: 01.09.2022

How exactly does a rolling review procedure work for COVID-19 vaccines?

In a rolling review procedure, the lead assessors from two Member States (the Rapporteur and Co-Rapporteur) on the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) assess individual submitted data packets as soon as they become available, ask questions and evaluate the applicant’s answers. The data required for a complete marketing authorisation application can thus be submitted gradually and not as a single, complete data package as is the usual practice.

This procedure serves to accelerate the progress of a COVID-19 vaccine candidate towards marketing authorisation. The assessment of the data packages from pharmaceutical and non-clinical development will have already started before the clinical data for the formal marketing authorisation application becomes available.

A rolling review procedure runs until such time as the study data can provide sufficient evidence to permit the formal application for marketing authorisation. The CHMP checks at what point reliable data is available as the basis for a positive risk-benefit assessment, and then recommends that a corresponding application should be submitted.

The CHMP can then decide relatively quickly whether or not to recommend to the European Commission that marketing authorisation should be granted to a vaccine candidate.

It is important to note that the processes in a rolling review are carried out in parallel – the collection of clinical study data and the assessment of non-clinical data and data on manufacturing and quality – so that the time to a potential marketing authorisation is reduced, but no compromises are made in the assessment. The level of safety remains just as high as in the usual centralised procedure. A vaccine can only be granted marketing authorisation if its quality, safety and efficacy have been proven.

Updated: 01.09.2022

What type and amount of data are required in order to approve a safe and effective COVID-19 vaccine?

With the application for marketing authorisation of a COVID-19 vaccine, a medicinal product developer must submit the following data:

  • information on the group of people to whom the vaccine is to be administered,
  • pharmaceutical quality data, including information on the identity and purity of the vaccine components, as well as their content and biological activity (potency),
  • data on each manufacturing step and on the checks that ensure each batch of vaccine is of a consistently high quality,
  • evidence of compliance with international standards for laboratory testing (Good Laboratory Practice, GLP), vaccine manufacture (Good Manufacturing Practice, GMP) and clinical trials (Good Clinical Practice, GCP),
  • data on the various immune responses achieved by the vaccine,
  • information regarding the effects and adverse reactions observed in the various groups of study participants,
  • the information that is to be obtained from follow-up studies after marketing authorisation (e.g. long-term data on safety and immunity),
  • product-specific information for those wishing to be vaccinated, such as the SPCs, package leaflets and the labelling; these are proposed by the applicant and are checked and approved by the scientific committees of the European Medicines Agency (EMA),
  • the Risk Management Plan (RMP). The RMP provides information on known and potential safety concerns about the vaccine. It shows how risks are handled and monitored after marketing authorisation and what knowledge is to be obtained in follow-up studies. The RMP is assessed by the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC),
  • the Paediatric Investigation Plan (PIP). The PIP is an integral part of the marketing authorisation documentation and must be submitted for each new medicinal product, regardless of which marketing authorisation procedure is being applied.

The data from the clinical trials must prove the vaccine’s efficacy, e.g. with regard to protection against COVID-19, and its safety.

Efficacy is determined in the framework of the clinical trials, in particular phase 3. It is at this stage that the researchers consider the extent to which the vaccine prevents COVID-19. To date there are no clear correlates of protection for the efficacy of COVID-19 vaccines (such as the required levels of neutralising antibodies in the blood).

The safety requirements for COVID-19 vaccines are the same as for any other vaccine in the EU and will not be reduced in the pandemic.

The Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMA), which brings together experts from all the medicines agencies of the EU Member States, conducts a thorough assessment of the submitted data. They check whether the vaccine is of good quality, is safe and effective and has a positive risk-benefit ratio. Only then will it be deemed suitable for human use.

Updated: 01.09.2022

How does the centralised marketing authorisation procedure work?

The centralised procedure, which is coordinated by the European Medicines Agency (EMA), is the standard procedure for the marketing authorisation of a medicinal product in Europe.

In the centralised procedure, the evaluation of a marketing authorisation application for a new medicinal product takes up to 210 working days. During this time the medicines experts of the national medicines agencies of the EU Member States assess, at the EMA, the documents submitted by the applicant on the quality, safety, efficacy and benefit-risk ratio of the vaccine candidate.

This period is interrupted by one or two “clock stops”. During a clock stop, the applicant prepares answers to the questions asked by the Committee for Medicinal Products for Human Use (CHMP). The maximum duration of a clock stop depends on how much time the applicant believes they will need to answer the questions. This duration must be approved by the CHMP. In general, the first clock stop lasts three to six months, while the second one lasts one to three months.

In total, the assessment of a new medicinal product normally takes around one year.

The urgent need for effective and safe COVID-19 vaccines to combat the pandemic has led to an acceleration of the processes, based on the established marketing authorisation procedures, but without any compromise in the quality of the data submitted for a risk-benefit assessment. An example of this is the rolling review procedure, in which individual data packages of the marketing authorisation dossier are submitted and assessed even before the application for marketing authorisation is presented.

Updated: 01.09.2022

How is a vaccine developed against a new, unknown virus such as SARS-CoV-2?

Firstly, the pathogen is analysed and tested to determine which components of the virus the human immune system reacts to and can build up protection against (via antibodies and the cellular immune response).

This is followed by the design of the vaccine: Which vaccine platform is suitable and what additives are required?

As part of the pharmacological/toxicological studies, the vaccine’s immunogenicity, i.e. its ability to produce a specific immune response against the target pathogen, is tested on animals; in addition, potential toxicological properties are investigated, including by the repeated administration of an increased vaccine dose (repeat-dose toxicity).These studies also examine the distribution of vaccine components in the organism, local reactions, potentially harmful effects on fertility and embryonic development, the inflammatory parameters after vaccination, the vaccination protection conferred and any indications of an intensification of infection.

Once it has been proven that the vaccine can be reliably and consistently manufactured at a level of quality suitable for human use, it is tested in phase 1 to phase 3 clinical trials on volunteers who have received comprehensive information. The tolerability, safety and efficacy of the vaccine candidate are tested clinically. If there is sufficient data from the quality-assured, consistent manufacture of a high-quality vaccine product, as well as satisfactory results from the preclinical and clinical trials, an application can be submitted for marketing authorisation.

For the countries of the European Economic Area (EEA), the assessment procedure for COVID-19 vaccines is coordinated by the European Medicines Agency (EMA). The EMA’s vaccine assessment is carried out by experts from the national medicines agencies of the EU member states and the EEA countries in the Committee for Medicinal Products for Human Use (CHMP), in cooperation with the CHMP’s Biologics Working Party (BWP) and the Pharmacovigilance Risk Assessment Committee (PRAC). If the vaccine meets all the legal conditions relating to medicinal products and the risk-benefit ratio is favourable, the CHMP issues a positive opinion with a recommendation for approval, based on which the European Commission can issue the marketing authorisation. The authorised vaccine product can then be marketed and used on humans after batch testing is carried out by the Paul-Ehrlich-Institut in Germany.

In Germany, the recommendation as to which groups of people should be vaccinated against an infectious disease and at which times is issued by the Standing Committee on Vaccination (STIKO) at the Robert Koch-Institut, in which the Paul-Ehrlich-Institut is represented as a guest.

Updated: 01.09.2022

Does a clinical trial of a COVID-19 vaccine in Germany also lead to a marketing authorisation for Germany?

The COVID-19 vaccines that are currently authorised or in development are modern biomedicines. They can only be authorised via centralised procedure in the European Economic Area. The European Medicines Agency (EMA) coordinates the procedures and issues marketing authorisations. Two Member States are given leadership roles in each centralised procedure (rapporteur, co-rapporteur). The Paul-Ehrlich-Institut often takes one of the leadership roles for centralised procedures.

Updated: 01.09.2022

Why are Cell Cultures from Human Foetal Tissue Used for the Manufacture of some Vaccines?

Since viruses require a live cell to replicate, a cell line (cell culture) from animals or humans is required to produce vaccine viruses. Depending on the virus type, various cell types or cell lines have proved to be particularly suitable for this purpose. For influenza vaccines, for instance, up to now, these have been primarily embryonised hen’s eggs; measles viruses and mumps viruses are replicated on chicken fibroblasts, rubella viruses and chicken pox viruses on human diploid cells (MRC-5).

There are currently two cell lines from human lung tissue for the production of marketable vaccines in Germany. In 1961, the scientist L. Hayflick developed the cell line WI-38, and in 1966, the scientist J. P. Jacobs developed the cell line MRC-5 (Medical Research Council). These cell lines are described as human diploid cells (HDC).

With the development and authorisation of vector vaccines to prevent COVID-19 disease caused by the SARS-CoV-2 virus, two additional cell lines have been added.

These vector vaccines require an attenuated virus as a means of transport (vector) for a harmless portion of the genetic information of SARS-CoV-2 into a small number of somatic cells. AstraZeneca's Vaxzevria and Johnson&Johnson's COVID-19 Vaccine Janssen use adenoviruses for this purpose.

In the case of Vaxzevria, these viruses are propagated on the cell line 293 HEK (Human Embryonic Kidney), in the case of Johnson&Johnson's vaccine on the cell line PER.C6 (from human fetal retinal cells).

The cell line 293 HEK was developed in 1973 by Frank. L. Graham, a doctoral student of Alex J. van der Eb.

The PER-C6 cell line was generated in 1998 by Frits J. Fallaux, also in the laboratory of van der Eb, by an immortalisation of embryonic retinal cells. These came from a fetus aborted in 1985.

The term "cell line" means that this line has been created as a unique line, and has since then been replicated and frozen. The cells are cultured. No new foetuses are required, as can be frequently read. No foetus was aborted in any case to serve as starting material for the establishment of cell cultures.

Updated: 01.09.2022

Are there new marketing authorisations being issued for the Omicron-adapted mRNA vaccines?

No. The mRNA booster vaccines adapted to the Omicron variant of the SARS-CoV-2 coronavirus from both BioNTech/Pfizer and Moderna have received approval for a variation to the marketing authorisation of the original COVID-19 vaccine product.

Legislation (see 'further information') has made it possible for changes to the antigen and/or the addition of new antigens (here mRNAs) to a parental COVID-19 vaccine already authorised in the EU to take place via a variation of the original marketing authorisation, so that no new authorisation is required.

The bivalent, Omicron-adapted booster mRNA vaccines, which were approved since September 2022 contain, in addition to the original mRNA with the spike protein blueprint of the original virus (Wuhan), a second version of the mRNA with the spike protein blueprint of the Omicron variant BA.1 or the Omicron variants BA.4/BA.5. Each vaccine dose will contain the same amount of total mRNA as the previous corresponding vaccine.

However, since these changes can have an effect on aspects such as immunogenicity, approval of a type II variation is required for vaccine adaptation. The risk-benefit assessment of the data required for approval is carried out by experts from the national medicines authorities of the EU Member States in the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA). The final approval of the variation is given by the European Commission.

Updated: 02.11.2022

What is a type II variation?

Regulation (EC) No 1234/2008 of the European Commission ("amending Regulation") defines a type II variation as a major variation to a marketing authorisation, i.e. a variation that may have a significant impact on the quality, safety or efficacy of a medicinal product.

The Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMA) is responsible for assessing most of the variations considered type II variations and recommends or opposes the approval of the variation.

Studies on quality, efficacy or safety are required for the application review procedure, depending on the nature of the medicinal product variation.

The EMA's Pharmacovigilance Risk Assessment Committee (PRAC) is also involved in the procedure for type II variations affecting clinical safety.

Updated: 20.09.2022

Which studies had to be carried out for the two mRNA vaccines against COVID-19 as part of the type II variation approval procedure?

For the first type II variations for the Comirnaty and Spikevax vaccines, studies on quality and non-clinical studies on tolerability and immunogenicity using a suitable animal model as well as clinical trials with volunteer trial participants were carried out.

Immunogenicity describes the ability of a vaccine to elicit a targeted immune response. The vaccines' immunogenicity was tested by determining the blood levels (titre) of neutralising antibodies against the SARS-CoV-2 virus variants Wuhan and the Omicron BA.1 subvariant. Neutralising antibodies can prevent or reduce the viral infection of cells. The adapted vaccines needed to achieve superiority over the Omicron BA.1 subvariant compared to previous vaccines. Statistically significantly higher titres of neutralising antibodies against the subvariant BA.1 were required to consider the new vaccines superior.

Superiority of the vaccines has been demonstrated in clinical trials.

In the subsequent type II variations for both of the mRNA vaccines, Comirnaty and Spikevax, which contain both the mRNA of the original Coronavirus (Wuhan) and the mRNA of the Omicron variants BA.4-5 (identical spike protein), the available clinical data for the previous type II variations as well as data on quality and the manufacturing process was used for the evaluation.

Updated: 02.11.2022

What is the difference between the Omicron-adapted mRNA booster vaccines Comirnaty (BioNTech/Pfizer) and Spikevax (Moderna) and the previous mRNA vaccines against COVID-19?

The vaccines differ in their mRNA composition. The variant vaccines are bivalent booster vaccines: they each contain two antigen components, i.e. two different mRNAs in each vaccine.

The components of the vaccine that lead to the targeted immune response are called antigens. In the case of the mRNA COVID-19 vaccines, the antigen is the mRNA sequence that is read after uptake into a few body cells and leads to the formation of the spike protein. The spike protein is presented to the immune system and initiates an immune response.

The version of the Comirnaty (BioNTech/Pfizer) monovalent vaccine for primary and booster vaccinations contains the blueprint of the original SARS-CoV-2 virus (Wuhan) spike protein mRNA. The adapted vaccine “Comirnaty Original/Omicron BA.1" contains both mRNA with the spike protein blueprint of the original SARS-CoV-2 variant (Wuhan) as well as mRNA with the spike protein blueprint of the Omicron subvariant BA.1. Comirnaty Original/Omicron BA.4-5 contains mRNA with the identical blueprints of the spike protein of the Omicron sub-variants BA.4 or BA.5 (their mRNA segments are identical) along with mRNA from the original SARS-CoV-2 variant. The total amount of mRNA in the Omicron variant vaccines is identical to the amount of mRNA in the originally authorised Comirnaty vaccine.

In the case of Spikevax (Moderna), the monovalent booster vaccine contains mRNA from the spike protein of the original variant (Wuhan). The modified vaccine “Spikevax Bivalent Original/Omicron BA.1” also contains mRNA with the blueprint of the origin virus (Wuhan) spike protein along with mRNA with the blueprint of the Omicron BA.1 spike protein. The adapted vaccine “Spikevax Bivalent Original/Omicron BA.4-5” also contains mRNA from the original virus (Wuhan) as well as mRNA from the Omicron subvariants BA.4-5, as the segments are identical. The total amount of mRNA is here again identical.

All other ingredients in the vaccines are identical to the ingredients in the original vaccines. With regard to the basic preparation and formulation, the bivalent vaccines therefore do not differ from the previously authorised and established monovalent vaccines except for the mRNA composition.

Updated: 02.11.2022

In the new bivalent mRNA vaccines, are both mRNA sequences mixed in the lipids or do the lipids each contain only one sequence?

Both variants are possible and are used differently in Spikevax and Comirnaty: It is possible first to mix the mRNA and then to have it taken up in lipid vesicles or first to produce the lipid vesicles with the respective mRNA and then to mix the lipid vesicles.

Updated: 20.09.2022

Batch Testing

What is the legal basis for batch testing in Germany?

In accordance with Section 32 of the German Medicinal Products Act (Arzneimittelgesetz, AMG) – "Official batch testing" – a batch (a production unit) of a vaccine may only be marketed in Germany if it has been tested and released by the competent higher federal authority, i.e. the Paul-Ehrlich-Institut, the Federal Institute for Vaccines and Biomedicines.

What is examined during the batch release?

Checks are carried out to determine whether the batch has been manufactured and tested according to methods of manufacture and control which comply with the prevailing standard of scientific knowledge and the requirements specified in the marketing authorisation. The tests that are required for batch testing are specific to each vaccine product and are defined by the European Directorate for the Quality of Medicines & HealthCare (EDQM).

Does batch release have to be carried out by the Paul-Ehrlich-Institut?

Yes, batch release in Germany must be carried out by the Paul-Ehrlich-Institut. However, the Paul-Ehrlich-Institut does not necessarily also have to perform the batch testing. A batch can also be released if the competent authority of another member state of the European Union has determined that the requirements for batch release have been met, after an experimental investigation and after checking the data submitted by the pharmaceutical company regarding the manufacture and testing of the batch.

How can the Paul-Ehrlich-Institut test batches of novel mRNA vaccines? Surely it does not have any experience in the batch testing of mRNA vaccines?

The marketing authorisation documents define how the manufacturing process of the authorised vaccine product must be carried out and what controls must be performed during manufacture. Batch testing includes checking the submitted batch documentation for compliance with the requirements of the marketing authorisation and checking whether the required criteria have been met in the corresponding control testing.

The Paul-Ehrlich-Institut also conducts its own experimental testing of the mRNA vaccines. Even if the actual RNA platform is in fact novel for vaccines, the methods for testing RNA vaccines are not fundamentally anything new for the Paul-Ehrlich-Institut. As a result, the RNA vaccine-specific methods only needed to be adapted on the basis of the experimental expertise already available at the Paul-Ehrlich-Institut.

The tests that are required for batch testing are specific to each vaccine product and are defined by the European Directorate for the Quality of Medicines & HealthCare (EDQM).

How, in concrete terms, are mRNA vaccines tested experimentally?

During batch testing, the identity, quantity, concentration and integrity of the RNA contained in the vaccine are all examined. In addition, the proportion of RNA that is encapsulated in lipid particles is determined. In addition, the vaccine's appearance is checked.

How exactly are the vector vaccines experimentally tested?

The batch test examines the identity and of the vectors (vaccine virus) contained within the vaccine, which contains the DNA with the genetic information for the spike protein of the SARS-CoV-2 coronavirus.

How long does batch testing take?

Section 32 of the Medicinal Products Act (AMG) specifies that the competent higher federal authority – in the case of vaccines, the Paul-Ehrlich-Institut – must reach a decision on batch release within a period of two months from receipt of the batch sample to be tested. This statutory period does not, however, need to be utilised in full. In general, the Paul-Ehrlich-Institut’s batch testing of vaccines only takes a few days. In many case, the Paul-Ehrlich-Institut aims for parallel testing, i.e. batch testing is carried out while the manufacturer is still also performing batch tests. This saves time. Parallel testing is also being carried out in the case of COVID-19 vaccines.

At what point does batch testing take place?

Batch testing by the Paul-Ehrlich-Institut often takes place in parallel to final testing by the manufacturer, so that batch testing does not require any additional time – or only a very small amount of time – after the application for batch release has been submitted for a vaccine product. Batch testing always precedes batch release. Only fully tested batches can be released by the Paul-Ehrlich-Institut for the German market.

How is the sample selected for batch testing: at random, or are large quantities of vaccine sent to the PEI for testing?

No, the manufacturer sends the Paul-Ehrlich-Institut samples of the relevant batches that are representative of the whole batch.

What happens after batch release by the Paul-Ehrlich-Institut?

After official batch release, the vaccine can be marketed and used in Germany.

Is the quality of vaccine batches guaranteed to be consistent?

Yes.

The authorisation documents for a COVID-19 vaccine include guidelines for each of the manufacturing steps and checks required to ensure a consistently good level of quality for all batches. The authorisation documents also contain the specifications (requirements) for batch testing.

In addition to the in-house (experimental) batch testing carried out by the company, there is further testing carried out on samples from each batch that is produced by the Official Medicines Control Laboratories (OMCLs) in the European Union (EU).

The Paul-Ehrlich-Institut is an OMCL for selected vaccines, including certain COVID-19 vaccines. OMCLs test samples from each vaccine batch for selected quality parameters (values) and confirm their compliance for the European Member States with a certificate. The Paul-Ehrlich-Institut only grants national batch release for the German market if the vaccine meets the criteria and specifications stated in the marketing authorisation documents and the manufacturer’s manufacturing process documentation is complete and correct, including provisions made for quality checks. This ensures a high level of quality for each batch of the vaccines. The specifications only allow for differences between individual batches within a narrow range. To date, there is no evidence that an individual batch was associated with a higher number of adverse events or any specific adverse events. This applies to Germany as well as the EU.

Does the Paul-Ehrlich-Institut ever not release a COVID-19 vaccine batch?

The Paul-Ehrlich-Institut will deny a batch release if the criteria and specifications stated in the authorisation document are not met. This is extremely rare because the strict quality control during the entire production process means that any defects are detected at an early stage. A vaccine that enters final product testing has therefore already been closely monitored and is most probably at the level of quality required in the marketing authorisation documentation.

The manufacturer must prepare and submit a separate test report for each batch in their batch release application. If a vaccine batch still shows deficiencies in the test report at this point, the batch will not receive federal batch release from the Paul-Ehrlich-Institut. Therefore, when there is non-compliance with the product specifications, the manufacturer usually refrains from submitting an application for release of that batch to the Paul-Ehrlich-Institut. So far, the Paul-Ehrlich-Institut has not denied the release of any batch of a COVID-19 vaccine due to quality defects.

Updated: 30.06.2023

Are mRNA vaccine batches checked for residual DNA content?

When a vaccine product is authorised, a determination is made as to which parameter specifications must be met before manufacturer can issue an in-house release for each individual vaccine batch. Only when the required specifications have been reached can the manufacturer submit an application for batch release to the medicines testing authority. In the case of centrally authorised vaccine products, such as the COVID-19 mRNA vaccines, the responsible medicines testing authority is the Official Medicines Control Laboratory (OMCL) in the European OMCL network designated for the official batch testing of each vaccine product.

The specifications set out in the authorisation include a DNA limit per dose. Each manufacturer of an EU-authorised COVID-19 mRNA vaccine product is required to verify compliance with the relevant limit set out in the authorisation for each batch during manufacture.

The European Directorate for the Quality of Medicines and HealthCare (EDQM), which coordinates batch testing in the OMCL network, publishes guidelines specifying which of the authorisation limits are to be tested solely by the manufacturer or by both the manufacturer and the OMCL laboratories.

In the case of manufacturer-tested parameters, such as residual DNA content in the vaccine, the OMCL checks the manufacturer's test results to see whether the limit values specified in the authorisation have been complied with in the specific batch (document check).

The Paul-Ehrlich-Institut is an official control laboratory in the European OMCL network. It has tested most batches of the EU Commission-authorised COVID-19 vaccine product Comirnaty (in all indications and concentrations) in accordance with OMCL guidelines and authorisation specifications and, after successful testing, granted federal batch releases for Germany.

Updated: 17.10.2023

Vaccines and Biomedicines

Which medicines for the treatment or prevention of COVID-19 are under development?

In various studies world-wide, scientists have examined a number of medicines to treat and prevent COVID-19. Some of them have already been used successfully to treat other virus infections and have been studied in clinical trials. All of these medicines must be re-evaluated scientifically for safety and efficacy in COVID-19. A combined use of multiple therapeutics is also conceivable.

Therapeutics

Antivirals

Antivirals inhibit the activity, structure, and replication of the virus in the human body (e.g. protease inhibitors, RNA-polymerase inhibitors).

Neutralising monoclonal antibodies

Monoclonal antibodies bind structures on the virus or block receptors on human cells thus preventing the virus from entering the cell, the human immune response from overreacting, or the virus from interacting with the immune system.

Antibodies from persons who have recovered from a COVID-19 (convalescent plasma)

The administration of serum from persons who have recovered from COVID-19 to those infected with the virus, or, alternatively, purified antibodies against SARS-CoV-2 (so-called hyper-immunoglobulins) represents a passive form of immunisation. These antibodies bind and neutralise the virus and thus support the immune system in fighting the infection.

Immunotherapy with monoclonal antibodies

Anti-inflammatory monoclonal antibodies bind to surface molecules on cells and interrupt inter- and intracellular signalling pathways, e.g. via the interleuikin-6 receptor. The aim is to prevent or inhibit an exuberant immune response which is often observed in the course of COVID-19.

Mesenchymal stem cells

These cells are precursors for many different cell types in the human body. Their purpose is to have an anti-inflammatory effect in patients severely affected by COVID-19 following a transplantation, thus protecting lung tissue and regenerating damaged lung tissue. In Germany, they always require a manufacturing authorisation pursuant to the Good Manufacturing Practice (GMP) for the use in humans.

Preventive Vaccines

Vaccines specifically stimulate the body’s own immune response so that this immune response can occur rapidly in the event of an infection, and so that it can combat SARS-CoV-2 viruses as well as SARS-CoV-2 infected cells in the body. Vaccines thus primarily serve to protect the body from the infectious disease caused by SARS-CoV-2. Vaccines are used for active immunisation.

What is the difference between active and passive immunisation?

In an active immunisation, the immune system is stimulated to confer an immune response, for example by the production of viral antigens, among other things, in order to develop a protective immune response through creating antibodies.

The administration of antibodies, however, represents a passive immunisation. Antibodies can be used for prevention or treatment. Unlike active immunisations, which also triggers a memory function of the immune system and thus lasts for a longer period of time, the effect of passive immunisation is linked to the availability of a sufficient amount of the specific immunoglobulins administrated. These immunoglobulins do not trigger a direct memory function.

Example SARS-CoV-2

During active immunisation, SARS-CoV-2 specific antigens (as a rule the viral spike protein or part of it) in the vaccine activate the immune system, which can then recognise and eliminate the pathogen in case of infection. In a passive immunisation, antibodies against SARS-CoV-2 (specific immunoglobulins) are administrated, which bind to the pathogen and mark it for the elimination (binding antibodies). Alternatively, the antibodies prevent the interaction of the spike protein with the cell receptor protein (ACE-2) and thus the infection of new cells (neutralising antibodies).

Vaccines

What is the difference between a preventive and a therapeutic vaccine?

A preventive vaccine prepares the immune system for an infection with a pathogen and confers protection against the infectious disease. Even if the infectious disease is not prevented, the vaccine will still prevent a serious outcome. Specific vaccines contain antigen(s) or the genetic information for the blueprint of the antigen(s) of the pathogen against which vaccination is targeted.

Therapeutic vaccines are used for the treatment of a (chronic or acute) infectious disease, but also for cancer immmunytherapy. As an adjuvant treatment in combination with other specific therapies, they are intended to alleviate the course of the disease, and, at best, to cure the disease. In addition to the therapeutic administration of a vaccine, specific antibodies for a therapeutic vaccination or specific immune cells can be used as an immune therapy.

What technologies are used to develop human viral vaccines?

There are various approaches to vaccines production based on so-called platform technologies. The principle of platform technologies is based on the modular principle, in which the same basic structures and technologies (platforms) are used and only the pathogen-specific component (antigen or genetic information of the antigen) is exchanged. These can be purified and inactivated virus particles (inactivated whole-virus vaccines) or parts thereof (split or subunit vaccines; vaccines with genetically engineered antigen, so-called recombinant subunit vaccines; peptide vaccines). These can be mixed with an active ingredient enhancer, the adjuvant.

Of particular importance are vaccines based on innocuous genetic information. These vaccines transmit the genetic information with the blueprint of the antigen(s) to a few body cells. Traditionally these are the attenuated live virus vaccines.

The modern platforms are replicating or non-replicating vector vaccines, DNA vaccines, and RNA vaccines. So far, research teams succeeded in developing various vaccine candidates against COVID-19 within months. Some of them are already being tested in animal models or in humans.

RNA/DNA vaccines

These vaccines contain parts of the genetic information of the virus in the form of RNA or DNA, which provide the blueprint for one or multiple virus proteins. After the vaccination, the RNA or DNA is taken up by just a few human body cells.

The absorption of the vaccine RNA or DNA by the cells is facilitated by packaging the genetic information in lipid nanoparticles. For some DNA vaccines, the absorp-tion into the body cells is also achieved by a short local and harmless electric shock (electroporation).

The body cells use the RNA or the DNA as a template to produce the virus pro-tein(s) themselves. However, since only one component of the virus is generated, it can be ruled out that replication competent viruses can be formed by this method. The newly formed, harmless virus proteins are called antigens, since they activate the immune system, thus creating the protective immune response.

Vector vaccines

An attenuated virus serves as a vehicle (vector) for an innocuous part of the genetic information of SARS-CoV-2 into a few body cells. Vector vaccines are capable or incapable of replication and transmit the blueprint for one or multiple antigens. Vectors can, for example, be certain adenoviruses, measles vaccine, modified vaccinia Ankara or genetically engineered (recombinant) vesicular stomatitis virus (rVSV). These vector vaccines do not cause disease in humans. An example of a vector vaccine is the Ebola vaccine Ervebo (rVSV-ZEBOV), which was granted a European marketing authorisation by the European Commission in November 2019.

Recombinant subunit vaccines

This method involves inserting the genetic information with the blueprint or a virus protein into bacteria, yeast, or mammalian cells, which will then produce the virus protein. After the purification, the virus protein is used as antigen in the vaccine. In some subunit vaccines and adjuvant is added to enhance the immune response.

Inactivated whole virus vaccines

With this method, infectious viruses are produced in a cell culture under the required safety conditions and then purified. The purified virus particles are inactivated under treatment with specific chemicals (e.g. formaldehyde) so that they are no longer in-fectious and can therefore be used as a vaccine (with or without adjuvant).

How do mRNA vaccines work?

RNA vaccines contain the genetic information from messenger RNA (mRNA), which comprises the blueprint of the antigen. The genetic information is used by body cells as a blueprint to produce the specific antigen in a small number of body cells by themselves. The cells present this antigen, which creates the desired specific immune response. If the vaccinee comes into contact with SARS-CoV-2 again, the immune system will recognise the antigen again, and will be able to combat the virus, and thus the infection, in a targeted manner.

Advantages of mRNA vaccines include the simple structure of the RNA and the possibility to produce several millions of vaccine doses within few weeks.

How do vector vaccines work?

Vector vaccines contain parts of the genetic material of the virus, which includes blueprints for the surface protein of coronavirus SARS-CoV-2 or part of it. After this genetic information has reached a few body cells of the vaccinated person through vaccination, it is read by the cells and the corresponding surface structures (proteins) of the virus are then produced. The immune system reacts to these formed proteins and produces defensive substances (including antibodies) against them. If the vaccinated person comes into contact with the SARS-CoV-2 pathogen later on, the immune system recognises the surface structure and can ward off and combat that virus specifically.

With vector vaccines, the genetic material is incorporated into harmless carrier viruses that are injected as a vaccine. The carrier virus may, for example, be an attenuated vaccine virus such as the vaccine measles virus. With the vaccine virus, the genetic information of coronavirus is thus introduced into the vaccinated person. Vector vaccines against Dengue fever or against Ebola had been authorised before the SARS-CoV-2 pandemic.

Monoclonal Antibodies

What are neutralising monoclonal antibodies against SARS-CoV-2?

Monoclonal antibodies for use against the SARS-CoV-2 coronavirus are proteins of the immune system (immunoglobulins) which have been developed to specifically bind to defined surface structures of the SARS-CoV-2 coronavirus. These antibodies are directed against the surface spike protein of SARS-CoV-2.

In contrast to hyperimmune globulins, convalescent plasma and sera, monoclonal antibodies consist of identical immunoglobulin molecules with a single amino acid sequence and a single recognition domain for a specific structure (epitope) of a single specific target molecule (antigen). Monoclonal antibody medicinal products may also contain combinations of a small number of precisely specified monoclonal antibodies; this is indicated in the composition of the medicinal product.

How do the SARS-CoV-2 neutralising monoclonal antibodies work?

These antibodies work by binding to the spike protein on the surface of the SARS-CoV-2 coronavirus. In this way, they block the SARS-CoV-2 viruses from binding to the receptors on the surface of human cells. As a result, the viruses cannot penetrate the cells and infect them. As viruses reproduce in cells and are released by the infected cells, the neutralisation of viral entry and infection of the cells is also associated with the prevention of viral reproduction (replication).

What benefits may be expected from the administration of these monoclonal antibodies?

The SARS-CoV-2 neutralising monoclonal antibodies may help to restrict the amount of virus in the patient (reduction of viral load). So far, only limited information is available on the safety and efficacy of their use in the treatment of COVID-19. According to the results of one clinical trial, after treatment patients were less likely to be admitted to hospital or A&E. Indications of a possible or anticipated benefit of treatment refer to a specific point in time during the treatment and to the patient group being treated.

Which monoclonal antibodies against SARS-CoV-2 are available?

In Germany, various monoclonal antibodies can be used to treat COVID-19.

These include the recently authorised antibody-containing drug Ronapreve, which has so far not been distributed in Germany via the usual distribution channel through Roche Pharma AG or through pharmaceutical wholesalers, but has been made available by the Federal Ministry of Health (Bundesgesundheitsministerium, BMG) under the Ordinance Assuring the Supply of Products for Medical Needs (MedBVSV) under the name Regn-CoV2. Regn-CoV2 corresponds to the drug Ronapreve (casivirimab/imdevimab), which has been authorised in the EU since 12 November 2021, and can be used in accordance with the authorised product information. It is distributed via star and satellite pharmacies, which are listed on the website of the Robert Koch Institute.

As of 12 November 2021, the monoclonal antibody Regkirona (regdanvimab) of the company Celltrion is also authorised in the European Union and can be used according to the product information after market launch in Germany.

On 7 December 2021, the European Commission expanded the conditions for use of the monoclonal antibody RoActemra (tocilizumab). The drug is now approved for treatment of adults with severe COVID-19.

Since 17 December 2021, the monoclonal antibody Xevudy (sotrovimab) from GlaxoSmithKline (GSK) has also been approved in the European Union and has been available in Germany since the end of January 2022.

Since 18 February 2022, the Federal Ministry of Health (Bundesministerium für Gesundheit, BMG) has also provided limited quotas of the drug Evusheld (tixagevimab/cilgavimab) for pre-exposure prophylaxis for certain groups of people and for use within the framework of the medical therapy decision.

Where should suspected cases of potential side effects of monoclonal antibodies be reported?

The Paul-Ehrlich-Institut accepts reports of suspected adverse reactions online at www.nebenwirkungen.bund.de. Healthcare professionals can also contact the Paul-Ehrlich-Institut directly if they have any questions, by email on cov2mab@pei.de and by telephone on +49 (0) 6103 77 8181.

Safety and Efficacy

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: 01.06.2022

On how many people were the COVID-19 vaccines tested before they received marketing authorisation in Europe?

At the time that the COVID-19 mRNA vaccines Comirnaty and COVID-19 Vaccine Moderna were authorised for use in the EU, data on efficacy was available from around 14,000 to 18,000 people who had been vaccinated with the respective vaccine in the phase 2/3 trials. In total, more than 30,000 study participants per vaccine product took part in the pivotal (decisive) clinical trial.

At the time that the vector vaccine Vaxzevria (COVID-19 Vaccine AstraZeneca) was authorised for use, data on efficacy was available from around 6,000 vaccinated persons (around 12,000 study participants) from the phase 2/3 studies.

At the time that the vector vaccine COVID-19 Vaccine Janssen (now: Jcovden) was authorised for use, data on efficacy was available from around 19,000 vaccinated persons (around 39,000 study participants).

At the time of authorisation for the protein-based vaccine Nuvaxovid, data was available from approximately 17,000 vaccinees (approximately 25,000 study participants) for the primary efficacy analysis.

For the safety analysis of all the authorised vaccines, data from more than 20,000 study participants (including at least 8,000 fully vaccinated persons) was evaluated; this data covered a period of up to two months after the final dose.

Updated: 01.06.2022

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).

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?

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.

Which vaccination reactions may occur after a vaccination with the authorised COVID-19 vaccines?

The safety of the vaccines is examined intensively both during and after the authorisation process. Information on the frequency and type of side effect(s) observed and vaccine complications can be found in the relevant technical information (section 4.8).

Possible expected vaccine reactions and knowledge about possible rare vaccine complications are also stated in the information leaflet that is given to people receiving the vaccine before vaccination for the respective vaccine as part of the information they receive (see further information).

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 there any evidence for the development of VAED (Vaccine associated enhanced disease) with the COVID-19 vaccine?

No. There is no evidence of enhanced COVID-19 disease in vaccinated individuals, either in clinical trials with COVID-19 vaccines or in the context of the now widespread use of COVID-19 vaccines in the general population. Also, studies in animals of different species infected with SARS-CoV-2 after vaccination have shown no evidence of VAED.

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 (see below under "Further Information").

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 (see below under "Further Information").
  • 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: 08.06.2022

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.

How do the Omicron BA.1 variant-adapted, bivalent mRNA vaccines Comirnaty Original/Omicron BA.1 (BioNTech/Pfizer) and Spikevax Bivalent Original/Omicron BA.1 (Moderna) differ with regard to the efficacy and tolerability to the previous mRNA vaccines?

Both vaccines show a tolerability comparable to that of the previous vaccines. There is no evidence of new, previously unknown side effects.

Both booster vaccines increase the blood levels (titres) of neutralising antibodies compared to the original SARS-Cov-2 variant (Wuhan) and the Omicron virus variant BA.1 along with other Omicron subvariants including BA.4/5.

In accordance with the authorisation requirements for the respective variation of the monovalent vaccine Comirnaty (BioNTech/Pfizer) or of the monovalent vaccine Spikevax (Moderna), a higher immunogenicity (meaning higher neutralising antibody levels) against the Omicron variant BA.1 was observed in clinical trials of the Omicron-adapted bivalent booster vaccine with BA.1 component as was observed after booster vaccination with the respective monovalent COVID-19 vaccine with the original virus antigen (Wuhan).

Updated: 20.09.2022

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) 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: 04.10.2022

Safety Reports

Which data is published in the safety report on suspected cases of side-effects and complications following vaccination with COVID-19 vaccines?

Suspected cases of adverse events or vaccination complications that had been reported to the Paul-Ehrlich-Institut as occurring after administration of the authorised COVID-19 vaccine products were presented in the safety reports published periodically until 21 December 2022, along with reports on safety signals. All reported cases of suspected adverse events and vaccination complications from Germany were taken into account, regardless of the way in which they were received (post, e-mail, telephone or electronically via the Paul-Ehrlich-Institut’s reporting portal www.nebenwirkungen.bund.de, via the EudraVigilance database at the European Medicines Agency (EMA) and/or via the SafeVac 2.0 app).

Further Information

www.pei.de/safety-report
Online-Reporting of Side Effects - www.nebenwirkungen.bund.de

Updated: 17.01.2023

Does the possibility of reporting suspected cases in different ways mean that the same suspected case may be reported more than once?

Yes, multiple reports are possible, but they are merged within the database. In individual cases, this may also occur with a time delay if investigations of the report subsequently reveal that it is a duplicated notification.

Who reports suspected cases of side-effects and vaccine complications following vaccination with COVID-19 vaccines?

As with all other vaccines, the Paul-Ehrlich-Institut receives reports of suspected side-effects or vaccine complications following vaccination with COVID-19 vaccine products from the following sources:

  • Via the public health offices in accordance with the German Infection Protection Act. Doctors and pharmacists who administer vaccines are required by law to report vaccine complications – i.e., health complaints that go beyond the usual extent of a reaction to a vaccine and cannot be clearly attributed to other causes – with names to the responsible public health office, which in turn reports these immediately and in anonymised form (i.e., without any names and addresses of patients) to Paul-Ehrlich-Institut.
  • From the Drug Commission of the German Medical Association (AkdÄ) and the Drug Commission of German Pharmacists (AMK).
  • From the license-holders via the EudraVigilance database of the European Medicines Agency (EMA).
  • Directly from doctors.
  • From vaccinated persons or their relatives.

Updated: 17.01.2023

How many suspected case reports relating to COVID-19 vaccines have been received by Paul-Ehrlich-Institut since the beginning of the vaccination campaign?

From the beginning of the vaccination campaign in Germany on 27 December 2020 through 31 October 2022, there were 333,492 suspected cases of adverse events and 50,833 suspected cases of serious adverse events following administration of COVID-19 vaccine products (primary or booster vaccination) reported to the Paul-Ehrlich-Institut.

Suspected case reports of adverse events and vaccination complications are reports of reactions that occurred in temporal association to vaccination and are not directly clearly attributable to other causes. When reactions that occurred after vaccination are reported as a suspected adverse event or vaccination complication, the Paul-Ehrlich-Institut examines whether such reactions could be causally related to vaccination with a specific vaccine product, specific batches of a vaccine product or vaccine products of a specific vaccine type. If necessary, the Paul-Ehrlich-Institut will take, coordinate or initiate appropriate measures to reduce risk.

Further information

www.pei.de/safety-report

Updated: 17.01.2023

Why does the Paul-Ehrlich-Institut intend to discontinue the preparation and publication of the regular safety reports on COVID-19 vaccines in their current form?

The regular safety reports on COVID-19 vaccines were a special format developed in response to the extraordinary pandemic situation. In a very short time, millions of people in Germany were vaccinated with the newly developed COVID-19 vaccines. It was therefore important to provide the public with as much information as possible on the safety of these vaccines.

The widespread use of the COVID-19 vaccines in immunisation programmes in the EU, as well as the willingness of experts and vaccinated persons to submit reports, led to the rapid availability of extensive safety data from spontaneous reports of suspected cases of adverse reactions or vaccination complications in addition to the data from clinical trials. On the basis of that data, insights were very quickly gained into very rare adverse events of COVID-19 vaccine products, which are listed in the current summaries of product information of the COVID-19 vaccine products. Overall, international data from clinical trials, other studies and suspected case reporting analyses confirm the favourable benefit-risk balance of the COVID-19 vaccine products authorised in Germany and the EU. Measures for further risk reduction were introduced in a timely manner through actions such as adapting the COVID-19 vaccination recommendations by the Standing Committee on Vaccination (STIKO), on which the Paul-Ehrlich-Institut participates as a guest.

There is now extensive data on the safety of COVID-19 vaccine products. The Paul-Ehrlich-Institut therefore intends to cease the preparation and publication of the regular safety reports on COVID-19 vaccine products in its current form.

The Pharmacovigilance Risk Assessment Committee (PRAC) at the European Medicines Agency (EMA), on which the Paul-Ehrlich-Institut is represented, has also stopped publishing monthly safety updates on COVID-19 vaccines with the December 2022 issue for the same reasons.

As with all authorised medicines, the safety of the COVID-19 vaccines continues to be closely monitored by the Paul-Ehrlich-Institut and its sister medicines authorities in the EU. Safety studies are continued by parties such as the marketing authorisation holders in accordance with the vaccine product-specific risk management plan. If new COVID-19 vaccine risks are identified, they will be published by the Paul-Ehrlich-Institut on its homepage or in the Bulletin on Drug Safety. All identified adverse reactions are listed in the product information of each vaccine product. This information is updated on a continuous basis as needed.

Updated: 17.01.2023

What happens to the suspected case reports of side-effects and complications?

Paul-Ehrlich-Institut compiles reports it receives regardless of the causal link to the vaccination. For the purposes of early recognition of potential new risk signals, it is important to set the reporting threshold low. This means that reports linked purely by time and not necessarily causally with the vaccination are also significant. Paul-Ehrlich-Institut obtains additional information on a large number of reports, and it also receives further data on reports from a variety of reporting sources. The current status of information on the cumulatively submitted reports is analyzed on an ongoing basis. The description of the suspected cases may therefore be subject to changes compared to the previous reports as a result of additional information.

In order to recognize potential risk signals early on, Paul-Ehrlich-Institut carries out a so-called “observed-to-expected” (O/E) analysis on an ongoing basis. Here, the frequency of unwanted events following vaccination as reported to Paul-Ehrlich-Institut is compared to the statistically random and expected frequencies in a comparable (unvaccinated) population, taking into consideration different time windows. If there is a significantly higher reporting rate for an event following vaccination than would be expected to occur statistically by chance in a comparable population, Paul-Ehrlich-Institut assumes a potential risk signal, which then needs to be further investigated by means of additional, generally epidemiological studies.

The report data also flow into the European EudraVigilance database https://www.adrreports.eu/de/, so that they can also be taken into account in risk analyses at EU level.

Do individuals who have reported suspected adverse events receive personalised feedback from the Paul-Ehrlich-Institut?

The Paul-Ehrlich-Institut cannot send acknowledgements of receipt or individual feedback for reports sent by letter, fax, or email due to the high number of reports.

Individuals who submit a report via www.nebenwirkungen.bund.de will receive a confirmation of receipt and a specific PEI number upon completion of the report. However, this number is not used for personal contact with the vaccinated person or their relatives.

The Paul-Ehrlich-Institut is not a clinical institution and therefore cannot offer individual vaccination advice or other feedback. More specifically, it is not possible for the Institute to give recommendations on diagnosis or therapy, as there are many factors to consider when it comes to issuing medical advice. These factors can only be adequately addressed via personal contact between doctor and patient. Please direct these questions to your physician.

Updated: 05.09.2022

SafeVac 2.0 App

What is the SafeVac 2.0 app?

The Paul-Ehrlich-Institut developed the SafeVac 2.0 smartphone app as part of a study for the active monitoring of the safety and tolerability of authorised COVID-19 vaccines used in Germany. The aim is that quantitative information on the safety profile of the COVID-19 vaccines, going beyond the marketing authorisation data, will be rapidly obtained using this app. The SafeVac 2.0 app should not be confused with the established online reporting system for the recording of suspected adverse reactions, which will continue to be available.

Users of the SafeVac 2.0 app are voluntarily taking part in an observational study carried out by the Paul-Ehrlich-Institut, which will run until the end of 2023. The vaccinated persons’ agreement and consent to participate in the Paul-Ehrlich-Institut’s observational study is a precondition for using the app. Participants who registered in the app by 30 September 2022 will be asked questions via the app about their current state of health at defined points in time. The recruiting phase ended on 1 October 2022. No new participants will be included in the SafeVac 2.0 survey.

The SafeVac 2.0 app survey will enable the Paul-Ehrlich-Institut to determine the frequency, severity and duration of an adverse reaction. This app will not only give the Paul-Ehrlich-Institut information on suspected adverse reactions, but also on the proportion of vaccinated persons who have tolerated vaccination well.

Updated: 04.10.2022

Who developed the SafeVac 2.0 app?

The SafeVac 2.0 app is a further development of the SafeVac 1.0 smartphone app, which was designed in collaboration with Materna Information & Communications SE and the Helmholtz Centre for Infection Research (HZI) in Braunschweig, and was used to record adverse events after seasonal influenza vaccination. The app was commissioned by the Paul-Ehrlich-Institut and was developed as a cross-platform app for the iOS (Apple) and Android (Google) operating systems.

Updated: 04.10.2022

What does participation in the SafeVac 2.0 study look like?

Individuals who had received the first COVID-19 vaccination in their primary vaccination course by 30 September 2022 had the opportunity to participate in the study. As of 1 October 2022, no new participants are allowed to register for the SafeVac 2.0 study. The tracking of the persons registered up to that point will continue according to the study protocol.

The vaccinated persons’ agreement and consent to participate in the Paul-Ehrlich-Institut’s observational study was a precondition for using the SafeVac 2.0 app. Participants were asked questions via the app on seven occasions after the first vaccination and on eight occasions after the second vaccination; this took place within three weeks after the first dose and four weeks after the second dose and was designed to determine how well the vaccines are tolerated. In addition, participants were or will be asked final questions about their state of health after six and twelve months.

The data protection concept was assessed by the Federal Commissioner for Data Protection. Steps have been taken to ensure that no participant or individual smartphone be identified at any time. On the first occasion that data is transmitted to the Paul-Ehrlich-Institut, a random number is created on the federal server and then stored in encrypted form in the participant's smartphone memory; with each new data transmission, this number is checked to ensure it is correct and then transferred with the random key to the Paul-Ehrlich-Institut in a secure connection via the federal government server.

None of this information contains any personal data and it cannot be traced by the Paul-Ehrlich-Institut. Details about the user or his/her smartphone cannot be derived from the case ID.

In the requested information, a distinction is made between required details and data that is not absolutely necessary. The required fields include the details on age and gender, the vaccine name and the batch number. If required information is not entered, the user will receive a message and will not be able to move to the other fields until these mandatory fields have been completed.

The transmitted data will be evaluated with reference to the occurrence of possible adverse reactions. This will include a record of how often the vaccination was well tolerated and how often adverse reactions have occurred. The type, severity and time interval between vaccination and reactions will also be analysed. The data after six and twelve months will be evaluated with regard to the frequency of possible SARS-CoV-2 infections and the severity of possible COVID-19 illness after the vaccination.

Reports on vaccination reactions will also be included in the Paul-Ehrlich-Institut’s database of adverse reactions. The Paul-Ehrlich-Institut is legally obliged to collect and evaluate all reported suspected cases of adverse reactions and to forward them to the European database of suspected adverse drug reactions.

Updated: 04.10.2022

Can I also submit information on my booster vaccination in the app?

Yes. If you entered the first COVID-19 vaccination in your primary vaccination course in the app before 30 September 2022, you can provide information about a booster vaccination. The app does not make a distinction between the new vaccines adapted to the Omicron variant and the original vaccines.

Updated: 04.10.2022

Is it only possible to record my booster vaccination in the SafeVac app within 48 hours of vaccination?

No. The 48-hour rule applied only upon first registration in the app, meaning upon initial vaccination. Your booster vaccination and any related information can also be submitted retroactively in the app.

Updated: 04.10.2022

I deleted the SafeVac app after completing the questions on my initial vaccination. Can I still submit information on my booster vaccination?

Unfortunately, no. If you deleted the app from your smartphone it is not possible to submit information on the booster vaccination, even after reinstalling the SafeVac app. Deleting the app removes the information on your initial vaccination from your smartphone. This information is necessary for the submission of booster vaccination information. However, any adverse side effects that you reported in the SafeVac app were anonymously logged in the adverse side effects database, and therefore were not lost.

If you would like to report adverse side effects following your booster vaccination, you can do so on the www.nebenwirkungen.bund.de online portal.

Updated: 04.10.2022

I have not yet participated in the SafeVac 2.0 survey, but I would like to report adverse side effects following my booster vaccination. Is this possible?

Only those who had registered by 30 September 2022 after the first COVID-19 vaccination in their primary vaccination course can submit information on their booster vaccination via the SafeVac app. The observational study is meant to provide knowledge on the entire process following each of the individual vaccinations. Therefore it is not possible to register for the first time after the booster vaccination.

Individuals who are not registered in the SafeVac app can always report any potential adverse side effects of a booster vaccination on the www.nebenwirkungen.bund.de online portal.

Updated: 04.10.2022

What are the particular benefits of the SafeVac 2.0 study?

Suspected adverse reactions to vaccination are indeed recorded via regular spontaneous reporting. What is left unknown, however, is how many reactions are not reported for various reasons. The SafeVac 2.0 study will enable the Paul-Ehrlich-Institut to make quantitative evaluations of the possible adverse reactions, since the number of participants will be known and adverse reactions will be documented on a daily basis. The Paul-Ehrlich-Institut will not only obtain information via the corresponding SafeVac app on suspected adverse reactions, but also on the percentage of vaccinated persons who have tolerated the vaccination well. The larger the number of participants, the more meaningful the corresponding data will be.

Updated: 04.10.2022

When will the information entered by participants in the SafeVac 2.0 app be evaluated?

By the conclusion of the recruitment phase at the end of September 2022, more than 730,000 people had provided information on how they had tolerated their COVID-19 vaccinations via the SafeVac 2.0 smartphone app. All suspected reports of adverse reactions associated with COVID-19 vaccination made by vaccinated individuals via the SafeVac app have also been registered in the Paul-Ehrlich-Institut's adverse reaction database. The Paul-Ehrlich-Institut evaluated the data together with reports from other reporting channels and analysed it for new signals. The results of these assessments are incorporated into the COVID-19 safety reports published periodically by the Paul-Ehrlich-Institut.

Data collection within the observational study does not conclude with the end of the recruitment phase. In accordance with the SafeVac 2.0 study protocol, the SafeVac app will remain available to all already registered participants for at least 12 months after the last vaccination in the primary vaccination course. The study design stipulates that participants will be asked again about their state of health one year after completion of the primary vaccination course. In addition, all participants can also provide information on a booster vaccination – if they have not done so already. The app does not make a distinction between the new vaccines adapted to the Omicron variant and the original vaccines. After completion of data collection at the end of 2023, the Paul-Ehrlich-Institut will evaluate the study and publish the results.

Updated: 04.10.2022

I’m not able to enter the batch number of my booster vaccine into the SafeVac 2.0 app. What can I do?

Please check whether you have a stable internet connection via LTE or WIFI. This is a requirement, enabling you to get feedback to your smartphone when checking the batch number. This feedback in turn is necessary for the app to function correctly.

The app checks the batch number very carefully. Entering special characters can lead to problems. In this case please enter the batch number without any special characters or space characters in its combination of numerals and letters.

Updated: 04.10.2022

I have a new smartphone. Can I transfer the information I previously submitted from my old device to my new one?

The SafeVac app does not offer a separate data transfer function.

However, your data can be transferred to your new device by using the backup copy function that is part of your phone’s operating system. This function allows you to make a backup copy of the data on your old smartphone and transfer it to your new device.

Updated: 04.10.2022

Why can't the fourth vaccination be recorded in the SafeVac app?

The SafeVac app is an observational study, which was originally planned to last 12 months. The third dose (booster) was added to obtain additional data on vaccine tolerability among individuals 12 years and over who have been vaccinated. A fourth dose is currently recommended by the Standing Committee on Vaccination (STIKO) for only a very limited group of people. Therefore, an expansion of the SafeVac app to include the fourth vaccination is not planned.

The online reporting portal www.nebenwirkungen.bund.de is available for persons who would like to report a suspected adverse event after their fourth vaccination. All suspected adverse events received via this portal are recorded and evaluated by pharmacovigilance experts at the Paul-Ehrlich-Institut.

Updated: 04.10.2022

Is there a way to report an adverse event via smartphone after the SafeVac 2.0 study has been concluded?

Even after completion of the SafeVac 2.0 study, suspected cases of vaccine adverse events can easily be reported to the Paul-Ehrlich-Institut using a smartphone. Please use the online reporting portal www.nebenwirkungen.bund.de for this purpose.

Updated: 04.10.2022

Antibody and Antigen Testing

General Information

What types of SARS-CoV-2 antigen tests are available and what purpose do they each serve?

SARS-CoV-2 antigen tests are available as self-tests (antigen tests for self-use) and as professional tests (rapid antigen tests for use by trained personnel in locations such as testing centres, also called Bürgertests in Germany). Both are used to quickly and easily identify people with a very high viral load and therefore also the associated potential risk of transmitting the virus to contacts.

The use of antigen tests is one of many measures to contain the pandemic. The advantage is that the results are available quickly. The downside is that they cannot detect SARS-CoV-2 infections with the same sensitivity as polymerase chain reaction (PCR) tests. PCR tests detect SARS-CoV-2 infections even with low viral loads, but they also take significantly longer to get a result.

Updated: 30.01.2023

What are the tasks of the Paul-Ehrlich-Institut and notified bodies in regards to the CE marking of in vitro diagnostics such as SARS-CoV-2 antigen tests?

The European In Vitro Diagnostic Medical Device Regulation (IVDR; Regulation EU 2017/746) changed the conditions for the CE marking (marketability) of in vitro diagnostic medical devices (IVD).

In the past, all IVDs not listed in Lists A or B of the previous IVD Directive 98/79/EC (In Vitro Diagnostic Device Directive, IVDD) could be placed on the market exclusively by the manufacturer on the basis of a declaration of conformity (self-certification). This was the cases for the majority of IVDs.

Under the new IVDR requirements, a conformity assessment procedure by a notified body is expected to be required for the majority of IVDs. In order to undergo the conformity assessment procedure, the manufacturer must submit the technical documentation for their IVD, e.g. a SARS-CoV-2 antigen test, to a notified body. On the basis of the technical documentation, the notified body then checks whether the product meets the basic safety and performance requirements detailed in the IVDR. If the requirements have been met, the notified body will issue a CE mark for the IVD. The CE mark signifies that the product conforms with the applicable requirements.

Performance assessment tests serve as a basis for the CE mark. These tests are used to assess and analyse data to determine or verify the scientific validity, analytical performance and, where applicable, the clinical performance of a device. This data is collected on the basis of performance studies that manufacturers are required to carry out. The studies may only be performed if they have been previously approved by the competent authority and an ethics committee. The competent authority in Germany, depending on the IVD, is either the Paul-Ehrlich-Institut or the Federal Institute for Drugs and Medical Devices (BfArM). During the approval process, these authorities check for elements such as whether the study is structured in such a way that it meets all the requirements of IVDR. The Paul-Ehrlich-Institut is responsible for Class D IVDs and certain Class C IVDs (all IVDs covered by Rules 1, 2 and 3 (a) to (e) and (g) of Annex VIII to Regulation (EU) 2017/746). The BfArM is responsible for all other IVDs included in the EU regulation. The Paul-Ehrlich-Institut or the BfArM authorises the performance evaluation tests, but does not carry out any evaluations itself and does not award CE marks. Independent examinations by the Paul-Ehrlich-Institut, such as examinations of SARS-CoV-2 antigen tests newly placed on the market, are no longer necessary due to the conformity assessment of the notified bodies.

A CE mark must be affixed to the outer packaging of the IVD and must always include the four-digit identification number of the notified body that issued the CE mark.

Updated: 11.01.2023

What is the EU Common List of COVID-19 Rapid Antigen Tests – Common RAT List for short – and why was this comprehensive common list drawn up?

The EU Common List of COVID-19 Rapid Antigen Tests – Common RAT List for short – is an informational document on rapid antigen tests provided by the Health Security Committee (HSC) of the European Union.

A digital EU COVID-19 certificate may be issued based on the tests included in categories A and B contained in the list in Annex I.

The Common RAT List is also important for Germany, because as of 30 June 2022, pursuant to the updated Coronavirus Testing Ordinance (Coronavirus-Testverordnung, Coronavirus TestV) of 29 June 2022, only the SARS-CoV-2 rapid antigen tests that have been included in the EU Common Rat List are eligible for future reimbursement.

European Commisson: Public Health - Common List of Coronavirus Rapid Antigentests (Common RAT List)11 July 2022: Information for Manufacturers and Distributors: COVID-19 Antigen Tests

How up-to-date is the Common RAT List?

The HSC's Common RAT List (list of COVID-19 rapid antigen tests for professional use) was regularly updated during the SARS-CoV-2 pandemic following discussions in the EU Health Safety Committee's COVID-19 Diagnostic Testing Technical Working Group. The EU regulation on digital COVID certificates expired on 30 June 2023. The technical working group and its activities were formally terminated at that point. The last applications for the inclusion of COVID-19 antigen tests on the list could be submitted by manufacturers until 31 March 2023.

The list of CE-marked COVID-19 antigen tests was last updated on 17 May 2023. The performance of nearly 300 COVID-19 antigen tests that met stringent criteria were reviewed in additional studies and these tests were included on the list. A document with background information on the decisions of the technical working group was also made available since the last update. This document lists the tests that have been removed or were not included at all.

Updated: 30.06.2023

How can I find out if a combination test for COVID-19, the flu and RSV is reliable?

Combination tests that detect infections with the SARS-CoV-2 coronavirus, influenza A and influenza B viruses and, in some cases, also respiratory syncytial virus (RSV) infections must receive a CE mark from a notified body in accordance with the EU In Vitro Diagnostic Medical Device Regulation (IVDR; Regulation EU 2017/746), which has been in force since 26 May 2022. The CE mark signifies that the product conforms with the applicable requirements.

The manufacturer must submit the complete technical documentation of the IVD product to a notified body in order to obtain a CE mark. The notified body then checks whether the product meets the basic safety and performance requirements detailed in the IVDR. If the requirements have been met, the notified body will issue a CE mark. The Paul-Ehrlich-Institut is not involved in test evaluation and therefore cannot provide any information about the reliability of the tests.

Several combination tests for the detection of SARS-CoV-2 and influenza A and B viruses, and in some cases also for the detection of RSV, have been added to the EU Common List of COVID-19 rapid antigen tests – or common RAT List for short. However, the combination tests on the list are professional tests, not self-tests. A search for the term “multiplex” in the list will bring up these combination tests.

The evaluation of the performance (sensitivity, specificity) of the tests included in the Common RAT List is performed only with regard to the detection of SARS-CoV-2. However, in the context of the conformity assessment procedure, the notified body generally assesses all components of the combination tests. Therefore, it can be assumed that a combination test that has received a CE mark meets the IVDR’s safety and performance requirements for all components.

The notified body that carried out the assessment is indicated by the four-digit identification number affixed to the packaging of the test next to the CE mark. All notified bodies are listed with their identification numbers in the NANDO list.

NANDO, which stands for New Approach Notified and Designated Organisations, provides information on notified bodies that are responsible for tasks such as assessing the conformity of in vitro diagnostic medical devices in accordance with the IVDR.

Specific information on a combination test may potentially be given by the notified body which has awarded the CE mark. Contact details are available via the NANDO listing.

Updated: 02.02.2023

Where can I find information on the quality of individual Coronavirus antigen tests, especially those intended for self-use?

In accordance with the new IVD Regulation (In-vitro Diagnostic Medical Device Regulation, IVDR; Regulation (EU) 2017/746), which entered into force in the EU on 26 May 2022, new SARS-CoV-2 antigen tests may only be placed on the market after undergoing a conformity assessment procedure and receiving a CE marking by a notified body. The Paul-Ehrlich-Institut's independent testing of new rapid antigen tests on the market is thus no longer necessary.

Information on which antigen tests have received CE marking can be found in the databases of the EU Commission (see "Further information").

The EU Commission maintains several databases on testing methods for in vitro diagnostic medical devices (IVD). These are only available in English.

You can filter the database according to different criteria. If you select "All Rapid antigen test devices with CE Marking" under "Quick searches", the list of all antigen tests (professional and self tests) with CE marking is automatically displayed.

If you want to see a list of self tests with CE marking, you can filter the results further under "Show advanced filters". A filter field opens with a drop-down menu, in which you can select "Self test" and click on the blue "Add" button. You will then be able to select the "Self test" filter by selecting "Yes" from the drop-down menu. Clicking on "Search" will apply the new filter and search the database for self tests.

Whether you are looking for professional or self tests, the results are always shown in the form of a list. The results list, in addition to applying the selected filters, specifies the manufacturer, the test name (Commercial Name), the method and the format (Manual, Near PoC, PoC, Other).

Clicking on the black arrow icon to the right of each item on the list will lead to a page with detailed information about that test, such as information on its sensitivity and specificity. Some tests are offered as both professional and self tests – this is noted on the detailed information page.

Updated: 30.01.2023

Can a SARS-CoV-2 antigen test produce a false positive?

Prior to marketing, the manufacturer of an antigen test must run tests to determine the specificity and sensitivity of their in vitro diagnostic device (IVD) in order to receive the required CE marking. According to the European Commission's common specifications, the specificity of SARS-CoV-2 antigen tests must be at least 98%, i.e., in 98% of the examinations of samples that do not contain SARS-CoV-2, the test must be correctly negative. The sensitivity of the SARS-CoV-2 antigen tests must be 80%, i.e., in 80% of the investigations of samples in a very high viral load range (corresponding to a CT value in the PCR of about 25 and less), the test must be positive. The common specifications were published by the European Commission in mid-2022 and apply to tests newly CE labelled under the EU IVD Regulation. Tests that received a CE marking before May 2022 may continue to be marketed until May 2025 and do not have to meet these requirements.

However, antigen tests, like all IVDs, can in rare cases react positively with some samples, even if the marker – in this case the antigen of the SARS-CoV-2 virus – is not present at all. This can occur in some tests in the range of up to two percent of results (see above information on the required specificity). In order to confirm or rule out an infection, if the test result is positive, the result can be repeated with another antigen test or a PCR test.

Vaccination with the COVID-19 vaccines approved in Germany does not lead to a positive test result, because most SARS-CoV-2 antigen tests do not respond to the antigen of these vaccines – the spike protein – but instead to the presence of the N protein of SARS-CoV-2 in swab samples. In addition, the spike protein of a vaccine is unlikely to appear in the test sample for an antigen test, because the levels of spike proteins and biodistribution after vaccination are too low.

Updated: 30.01.2023

Can a SARS-CoV-2 antigen test produce a false negative?

SARS-CoV-2 antigen tests are primarily used to quickly and easily identify people with a very high viral load and therefore also the associated potential risk of transmitting the virus to contacts. The lower the viral load, the lower the chance of transmission to close contacts and the lower the chance that the antigen test recognises the infection, i.e., the test is positive.

Prior to marketing, the manufacturer of an antigen test must run tests to determine the specificity and sensitivity of their in vitro diagnostic device (IVD) in order to receive the required CE marking. According to the European Commission's common specifications, the specificity of SARS-CoV-2 antigen tests must be at least 98%, i.e., in 98% of the examinations of samples that do not contain SARS-CoV-2, the test must be correctly negative. The sensitivity of the SARS-CoV-2 antigen tests must be 80%, i.e., in 80% of the investigations of samples in a very high viral load range (corresponding to a CT value in the PCR of about 25 and less), the test must be positive. These sensitivity requirements have taken into account the fact that the antigen tests can also produce negative results for some samples, in particular those containing SARS-CoV-2 in a lower concentration. The common specifications were published by the European Commission in mid-2022 and apply to tests newly CE labelled under the EU IVD Regulation. Tests that received a CE marking before May 2022 may continue to be marketed until May 2025 and do not have to meet these requirements.

A test can also produce a false negative if the sampling was not carried out exactly according to the instructions for use and therefore there is too little viral material in the sample. In addition, the performance of the SARS-CoV-2 antigen test used plays a major role.

Updated: 30.01.2023

Can the vaccination with COVID-19-mRNA vaccines lead to positive test results after antigen tests or PCR tests?

It can be assumed that the COVID-19 vaccination does not lead to a positive test result after antigen or PCR tests.

After an mRNA vaccination, the so-called spike protein (S protein) is formed in immune cells and other body cells. The S protein confers an immune response. Almost all antigen tests listed in the Common RAT List and used in Germany for both professional and private use are based on the detection of another protein, the nucleocapsid protein (N-protein). Therefore, since antigen tests detect a virus protein other than the protein formed by the mRNA vaccination, the vaccination will not affect the test result. The summary of product characteristics provided with the test usually indicates whether the respective test is an S-protein or an N-protein based test.

Besides, the test is performed as a nasopharyngeal or throat swab. Even if the antigen test is designed to detect the S-protein, it appears highly unlikely that a sufficient amount of S-protein will be available in the mucosa cells of the nasopharynx to be recognised by the antigen test the sensitivity of which is only limited.

The quantitative real-time PCR methods for the detection of SARS-CoV-2 mRNA are usually based on the detection of two different virus genes (dual target principle: e. g. envelope [E] plus N2; N1 plus N2; orf1a/b plus E). Interference with a previously performed vaccination with SARS-CoV-2-mRNA, which codes for the S protein can be ruled out if this type of PCR test is used.

Updated: 30.01.2023

Do SARS-CoV-2 antigen tests reliably detect infections in vaccinated individuals?

SARS-CoV-2 antigen tests are available as self-tests (antigen tests for self-use) and as rapid tests (antigen tests for use by trained personnel in locations such as testing centres, where they are also referred to as Bürgertests). Both are used to quickly and easily identify people with a very high viral load and thereby also identify the associated potential risk of transmitting the virus to close contacts.

The use of antigen tests is one of many measures used to contain the pandemic. The advantage of these tests is that the results are available quickly. The downside is that they cannot detect SARS-CoV-2 infections with the same sensitivity as polymerase chain reaction (PCR) tests. PCR tests detect SARS-CoV-2 infections even if the viral load is low, but they also take significantly longer to get a result. In the event of a positive test result, typical COVID-19 symptoms, or known contact with an infected person, a PCR test – the gold standard of SARS-CoV-2 diagnostics – should be carried out if possible, unless otherwise specified in the current national test strategy.

A high viral load develops at the beginning of an infection and can also be present without symptoms. The lower the viral load, the lower the chance that the antigen test will be able to detect the infection. However, the lower the viral load, the lower the risk of infection, i.e., the risk of the virus being transmitted to people with whom you've come in contact. The risk of fully vaccinated people becoming PCR-positive and transmitting the virus despite vaccination was significantly reduced in the course of the previously dominant virus variants, including Delta. It is currently not possible to say with certainty how high the risk of transmission of the Omicron virus variant is, even for those who are vaccinated. But the same principle applies: the lower the viral load, the less certain it is that an antigen test will detect the infection. Therefore, vaccinated people should also comply with the standard “AHA+L+A” rules (keep your distance, follow hygiene rules, wear a mask during everyday activities, air rooms out regularly, and use the Corona-Warn app).

According to the latest scientific and technological information, all antigen tests positively assessed by the Paul-Ehrlich-Institut are suitable for detecting very high viral loads.

Updated: 30.01.2023

Do the antibodies produced after a COVID-19 vaccination distort antigen test results?

No. Concerns that post-vaccination antibodies against spike proteins (S proteins) will interfere with antigen tests that detect the presence of nucleocapsid proteins (N proteins) are unfounded. This is stated in the table of the common EU list of COVID-19 antigen rapid tests ("Common RAT list") and often also in the instructions for use.

Updated: 30.01.2023

Can the user have influence on the reliability of a self-test?

Yes. In order for an antigen test to be as conclusive as possible, the tester must precisely follow the instructions on how to collect the sample and perform the test.

Errors in sampling are a source of error that should not be underestimated in self-use antigen tests (self-tests).

These errors include: the length of time the swab is rotated during sampling (smear), the length of time and process of soaking the sample in the buffer, the number of drops to be applied, and the duration of the exposure time. Also, when reading the test result, the control band should be clearly visible. The band is also sometimes difficult to see when the result is positive. Even a faint test band that appears within the time specified in the instructions is to be regarded as SARS-CoV-2 positive.

Updated: 30.01.2023

Do the antigen tests also detect the Omicron variant?

Almost all rapid antigen tests examined by the Paul-Ehrlich-Institut through the end of May 2022 are based on the detection of the SARS-CoV-2 nucleocapsid proteins (N proteins). This is also the case for the rapid antigen tests (professional tests) listed in the common EU list of COVID-19 rapid antigen tests ("Common RAT List") and for self-tests that function according to the same test procedure.

The N protein is much more strongly preserved than the spike protein, which is greatly altered in the Omicron variant. Of four mutations of the Omicron N-protein, two also occurred in the previously known variants (e.g., Delta) and have no impact on the performance or reliability of the rapid antigen tests.

Targeted evaluations by the Paul-Ehrlich-Institut through the end of May 2022 revealed no evidence that the detection of the Omicron variant is impaired by SARS-CoV-2 antigen tests. In addition, a query by the Paul-Ehrlich-Institut and the Federal Institute for Drugs and Medical Devices (BfArM) with the corresponding IVD manufacturers showed that most antigen tests use specific target sequences (epitopes) for the detection of the N protein, which are not affected by Omicron variant mutations.

This information on Omicron was presented in the Paul-Ehrlich-Institut tables as well as in the lists for self-tests and professional tests for the relevant tests ("Omicron detection according to the bridging test: Yes").

The Paul-Ehrlich-Institut offers archive versions of the SARS-CoV-2 antigen test lists for documentation purposes. These lists were discontinued pursuant to the amendment of the TestV of 29 June 2022. Links to the archived versions can be found in the FAQ "Where can I find information on antigen tests, such as their detection of high viral loads and Omicron or which test products are reimbursable?" specified.

Updated: 30.01.2023

Are there one or more antigen tests that are particularly recommended?

The Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, is an independent testing authority and does not make any recommendations for specific products.

Where can I find information on antigen tests, such as their detection of high viral loads and Omicron or which testing products are reimbursable?

On behalf of the Federal Ministry of Health (Bundesgesundheitsministerium, BMG), the Testing Laboratory for In Vitro Diagnostics at the Paul-Ehrlich-Institut (PEI-IVD) conducted its own comparative experimental studies between October 2020 and May 2022 to investigate the sensitivity of SARS-CoV-2 rapid antigen tests (for professional use) offered in Germany. The test results could also be transferred to structurally identical SARS-CoV-2 antigen tests for self-use (self-tests).

A prerequisite for inclusion in the comparative evaluation tables was the ability of the rapid antigen testing product, as demonstrated in the comparative experimental study, to detect SARS-CoV-2 infection in at least 75% of samples tested with a very high viral load (CT ≤ 25).

The studies carried out by the Paul-Ehrlich-Institut through May 2022 had shown no evidence that the detection of the Omicron variant was impaired by SARS-CoV-2 rapid antigen tests. In addition, a query by the Federal Institute for Drugs and Medical Devices (BfArM), which was responsible for IVD until 25 May 2022, was carried out among IVD manufacturers of rapid antigen tests. This query showed that most rapid antigen tests use specific target sequences (epitopes) for the detection of the N protein that are not affected by mutations in the Omicron variant. This information on Omicron was provided in the tables ("Omicron detection according to the bridging test: Yes").

Since the new EU IVD Regulation (In-vitro Diagnostic Medical Device Regulation, IVDR; Regulation (EU) 2017/746) came into force on 26 May 2022, new SARS-CoV-2 antigen tests may only be placed on the market after undergoing a conformity assessment procedure and receiving a CE marking from a notified body. = The Paul-Ehrlich-Institut's independent testing of rapid antigen tests newly placed on the market is thus no longer necessary.

With the amendment of the Coronavirus Testing Ordinance (Coronavirus-Testverordnung, TestV) of 29 June 2022, only the SARS-CoV-2 rapid antigen tests that have been or will be included in the common list of COVID-19 rapid antigen tests (professional tests, point-of-care (POC) tests) of the European Union Health Security Committee are eligible for reimbursement (Common RAT List of the HSC). This means that the previous market overview of rapid antigen tests that meet the minimum criteria of the Paul-Ehrlich-Institut and Robert Koch-Institut (RKI), as well as the table of the "Comparative Evaluation of the Sensitivity of SARS-CoV-2 Rapid Antigen Tests" are no longer relevant for test reimbursement.

However, the results of the Paul-Ehrlich-Institut's “Comparative Evaluation” are taken into account in Annex I, Category B (COVID-19 antigen tests evaluated by retrospective in vitro studies) of the Common RAT List of the HSC and are reflected therein with regard to the sensitivity of the tests in the detection of very high viral loads (CT value ≤ 25). The Common RAT List also contains information on whether a test targets the nucleocapsid protein (N protein). Tests that target the N protein of SARS-CoV-2 are suitable for detection of the Omicron variant.

The Paul-Ehrlich-Institut offers archived versions of the SARS-CoV-2 antigen test lists for documentation purposes. These lists will no longer be updated pursuant to the amendment of the TestV of 29 June 2022:

Archived Version of the Minimum Criteria for SARS-CoV-2 Antigen Tests Pursuant to Section 1 Paragraph 1 Sentence 1 of the TestV: Rapid antigen tests
PDF Document: Archived version of the "Comparative Evaluation of the Sensitivity of SARS-CoV-2 Rapid Antigen Tests" (Status: 30 May 2022)
Excel Table: Archived version of the "Comparative Evaluation of the Sensitivity of SARS-CoV-2 Rapid Antigen Tests" (Status: 30 May 2022)
Excel Table: Archived version of the BfArM list pursuant to the TestV - Antigen Tests for Self-Use (Status: 24 June 2022) (German only)
Excel Table: Archived version of the BfArM list pursuant to the TestV - Antigen Tests for Professional Use (Status: 24 June 2022) (German only)

Further Information

European Commisson: Public Health - Common List of Coronavirus Rapid Antigentests (Common RAT List)
FAQ with explanations on using the Common RAT List

Updated: 30.01.2023

What can I do if my COVID-19 antigen test looks odd or doesn't function normally?

If you notice that a test kit looks significantly different (discoloration, etc.) or doesn't work normally, this could indicate a quality defect. If you suspect a test kit has a quality defect, you can report it to the manufacturer. The manufacturer can then investigate the report and take any measures that may be necessary, such as recalling the product.

As a test user, you can also report possible quality defects to the Paul-Ehrlich-Institut. Please use the Paul-Ehrlich-Institut's online reporting form ("Incident report form for users, operators and other distributors", available in German only) to file an incident report. Any reports submitted via the Federal Institute for Drugs and Medical Devices (BfArM) online form are forwarded by the BfArM to the Paul-Ehrlich-Institut.

According to EU Regulation 2017/746 (IVDR), in vitro diagnostic medical devices (IVD), including coronavirus (SARS-Coronavirus-2) antigen tests, fall within the remit of the Paul-Ehrlich-Institut. The Paul-Ehrlich-Institut is the competent higher federal authority for centralised report collection and risk assessment. The Institute records, examines and evaluates reported incidents. If reports concerning a particular COVID-19 antigen test accumulate, the Paul-Ehrlich-Institut contacts the manufacturer and asks them for a statement. As part of the risk assessment process, the Paul-Ehrlich-Institut can ask the manufacturer to take corrective or preventive measures.

Please note that the Paul-Ehrlich-Institut only contacts test users who report an incident if further information for the evaluation of an incident report is required. For organisational reasons, no acknowledgements of receipt will be sent.

Further Information

Online Incident Reporting Forms (German only)
Incident Report – Online Form (BfArM, German only)

Why are SARS-CoV-2 antigen tests not tested and certified like HIV tests before they are placed on the market?

Tests for the human immunodeficiency virus (HIV) belonged to the high-risk class even before the new EU regulation for in vitro diagnostic medical devices (EU) 2017/746 (IVDR) came into force and were therefore already subject to the obligation of certification by a notified body before they could be sold and used. Until 25 May 2022, SARS-CoV-2 tests were classified as "low risk IVDs" and could be certified by the manufacturers themselves in accordance with the EU IVD Directive 98/97/EC (In Vitro Diagnostic Device Directive, IVDD) and corresponding implementation into German legislation. Manufacturers did not need an independent review for certification before their antigen test could be placed on the market. In the case of SARS-CoV-2 antigen tests for individual use (self-tests), a notified body only had to assess the suitability for self-testing.

The new EU IVD Regulation IVDR came into force on 26 May 2022. According to this regulation, a conformity assessment of IVDs in the highest risk class, D – which now also includes SARS-CoV-2 tests – must be carried out by a notified body. As part of the conformity assessment, the notified body shall verify on the basis of the technical documentation whether the respective product meets the basic safety and performance requirements detailed in the IVDR. The requirements set out in the common specifications apply to SARS-CoV-2 tests certified since 26 May 2022. Tests that were received a CE marking before 26 May 2022 do not have to meet these requirements and may still be marketed until May 2025, according to the transitional provisions.

In the future, an EU reference laboratory will also have to be included in the conformity assessment for the testing of a SARS-CoV-2 test by a notified body. An EU reference laboratory brought in by a notified body must verify the sensitivity of an IVD product as specified by the manufacturer. The procedure for designating the EU reference laboratories is ongoing and is expected to be completed in 2023.

Due to delays in the designation of notified bodies by EU Member States and the European Commission and because none of the EU reference laboratories envisaged in the IVDR had been designated as of June 2022, the EU Commission has decided to allow those SARS-CoV-2 tests that were self-certified under the IVDD to remain on the market until May 2025 without having to go through the certification procedures detailed in the IVDR. As of 26 May 2022, the requirements of the IVDR apply to new, hitherto uncertified SARS-CoV-2 antigen tests.

In the future, the designated EU reference laboratories will be able to carry out tests on risk group D pathogens in the laboratory, including SARS-CoV-2 tests.

Updated: 30.01.2023

EU Common List of COVID-19 Rapid Antigen Tests (Common RAT List)

The Common RAT List is only available in English and in PDF format – how can I work with it?

A search can be conducted in the PDF document by the name of the company offering the test and by the test name. This information is usually the same in all languages. A search for institutions that have carried out retrospective studies, such as the Paul-Ehrlich-Institut, is also possible.

What is the general structure of the Common RAT List?

The Common RAT List consists of three parts, beginning with the extensive and informational main section. This is followed by two annexes – Annex I and Annex II. These contain the antigen test tables.

  • Annex I contains tables of SARS-CoV-2 rapid antigen tests for which EU certificates can be issued.
  • Annex II contains laboratory-based antigen tests (e.g. enzyme immunoassays such as ELISA or automated tests). EU certificates cannot currently be issued based on these tests.

Where can I find out which criteria the tests must meet in order to be included in Annex I?

This information can be found in the main section, Section 2.1 of the Common RAT List.

European Commisson: Public Health - Common List of Coronavirus Rapid Antigentests (Common RAT List)

What information is contained in the tables in Annex I of the Common RAT List?

  • ID – Identification number, which is NOT the same number as the AT numbers included in the lists previously issued by the Federal Institute for Drugs and Medical Devices (BfArM) and in the table for comparative evaluation issued by the Paul-Ehrlich-Institut.
  • Name of submitting company – name of the applicant and their role, e.g. manufacturer
  • Commercial Name of the Device – the name under which the test is marketed
  • Clinical Performance of the Device – results of field studies (category A) and retrospective studies (category B)
  • Category A: Evaluated Specimen Type(s) - evaluated specimens that qualify for the issuance of a digital EU COVID-19 certificate
  • Category A: Other Specimen Type(s) – other specimens offered but not evaluated
  • Category B: Specimen Type – Type/location of specimen taken
  • SARS-CoV-2 Target Protein – SARS-CoV-2 target protein (usually the nucleocapsid protein, with a few exceptions; red text indicates detection of spike protein)
  • Included in the EU Common List since - date of inclusion in the list

What is the difference between the category A and category B tables in Annex I?

  • Category A includes tests for which clinical field studies have been performed prior to inclusion in the list. If retrospective analyses are also available, such as the "Comparative Sensitivity Evaluation of the Paul-Ehrlich-Institut", this is indicated in the column "Clinical performance of the device".
  • Tests listed in category B were only examined in retrospective analyses, such as the "Comparative Evaluation of the Paul-Ehrlich-Institut".

Some rows of the tables in Annex I and II use different colours. What does that mean?

Rows highlighted in light grey indicate that the test was removed from the Common RAT List on the last date it was updated, but these tests can still be used (digital COVID-19 certificate, cost reimbursement) for a transitional period (date is specified).

Rows highlighted in blue are identical in their design and construction, but vary, for example, in the name under which they are marketed. The results of validation studies can be applied to products that are identical in design and construction.

Some of the text is red – what does that mean?

Text in red may indicate, for example, that a test also works with saliva or sputum samples. This type of sampling has not been evaluated and cannot be used to issue an EU certificate.

Red may also indicate that the test's target protein is the spike protein. Most Omicron mutations are also found in the spike protein.

How do I know if a test for self-use can be refunded?

For the reimbursement of supervised SARS-CoV-2 antigen tests for self-use, it is crucial to determine whether they have received CE marking from a notified body. The number of the notified body is indicated next to the CE marking.

Miscellaneous

Are blood donations, blood products, and stem cell preparations safe after an infection with SARS-CoV-2?

In two studies supported by the Paul-Ehrlich-Institut, it was confirmed that genetic virus material is not detectable in the blood of individuals infected with SARS-CoV-2 with minor or moderate symptoms. The transmission of infectious SARS-CoV-2 viruses via blood components can therefore be ruled out for persons who meet the donor inclusion criteria.

In order to ensure the safety of both the recipient and the donor, donor selection criteria have been established in a federal guideline, the Haemotherapy Guideline. These include routine checks of body temperature and haemoglobin levels as well as an infection-related survey of potential donors. Any indications of an infectious disease will lead to a temporary deferral of the donor.

In addition, laboratory tests and recovery periods have been established to prevent the transmission of certain infectious agents, such as HIV, HBV, HCV, HEV, malaria pathogens, Chikungunya virus, WNV (West Nile virus) and Zika virus.

For blood donations from persons with a confirmed SARS-CoV-2 infection or with confirmed contact with an infected person, recommendations have been made by the Paul-Ehrlich-Institut and are adapted as new information becomes available.

The recommendations states that individuals with a SARS-CoV-2 infection accompanied by fever who wish to donate should be deferred from donation for at least four weeks after full recovery for their own protection. Individuals with an uncomplicated, symptom-free infection confirmed with a positive test result should not be allowed to donate blood for at least one week. However, the latest recommendations (COVID-19 regulations, RKI, etc.) must always be observed.

According to the current guidelines, individuals who have had confirmed contact with a SARS-CoV-2-infected person as well as COVID-19 patients may donate if the presence of an infection has been excluded (negative antigen test or PCR result).

In order to avoid temporary shortages in the supply of blood components, it is still urgently necessary to continue donating blood in sufficient quantities. All persons who are willing to donate and are free of acute infection should therefore donate blood.

Within the scope of its responsibilities, the Paul-Ehrlich-Institut is available to the German state authorities to answer questions about safety and to ensure the supply of blood, plasma and stem cell products.

As soon as new findings are available that require a change to the previous recommendations, the Paul-Ehrlich-Institut will inform the blood donation facilities and the public in a timely manner.

Updated: 14.03.2023

Is it possible to donate blood or plasma after receiving a vaccination? Do special rules apply after vaccination against SARS-CoV-2?

Yes, blood or plasma can be donated after a vaccination. How soon afterwards depends on the type of vaccine.

Blood donation is possible one day after vaccination with a dead vaccine (e.g. tetanus vaccines, many influenza vaccines).

After vaccinations with vaccines containing live or attenuated viruses (e.g. mumps, measles, yellow fever), a waiting period of four weeks must be observed. The Robert Koch-Institut provides details on the waiting period for blood donation after specific vaccinations.

Blood or plasma can also be donated after a COVID-19 vaccination with the currently authorised vaccine products. The COVID-19 vaccine products authorised in Europe so far include mRNA vaccines, inactivated whole virus vaccines, vector-based vaccines, and protein-based vaccines. Blood donation is possible as soon as the vaccinated individual is free from any adverse reactions (such as local skin reactions, fever, pain in the limbs). In any case, the donation shall be released by a physician in accordance with the federal requirements detailed in the Haemotherapy Guideline.

Updated: 14.03.2023

Can a Pneumococcal Vaccination Help in the Case of COVID-19?

As a rule, an up-to-date vaccination protection is important. This is especially true in times of a pandemic. In Germany, the German Standing Committee on Vaccination (Ständige Impfkommission, STIKO) makes recommendations on which groups of people should receive vaccinations against particular infectious diseases.

Pneumococci are the most frequent cause of bacterial pneumonia. A pneumococ-cal vaccination does not prevent a virus infection such as SARS-CoV-2. However, if a pneumococcal infection occurs on top of this virus infection, the patient's body, which is already weakened, must fight an additional lung infection caused by a bacterium. This additional risk can be minimised by a pneumococcal vaccination.

Furthermore, by preventing a bacterial pneumonia, pneumococcal vaccination can help to ensure that urgently needed capacities (such as ventilation sites) are available for patients with severe COVID-19 progression.

Who should Receive a Vaccination against Pneumococci?

The German Standing Committee on Vaccination (Ständige Impfkommission, STIKO) has adjusted their recommendations regarding the pneumococcal vaccination during the current pandemic. Seniors of 70 years and older as well as persons with particular underlying diseases have been requested to have themselves vaccinated against pneumococci, since persons in this age group have an increased risk of SARS-CoV-2 infection. Besides, the vaccination of infants and young children up to the age of 2 years is recommended.

Where can I get Information about a Participation in the Clinical Trial of the COVID-19 Vaccine?

In Germany, the Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, authorises clinical trials of vaccines and approves the trials if the data situation is positive. The Paul-Ehrlich-Institut is not involved in the recruitment of study participants. This is the responsibility of the respective applicant, who has the relevant information (e.g. place of performance).

Is it possible to use Animal Vaccines against Corona Viruses in Humans?

No, it is not possible to use animal vaccines in humans.

The animal vaccines authorised against coronaviruses contain antigens of viruses that belong to the large family of coronaviruses, but are clearly different from the SARS-CoV-2 pathogen. Therefore, if administered, no protective effect against SARS-CoV-2 would be expected.

There are no data on the safety and efficacy of animal vaccines against coronaviruses when used in humans. Furthermore, the different types of coronaviruses show different clinical pictures and infect different species.

Veterinary medicinal products are not authorised for use in humans, which means that safety has not been assessed in this respect. The Paul-Ehrlich-Institut strongly advises against experimental use in humans.

Where do I Find Further Reliable Information on the Coronavirus?

If people base their behaviour in dealing with the Coronavirus on false information, disinformation and misinformation can become a risk. Especially social networks spread fake news. For this reason, it is important to obtain information from reliable sources.

Reliable Sources

When does complete protective vaccination against the SARS-CoV-2 coronavirus exist?

The requirements for proof of vaccination are directly regulated in section 22a of the Infection Protection Act (Infektionsschutzgesetz, IfSG) as of 19 March 2022. The requirements for proof of vaccination published at www.pei.de/impfstoffe/covid-19 expired on 19 March 2022. The regulations for complete vaccination protection can be found in section 22a paragraph 1 of the IfSG.

How must complete vaccination protection be documented – what is considered valid proof of vaccination?

The requirements for proof of vaccination are directly regulated in section 22a of the Infection Protection Act (Infektionsschutzgesetz, IfSG) as of 19 March 2022. The requirements for proof of vaccination published at www.pei.de/impfstoffe/covid-19 expired on 19 March 2022. The definition of "vaccination certificate" (Impfnachweis) can be found in section 22a paragraph 1 sentence 1 of the IfSG.

Content

  1. Role of the Paul-Ehrlich-Institut
  2. COVID-19 Vaccines
  3. Proof of vaccination within the meaning of the Infection Protection Act (IfSG)
  4. FAQ Coronavirus
  5. Safety of COVID-19 Vaccines
  6. Research Work
  7. SARS-CoV-2 Test Systems