Currently, five vaccines against COVID-19 have been granted a conditional marketing authorisation, two mRNA and two vector vaccines as well as one protein-based vaccine. Further vaccine candidates against COVID-19 are in approval or in clinical trials.

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.

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. Currently, there are four authorised COVID-19 vaccines available (as of 23 April 2021). 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.

Misleading coverage in some media about a vaccine development from Lübeck

Currently, there are a number of misleading reports in the media about the role of the authorities in the vaccine development of Professor Winfried Stöcker from Lübeck.

A number of vaccine candidates world-wide with a similar concept of that conceived by Professor Stöcker are currently undergoing clinical trials at different stages, and in conformity with the regulatory requirements.

Professor Stöcker had contacted the Paul-Ehrlich-Institut on 2 September 2020 using an email address which is open to the communication with citizens and health care professionals. On the occasion of this contact, the Paul-Ehrlich-Institut offered him its scientific and regulatory advice by phone on 3 September 2020. Besides, the institute had informed Professor Stöcker as part of this conversation that administering his vaccine to third parties for the purpose of gaining insights might legally fulfil the criteria of a clinical trial of the vaccine candidate pursuant to the German Medicines Act (Arzneimittelgesetz), and that performing such a clinical trial without the required authorisation for a clinical trial, including from the Paul-Ehrlich-Institut, might be relevant under criminal law.

The access to scientific advice provided by the Paul-Ehrlich-Institut is standardised and was thus offered accordingly to Professor Stöcker by the Innovation Office of the Paul-Ehrlich-Institut. This office coordinates the appropriate appointments for the talks and performs the scientific advice with medicines experts, including the president of the Paul-Ehrlich-Institut.

In December 2020, Professor Stöcker again made an enquiry to the Paul-Ehrlich-Institut using the indirect channel of communication of the email address for health care professionals and the general public. Upon this enquiry, the Innovation Office offered Professor Stöcker, on 6 January 2021, by email that he could present his concept as part of a structured advisory talk. Professor Stöcker turned down the offer. Of course, this offer is still valid.

A scientific advice talk with Professor Stöcker has not taken place to date.

To fulfil legal tasks, medicines authorities have mutual information obligations. Against this background, the Paul-Ehrlich-Institut has directed a letter to the Office for Social Services of the land (federal state) (Landesamt for soziale Dienste, LAsD) on 7 September 2020. This is in keeping with the legal conduct.

Further Information

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

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.

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.

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 comprehensive data on the medicinal product has been obtained, the marketing authorisation may be 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.

All currently authorised COVID-19 vaccines have received a conditional marketing authorisation (as of 23 April 2021).

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).

The view of the Paul-Ehrlich-Institut is that marketing authorisation in exceptional circumstances is not relevant for the authorisation of COVID-19 vaccines.

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.

All currently authorised COVID-19 vaccines have received a conditional marketing authorisation (as of 23 April 2021). A marketing authorisation in exceptional circumstances is not relevant.

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.

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, 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),
• the various immune responses achieved by the vaccine,
• 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. COVID-19 is a new infectious disease, for which to date there are no clear correlates of protection for efficacy (such as the neutralising antibody level 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.

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 European Medicines Agency (EMA), the documents submitted by the applicant on the quality, safety, efficacy and positive 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 long the applicant believes will be necessary 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.

SARS-CoV-2 is a novel pathogen. Every vaccine product is complex and has individual characteristics. The production of a vaccine for the use in humans is complex. It is performed under high quality assurance standards with in-process controls und under clean room conditions (Good Manufacturing Practice, GMP) to obtain a consistently homogenous product with defined specifications. For this purpose, a manufacturing authorisation is required, which, in Germany, is granted by the competent authority in the respective federal German state following an inspection. Scientists examine the characteristics of a vaccine candidate within non-clinical trials in the laboratory and in animal models, the most important ones also under quality assurance conditions (Good Laboratory Practice, GLP), and in humans in clinical trials under controlled conditions of Good Clinical Practice (GCP).

Clinical trials in particular require time to thorouly analyse the safety (tolerability) and efficacy of each vaccine product. Experts from medicines authorities such as the Paul-Ehrlich-Institut assess the risk/benefit profile of a vaccine product during the authorisation procedure.

However, preliminary work can be used as a basis for the development of a vaccine against SARS-CoV-2 infections. This is possible because similar Coronaviruses caused the SARS epidemic in 2002/2003 and the MERS (Middle-East-Respiratory-Syndrome) epidemic in 2012. Authorised SARS and MERS vaccines are not yet available.

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 (e.g. through 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 manufactured in a 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 are sufficient results from the quality-assured, consistent manufacture of a high-quality vaccine product, as well as satisfactory results from the preclinical and clinical trials, a application can be submitted for marketing authorisation.

For the European Union (EU) and 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 in 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.

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.

COVID-19 vaccines are modern biomedicines which can only be authorised jointly with in the EU and the European Economic Area in a centralised marketing procedure by the European Commission coordinated by the European Medicines Agency (EMA).

Since viruses always 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.

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.

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).

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.

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).

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.

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.

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.

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.

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

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

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.

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. As of 31 March 2022, the Paul-Ehrlich-Institut has not denied the release of any batch of a COVID-19 vaccine due to quality defects.

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.

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).

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.

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).

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.

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.

Currently, five vaccines against COVID-19 have been granted a conditional marketing authorisation, two mRNA and two vector vaccines as well as one protein-based vaccine. Further vaccine candidates against COVID-19 are in approval or in clinical trials.

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.

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).

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.

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.

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.

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

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

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).

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

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

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

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

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.

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

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.

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.

No. All ingredients are listed in the relevant Summary of Product Characteristics (SmPC).

Further Information

Comirnaty summary of product characteristics (SmPC) (see e.g. package leaflet, section 6)
COVID-19 Vaccine Moderna summary of product characteristics (SmPC)
COVID-19 Vaccine AstraZeneca summary of product characteristics (SmPC)

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.

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.

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.

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).

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.

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

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

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.

Infection-enhancing antibodies (Antibody-Dependent Enhancement, ADE) bind to the surface of viruses but do not neutralise them. Instead, they facilitate the uptake of the virus into the cell and enhance the infection.

The possibility of ADE formation is generally addressed early in vaccine development in both non-clinical trials and clinical trials.

One viral infection in which ADE is occasionally observed is the dengue virus infection. After an initial infection that usually runs uncomplicatedly, the second infection occasionally leads to a severe course that is attributed to ADE. Such amplifications of infection by antibodies can also be induced by the dengue vaccine Dengvaxia when vaccinating people who have no previous immunity to dengue viruses. Therefore, the vaccine is only authorised for use in people who have been infected with dengue virus in the past and live in endemic areas.

So far, there is no evidence of the presence of ADE-induced amplification of infection, either in animal models of SARS-CoV-2 infection, in COVID-19 recovered people or in SARS-CoV-2 infected people. Scientists, including those in the clinical field, continue to closely monitor SARS-CoV-2 infections in vaccinated and recovered individuals. From the beginning of COVID-19 vaccine development, the question of ADE development has been under intense investigation, as there was evidence of ADE development in the preclinical development of vaccines against other beta coronaviruses - SARS-CoV-1 and MERS. There has been no evidence of ADE in any of the COVID-19 vaccines authorised in Europe, either in preclinical development, clinical trials or post-market use.

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.

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.

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.

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

The periodically published report (www.pei.de/sicherheitsbericht) presents suspected cases of side-effects or vaccine complications reported to Paul-Ehrlich-Institut that correlate timewise with the administering of authorized COVID-19 vaccines and discusses these in relation to possible risk signals.

The reports of suspected cases reach us by post, e-mail, telephone or electronically via 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/sicherheitsbericht
Online-Reporting of Side Effects - www.nebenwirkungen.bund.de

Yes, messages received by Paul-Ehrlich-Institut via the SafeVac 2.0 app are registered, evaluated, and analyzed for any new content.

The periodic safety reports by Paul-Ehrlich-Institut contain an aggregated evaluation of the current information from the SafeVac 2.0 study in a separate chapter of the report.

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.

As with all other vaccines, Paul-Ehrlich-Institut receives reports of suspected side-effects and vaccine complications following vaccination with COVID-19 vaccines from a variety of sources. Generally, reports reach the Paul-Ehrlich-Institut:

• through the public health offices in line with the German Infection Protection Act. Doctors 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 anonymized 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 database of the European Medicines Agency (EMA),
• directly from doctors, and
• from vaccinated persons or their relatives.

The number of suspected case reports can always be found in the most recent safety report.

www.pei.de/sicherheitsbericht

Paul-Ehrlich-Institut is committed to increasing public confidence in vaccines by providing the greatest possible transparency on the potential risks of vaccines. Paul-Ehrlich-Institut therefore regularly publishes a report with annual data on pharmacovigilance of vaccines in the Bulletin on Drug Safety. This usually coincides with the first edition of any year, but is in a later edition in 2021 due to COVID-19. In general, therefore, there is transparent reporting of suspected cases for all vaccines.

For COVID-19 vaccines the situation is a special one, however: Never before have multiple vaccines been developed through worldwide efforts, with which millions of people have been and are being vaccinated in a very short period of time. The desire for transparency and as much information as possible on the effectiveness and safety of these vaccines is understandable and justified. Paul-Ehrlich-Institut decided in advance that despite the immense workload caused by the correspondingly high number of suspected case reports it would also report on these suspected cases periodically.

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.

The Paul-Ehrlich-Institut has developed the SafeVac 2.0 smartphone app as part of an active monitoring of the safety and tolerability of COVID-19 vaccines. 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.

Users of the SafeVac 2.0 app are voluntarily taking part in an observational study carried out by the Paul-Ehrlich-Institut. The vaccinated persons’ agreement and consent to participate in the Paul-Ehrlich-Institut’s observational study is a precondition for using the app. Via the app, the participants will be asked questions about their current state of health at defined points in time. 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 tolerate the vaccination well.

SafeVac 2.0 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; it supports iOS 12-14 and Android 5.0-10.0.

Yes, vaccinated persons who do not wish to take part in the survey using the SafeVac 2.0 app can report suspected adverse vaccination reactions via the online reporting portal www.nebenwirkungen.bund.de.

The vaccinated persons’ agreement and consent to participate in the Paul-Ehrlich-Institut’s observational study is a precondition for using the SafeVac 2.0 app. Via the app, the participants will be asked questions on seven occasions after the first vaccination and on eight occasions after the second vaccination; this will take place within three weeks after the first dose and four weeks after the second dose, and is designed to determine how well the vaccines are tolerated. In addition, the participants 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. At no time can a participant or his/her smartphone be identified. 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 possible 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.

In the regular spontaneous recording of suspected adverse reactions to vaccination, suspected cases are indeed recorded, but what is not known is how many reactions are not reported for various reasons. The SafeVac 2.0 app 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. With this app, the Paul-Ehrlich-Institut will not only obtain information 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.

It will be possible to use the app as soon as vaccination against COVID-19 begins in Germany. It is already available in the app stores.

If you would like to take part in the survey on the tolerability of COVID-19 vaccines, you can download the SafeVac 2.0 app using the following QR codes.

Google App Store

Apple App Store

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 the batch number ist checked. 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.

Children 12 years of age or older are generally allowed to participate in the observational study via the SafeVac App 2.0, but a separate mobile device (e.g., smartphone or tablet) is required. It is not possible to submit information on two people in the app using the same device.

If a separate mobile device is not available, it is possible to report any potential adverse side effects experienced by your child via the www.nebenwirkungen.bund.de online portal.

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.

Yes, as of version 2.3.1 it is also possible to report how you tolerated your booster vaccination.

Evaluation of the reports received in the last few months have shown that most adverse side effects occur within seven days of vaccination. Therefore the booster vaccination survey only requires one report from the user.

No, the 48-hour rule applies only when you first register for the app, meaning upon initial vaccination. Your booster vaccination and any related information can also be submitted retroactively in the app.

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.

Only those who registered after their initial vaccination 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.

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, no expansion of the SafeVac app is currently planned for the fourth vaccination. After completion of the study, the Paul-Ehrlich-Institut will consider whether it should offer an app to record adverse events in the future.

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 or who do not meet the requirements for participation in the survey via the SafeVac app. All suspected adverse events received via this portal are recorded and evaluated by pharmacovigilance experts at the Paul-Ehrlich-Institut.

The following requirements must be met to participate in the SafeVac app survey:

• 12 years of age or older
• at least one vaccination with a COVID-19 vaccine
• vaccination occurred less than 48 hours ago
• has a compatible smartphone (IOS 12 or higher, Android 5 or higher)
• access to the Apple App Store or Google Play Store
• electronic consent to the survey.

It can be assumed that the COVID-19 vaccination does not lead to a positive test result after rapid 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 rapid antigen tests used in Germany 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 antigen 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.

If an antigen test result is positive after a COVID-19 vaccination, this is in all probability due to the following causes:

• The vaccinated person was probably infected before the vaccination. The mean incubation period for COVID-19 is five to six days.
• The vaccinated person may have become infected shortly after the vaccination. Complete 95 percent protection can be expected from the vaccination only as from seven to 14 days after the second vaccination.
• Since it is not yet fully clarified whether the vaccination not only protects a person from the COVID-19 disease but also from the infection with the SARS-CoV-2 virus, it cannot be ruled out in principle that a person will become infected even if vaccinated.

The antigen test may be false positive, as is the case with all diagnostic devices, which, in rare cases react with some samples, even if the marker – in this case the antigen of the SARS-CoV-2 virus – is not present at all. In some tests, this can certainly occur in the order of magnitude of one to two percent of the tests. For this reason, a PCR test should be performed following a positive rapid antigen test in order to confirm or rule out an infection.

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.

Tests for the human immunodeficiency virus (HIV) belonged to the high-risk class even before the new EU IVD (in vitro diagnostic medical devices) regulation came into force and were therefore already subject to the obligation of certification by a notified body before they could be sold and used. SARS-CoV-2 tests were classified as "low risk IVD" until 25 May 2022 and could be certified by the manufacturers themselves in accordance with the EU directive and corresponding implementation in German legislation. They did not need an independent review before they were put on the market. The only exceptions were SARS-CoV-2 self-tests, for which a notified body had to assess the suitability for self-testing.

As of 26 May 2022, the new EU IVD Regulation applies. According to this regulation, a notified body must consult an EU reference laboratory for laboratory verification of the test when assessing the conformity of SARS-CoV-2 tests. These tests also belong to the highest risk class since the regulation came into effect. Therefore, not only is the verification of the data by a notified body required, but also laboratory testing of the tests by an EU reference laboratory.
However, due to delays in the designation of notified bodies by Member States and the European Commission and because no EU reference laboratories have been designated as of June 2022, the EU Commission has decided to allow those SARS-CoV-2 tests that were self-certified under the IVD Directive to remain on the market until May 2025 without having to go through the stricter certification procedures.

As of June 2022, the Paul-Ehrlich-Institut plans to apply as an EU reference laboratory. In the future, the designated EU reference laboratories will be able to carry out tests on risk group D markers in the laboratory, including SARS-CoV-2 tests.

The IVD Regulation, which has been in force since May 2022 and classifies SARS-CoV-2 antigen tests as high-risk class D, stipulates that new SARS-CoV-2 antigen tests must undergo a manufacturer-independent review and evaluation in the future. This regulation will increase confidence in the performance of these in vitro diagnostics.

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.

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 detailing the results of the tests evaluated at the Paul-Ehrlich-Institut and often also in the instructions for use.

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.

Almost all antigen tests examined by the Paul-Ehrlich-Institut are based on the detection of the SARS-CoV-2 nucleocapsid proteins (N proteins). This 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 antigen rapid tests.

Targeted evaluations by the Paul-Ehrlich-Institut have (as of June 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/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 is 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, Federal Institute for Vaccines and Biomedicines, is an independent testing authority and does not make any recommendations for specific products.

According to the directive, complete vaccination protection exists when

• vaccination with the required number of vaccine doses for each licensed COVID-19 vaccine has been documented and at least 14 days have passed since the last required single vaccination. The number of vaccine doses required for each COVID-19 vaccine is available at www.pei.de/impfstoffe/covid-19.
• a recovered person has received one vaccine dose.

The complete vaccination protection must be documented in a vaccination certificate in German, English, French, Italian or Spanish in paper form (paper vaccination certificate) or digital form. The underlying vaccination must have been given with one or more vaccines listed by the Paul-Ehrlich-Institut on the internet on www.pei.de/impfstoffe/covid-19 and at least 14 days must have passed since the last required single vaccination.

In general, it should be noted that the recommendations of the German Standing Commission on Vaccination (Ständige Impfkommission, STIKO) at the Robert Koch Institute are based on the currently available data and scientific findings. How long the vaccination protection will last with the currently available vaccines and whether further vaccinations (so-called booster vaccinations) are necessary for long-term immune protection, especially with regard to possibly emerging virus variants of concern (VOC), cannot be answered at present. The STIKO will adapt its recommendations to new developments and findings.

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.

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.

The demand for pneumococcal vaccines has increased in 2020 due to the Corona crisis, since many more people chose to have themselves compared to the previous year. The Paul-Ehrlich-Institut has improved the supply situation by taking various measures. You can find the current situation in our overview of supply shortages.

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).

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.

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

• European Medicines Agency, EMA
• Federal Centre for Health Education, (German only)
  (Bundeszentrale für gesundheitliche Aufklärung, BZgA)
  including recommendations on hygiene and conduct for the prevention of infections
• Federal Institute of Drugs and Medicial Devices, (German only)
  (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM)
  e.g. duties of the BfArM in the context of COVID-19
• Federal Ministry of Health
  (Bundesministerium für Gesundheit , BMG)
  including political activities, Corona warning app
• Foreign Office of the Federal Republic of Germany
  (Auswärtiges Amt)
  e.g. travel warnings
• Health Innovation Hub of the Federal Ministry of Health, (German only)
  (Zentrum für Gesundheitsinnovation des Bundesministeriums für Gesundheit)
  including providers of telemedicine, information from the Charité and the Robert Koch-Institute (German only)
• Paul-Ehrlich-Institut (PEI)
  including regulatory and research duties in the context of COVID-19
• Robert Koch-Institut (RKI)
  including officially confirmed COVID-19 cases, epidemiologic information on Coronavirus SARS-CoV-2