Coronavirus and COVID-19
Development and Authorisation
How many vaccines against COVID-19 have already been granted a marketing authorisation?
Currently, four vaccines against COVID-19 are approved, two mRNA and two vector vaccines. Further vaccine candidates against COVID-19 are in approval or in clinical trials.
How can a COVID-19 vaccine be authorised so quickly and at the same time be safe?
The development of vaccines for new pathogens is a complex and laborious process that usually takes several years.
Before being authorised, a vaccine candidate must successfully complete all the phases of medicinal product development. This begins with the isolation and characterisation of the pathogen and the identification of suitable antigens. Antigens are the components of the pathogen that are intended to bring about the immune protection. This is followed by the development of the vaccine candidate, the preclinical investigations and the clinical trials in phase 1 (immunogenicity), phase 2 (tolerability, dosage) and phase 3 (statistically significant data on safety and efficacy). In order for a vaccine to be authorised, its quality, safety and efficacy must be proven. In addition, its benefits must clearly outweigh the risks. COVID-19 vaccines are also developed and authorised in accordance with this principle.
In Europe, the COVID-19 vaccines are assessed in the centralised marketing authorisation procedure, which is coordinated by the European Medicines Agency (EMA). In the event of a positive assessment, the Committee for Medicinal Products for Human Use (CHMP) at the EMA issues an opinion to the European Commission with a recommendation for authorisation. The European Commission decides on the marketing authorisation of a vaccine product in Europe and thus also in Germany. After being authorised, the vaccine can be marketed in the EU Member States, including the EEA states, and can be made available to all members of the public.
The coronavirus pandemic has presented the modern world with unprecedented challenges – economically, socially and in terms of health. Vaccines are the most effective way to contain the pandemic and to protect ourselves from COVID-19. This understanding motivated all the experts involved in vaccine development to work together more closely and to make processes more efficient, without compromising on due care and diligence. This has also led to significant optimisation of the process flows and time savings in development.
#1 Time savings through scientific advice
Vaccine developers benefit from early and ongoing scientific and regulatory advice from medicines agencies. This scientific advice is initially provided on a national level, and then in the case of advanced development on a European level. It prepares the pharmaceutical company for the regulatory requirements that will need to be observed during development, for the requirements in terms of the content of applications for the approval of clinical trials, for marketing authorisation and for batch release. It makes a smooth submission process possible without undue delays.
#2 Time savings through rolling reviews
A rolling review procedure for marketing authorisation allows the vaccine manufacturer at an early stage – even while the clinical phase 3 trial is still ongoing – to submit individual data packages for a preliminary assessment for marketing authorisation and to answer any questions that arise during the regulatory evaluation of the application. In this way, parts of the application dossier can be checked, improved and assessed before the actual application is submitted. Once all the necessary documents for marketing authorisation have been submitted and the marketing authorisation application has been made, processing will take significantly less time. The assessment process therefore starts much earlier. The rolling review procedure precedes the marketing authorisation application with the submission of the complete data packages.
The Paul-Ehrlich-Institut has also used the rolling review procedure for the approval of clinical trials.
#3 Time savings by combining clinical trial phases
Clinical trials, which generally take place one after the other, have been combined, e.g. phase 1 with phase 2 or phase 2 with phase 3. Organisational processes, for example the recruitment of test subjects for two phases of the clinical trial, can be bundled into one process. In addition, the necessary investigations can be combined.
#4 Time savings through existing research on coronaviruses
In the development of a COVID-19 vaccine, scientists were able to build on preparatory research work that had already taken place into other coronaviruses and corresponding vaccine developments, e.g. the SARS coronavirus in 2003 and the MERS coronaviruses. These coronaviruses, which are similar to SARS-CoV-2, triggered the SARS epidemic in 2002/2003 and the MERS (Middle East Respiratory Syndrome) epidemic in 2012.
Can individual phases of the vaccine development be omitted?
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.
What accelerated authorisation procedures are available in the EU?
In the EU, there are three standardised procedures, each of which permits early marketing authorisation under certain conditions:
- accelerated assessment
- conditional marketing authorisation
- authorisation under exceptional circumstances.
In addition to these procedures, medicine developers can participate in a voluntary programme for accelerating the marketing authorisation process, the PRIME scheme of the European Medicines Agency (EMA).
In order to accelerate the authorisation of COVID-19 vaccines as much as possible, the rolling review procedure has been used. This procedure was established for precisely this type of pandemic health situation.
What is an accelerated assessment?
In the accelerated assessment procedure, the timeframe for regulatory assessment is reduced from 210 days to 150 days. The prerequisite is that the European Medicines Agency (EMA) must approve the medicine developer’s request for an accelerated assessment.
This procedure is possible for medicinal products that are of major interest for public health, e.g. because they target a disease for which there is currently no treatment option or address an unmet medical need.
What is a conditional marketing authorisation?
A conditional marketing authorisation is a marketing authorisation that is linked to certain conditions. It can be granted for a medicine in the interest of public health,
- if the benefit of immediate availability of the medicinal product outweighs the risk of less comprehensive data than normally required.
- if the medicinal product aims to treat or prevent a life-threatening illness. This also includes orphan medicines,
if the CHMP finds that all the following requirements are met:
- A positive benefit-risk balance of the product, i.e. the benefit to public health of the medicinal product’s immediate availability on the market outweighs the risks due to the need to submit further data.
- The applicant will provide comprehensive data at a later date.
- An unmet medical need will be fulfilled.
Conditional marketing authorisations are valid for one year and can be renewed annually. They can be converted into a full marketing authorisation.
The marketing authorisation holder is required to fulfil specific obligations (ongoing or new studies, and in some cases additional activities) in the specified timeframe with a view to providing comprehensive data that confirms that the benefit-risk balance continues to be positive.
Once 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).
What is a marketing authorisation under exceptional circumstances (generally medicinal products for rare diseases)?
In very rare cases, a marketing authorisation under exceptional circumstances can be granted. In such cases, the European Medicines Agency (EMA) and the European Commission, as the authorising body, understand that the comprehensive clinical data that is usually required cannot be provided, but that there is a reasonable assumption that a medicinal product can help patients in the event of a high medical need.
If the usually required clinical data cannot be produced for a particular treatment option or a particular medicinal product, it would not be in the interests of the patients concerned to formally insist on compliance with this requirement. This may be the case if a disease is very rare (orphan disease) or if there are ethical concerns about specific studies in the therapeutic situation.
This form of marketing authorisation is linked to particularly strict conditions: the authorisation is reviewed annually and is generally not converted into a standard marketing authorisation. Almost all the medicinal products concerned are for rare diseases (orphan drugs).
The view of the Paul-Ehrlich-Institut is that marketing authorisation in exceptional circumstances is not relevant for the authorisation of COVID-19 vaccines.
How does a conditional marketing authorisation differ from a marketing authorisation under exceptional circumstances?
A conditional marketing authorisation is granted with the requirement that the applicant will provide the required comprehensive data within an agreed timeframe.
A marketing authorisation in exceptional circumstances is granted if it is unlikely that the normally required comprehensive data can be collected. This applies, for example, to very rare disorders (orphan diseases). This approval route does not generally lead to a standard marketing authorisation.
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.
How exactly does a rolling review procedure work for COVID-19 vaccines?
In a rolling review procedure, the lead assessors from two Member States (the Rapporteur and Co-Rapporteur) on the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) assess individual submitted data packets as soon as they become available, ask questions and evaluate the applicant’s answers. The data required for a complete marketing authorisation application can thus be submitted gradually and not as a single, complete data package as is the usual practice.
This procedure serves to accelerate the progress of a COVID-19 vaccine candidate towards marketing authorisation. The assessment of the data packages from pharmaceutical and non-clinical development will have already started before the clinical data for the formal marketing authorisation application becomes available.
A rolling review procedure runs until such time as the study data can provide sufficient evidence to permit the formal application for marketing authorisation. The CHMP checks at what point reliable data is available as the basis for a positive risk-benefit assessment, and then recommends that a corresponding application should be submitted.
The CHMP can then decide relatively quickly whether or not to recommend to the European Commission that marketing authorisation should be granted to a vaccine candidate.
It is important to note that the processes in a rolling review are carried out in parallel – the collection of clinical study data and the assessment of non-clinical data and data on manufacturing and quality – so that the time to a potential marketing authorisation is reduced, but no compromises are made in the assessment. The level of safety remains just as high as in the usual centralised procedure. A vaccine can only be granted marketing authorisation if its quality, safety and efficacy have been proven.
What type and amount of data are required in order to approve a safe and effective COVID-19 vaccine?
With the application for marketing authorisation of a COVID-19 vaccine, a medicinal product developer must submit the following data:
- information on the group of people to whom the vaccine is to be administered,
- pharmaceutical quality, 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 for European marketing authorisation
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.
Why was there no approved vaccine against SARS-CoV-2 by 21.12.2020?
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.
How is a vaccine developed against a new, unknown virus such as SARS-CoV-2?
Firstly, the pathogen is analysed and tested to determine which components of the virus the human immune system reacts to and can build up protection against (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.
Does a clinical trial of a COVID-19 vaccine in Germany also lead to a marketing authorisation for Germany?
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).
What is the legal basis for batch testing in Germany?
In accordance with Section 32 of the German Medicinal Products Act (Arzneimittelgesetz, AMG) – "Official batch testing" – a batch (a production unit) of a vaccine may only be marketed in Germany if it has been tested and released by the competent higher federal authority, i.e. the Paul-Ehrlich-Institut, the Federal Institute for Vaccines and Biomedicines.
What is examined during the batch release?
Checks are carried out to determine whether the batch has been manufactured and tested according to methods of manufacture and control which comply with the prevailing standard of scientific knowledge and the requirements specified in the marketing authorisation. The tests that are required for batch testing are specific to each vaccine product and are defined by the European Directorate for the Quality of Medicines & HealthCare (EDQM).
Does batch release have to be carried out by the Paul-Ehrlich-Institut?
Yes, batch release in Germany must be carried out by the Paul-Ehrlich-Institut. However, the Paul-Ehrlich-Institut does not necessarily also have to perform the batch testing. A batch can also be released if the competent authority of another member state of the European Union has determined that the requirements for batch release have been met, after an experimental investigation and after checking the data submitted by the pharmaceutical company regarding the manufacture and testing of the batch.
How can the Paul-Ehrlich-Institut test batches of novel mRNA vaccines? Surely it does not have any experience in the batch testing of mRNA vaccines?
The marketing authorisation documents define how the manufacturing process of the authorised vaccine product must be carried out and what controls must be performed during manufacture. Batch testing includes checking the submitted batch documentation for compliance with the requirements of the marketing authorisation and checking whether the required criteria have been met in the corresponding control testing.
The Paul-Ehrlich-Institut also conducts its own experimental testing of the mRNA vaccines. Even if the actual RNA platform is in fact novel for vaccines, the methods for testing RNA vaccines are not fundamentally anything new for the Paul-Ehrlich-Institut. As a result, the RNA vaccine-specific methods only needed to be adapted on the basis of the experimental expertise already available at the Paul-Ehrlich-Institut.
The tests that are required for batch testing are specific to each vaccine product and are defined by the European Directorate for the Quality of Medicines & HealthCare (EDQM).
How, in concrete terms, are mRNA vaccines tested experimentally?
During batch testing, the identity, quantity, concentration and integrity of the RNA contained in the vaccine are all examined. In addition, the proportion of RNA that is encapsulated in lipid particles is determined.
How long does batch testing take?
Section 32 of the Medicinal Products Act (AMG) specifies that the competent higher federal authority – in the case of vaccines, the Paul-Ehrlich-Institut – must reach a decision on batch release within a period of two months from receipt of the batch sample to be tested. This statutory period does not, however, need to be utilised in full. In general, the Paul-Ehrlich-Institut’s batch testing of vaccines only takes a few days. In many case, the Paul-Ehrlich-Institut aims for parallel testing, i.e. batch testing is carried out while the manufacturer is still also performing batch tests. This saves time. Parallel testing is also being carried out in the case of COVID-19 vaccines.
At what point does batch testing take place?
Batch testing by the Paul-Ehrlich-Institut often takes place in parallel to final testing by the manufacturer, so that batch testing does not require any additional time – or only a very small amount of time – after the application for batch release has been submitted for a vaccine product. Batch testing always precedes batch release. Only fully tested batches can be released by the Paul-Ehrlich-Institut for the German market.
How is the sample selected for batch testing: at random, or are large quantities of vaccine sent to the PEI for testing?
No, the manufacturer sends the Paul-Ehrlich-Institut samples of the relevant batches that are representative of the whole batch.
What happens after batch release by the Paul-Ehrlich-Institut?
After official batch release, the vaccine can be marketed and used in Germany.
The Paul-Ehrlich-Institut is part of the OMCL network. What does that mean?
The Paul-Ehrlich-Institut is a member of the network of Official Medicines Control Laboratories (OMCL) which can undertake the experimental testing of medicinal products in Europe. The European Directorate for the Quality of Medicines & HealthCare (EDQM), a directorate of the Council of Europe, coordinates this network of Official Medicines Control Laboratories.
Vaccines and Biomedicines
Which medicines for the treatment or prevention of COVID-19 are under development?
In various studies world-wide, scientists have examined a number of medicines to treat and prevent COVID-19. Some of them have already been used successfully to treat other virus infections and have been studied in clinical trials. All of these medicines must be re-evaluated scientifically for safety and efficacy in COVID-19. A combined use of multiple therapeutics is also conceivable.
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.
Vaccines specifically stimulate the body’s own immune response so that this immune response can occur rapidly in the event of an infection, and so that it can combat SARS-CoV-2 viruses as well as SARS-CoV-2 infected cells in the body. Vaccines thus primarily serve to protect the body from the infectious disease caused by SARS-CoV-2. Vaccines are used for active immunisation.
What is the difference between active and passive immunisation?
In an active immunisation, the immune system is stimulated to confer an immune response, for example by the production of viral antigens, among other things, in order to develop a protective immune response through creating antibodies.
The administration of antibodies, however, represents a passive immunisation. Antibodies can be used for prevention or treatment. Unlike active immunisations, which also triggers a memory function of the immune system and thus lasts for a longer period of time, the effect of passive immunisation is linked to the availability of a sufficient amount of the specific immunoglobulins administrated. These immunoglobulins do not trigger a direct memory function.
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).
What is the difference between a preventive and a therapeutic vaccine?
A preventive vaccine prepares the immune system for an infection with a pathogen and confers protection against the infectious disease. Even if the infectious disease is not prevented, the vaccine will still prevent a serious outcome. Specific vaccines contain antigen(s) or the genetic information for the blueprint of the antigen(s) of the pathogen against which vaccination is targeted.
Therapeutic vaccines are used for the treatment of a (chronic or acute) infectious disease, but also for cancer immmunytherapy. As an adjuvant treatment in combination with other specific therapies, they are intended to alleviate the course of the disease, and, at best, to cure the disease. In addition to the therapeutic administration of a vaccine, specific antibodies for a therapeutic vaccination or specific immune cells can be used as an immune therapy.
What technologies are used to develop human viral vaccines?
There are various approaches to vaccines production based on so-called platform technologies. The principle of platform technologies is based on the modular principle, in which the same basic structures and technologies (platforms) are used and only the pathogen-specific component (antigen or genetic information of the antigen) is exchanged. These can be purified and inactivated virus particles (inactivated whole-virus vaccines) or parts thereof (split or subunit vaccines; vaccines with genetically engineered antigen, so-called recombinant subunit vaccines; peptide vaccines). These can be mixed with an active ingredient enhancer, the adjuvant.
Of particular importance are vaccines based on innocuous genetic information. These vaccines transmit the genetic information with the blueprint of the antigen(s) to a few body cells. Traditionally these are the attenuated live virus vaccines.
The modern platforms are replicating or non-replicating vector vaccines, DNA vaccines, and RNA vaccines. So far, research teams succeeded in developing various vaccine candidates against COVID-19 within months. Some of them are already being tested in animal models or in humans.
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.
An attenuated virus serves as a vehicle (vector) for an innocuous part of the genetic information of SARS-CoV-2 into a few body cells. Vector vaccines are capable or incapable of replication and transmit the blueprint for one or multiple antigens. Vectors can, for example, be certain adenoviruses, measles vaccine, modified vaccinia Ankara or genetically engineered (recombinant) vesicular stomatitis virus (rVSV). These vector vaccines do not cause disease in humans. An example of a vector vaccine is the Ebola vaccine Ervebo (rVSV-ZEBOV), which was granted a European marketing authorisation by the European Commission in November 2019.
Recombinant subunit vaccines
This method involves inserting the genetic information with the blueprint or a virus protein into bacteria, yeast, or mammalian cells, which will then produce the virus protein. After the purification, the virus protein is used as antigen in the vaccine. In some subunit vaccines and adjuvant is added to enhance the immune response.
Inactivated whole virus vaccines
With this method, infectious viruses are produced in a cell culture under the required safety conditions and then purified. The purified virus particles are inactivated under treatment with specific chemicals (e.g. formaldehyde) so that they are no longer in-fectious and can therefore be used as a vaccine (with or without adjuvant).
How do mRNA vaccines work and what are their advantages?
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 blueprint to produce the specific antigen in a small number of body cells by themselves. The cells present this antigen, which creates the desired specif-ic immune response. If the vaccinee comes into contact with SARS-CoV-2 again, the immune system will recognise the antigen again, and will be able to combat the virus, and thus the infection, in a targeted manner.
Advantages of mRNA vaccines include the simple structure of the RNA and the possibility to produce several millions of vaccine doses within few weeks.
How many vaccines against COVID-19 have already been granted a marketing authorisation?
Currently, four vaccines against COVID-19 are approved, two mRNA and two vector vaccines. Further vaccine candidates against COVID-19 are in approval or in clinical trials.
At what point in time should the second vaccination with the COVID-19 vaccine Comirnaty be given after the first one?
The Summary of Product Characteristics (SmPC) for the vaccine Comirnaty from BioNTech recommends the administration of the second dose three weeks after the administration of the first dose. The data determined in the clinical trial cover the period of 19 to 42 days for the second vaccination. If the recommended interval of three weeks cannot be adhered to, the vaccination should be given soon after that. An interval of 42 days should not be exceeded.
How was this recommended vaccination interval determined?
The recommended interval results from the vaccination regimen used for proof of efficacy and safety in the clinical trials. Here, a specific interval is indicated, wherever possible. In clinical trials, too, planned vaccination intervals cannot always be observed. For this reason, specific time intervals for the administration of the second dose or follow-up vaccination are also defined in clinical trials. Therefore, specific intervals are already defined for the administration of the second dose in the clinical trials.
The SmPC (Section 5.1) describes the vaccination intervals used (intervals for follow-up vaccinations) and the results. When vaccines are authorised, the recommended interval to be used for a vaccination regimen is described in the SmPC (Section 4.2) in days/weeks/months. Since this is a recommendation, deviations may be possible.
The vaccination intervals recommended by the Standing Vaccination Committee (Ständige Impfkommission, STIKO) usually refer to the period mentioned in Section 5.1. This allows for a certain amount of flexibility in performing the vaccination, since, in practice, vaccination appointments cannot always be fixed on an exactly determined day.
This means: ideally, the vaccination should be administered in the time interval de-scribed in 4.2; a delay in the vaccination, however, is covered both by the marketing authorisation and by the STIKO recommendation.
What are neutralising monoclonal antibodies against SARS-CoV-2?
Monoclonal antibodies for use against the SARS-CoV-2 coronavirus are proteins of the immune system (immunoglobulins) which have been developed to specifically bind to defined surface structures of the SARS-CoV-2 coronavirus. These antibodies are directed against the surface spike protein of SARS-CoV-2.
In contrast to hyperimmune globulins, convalescent plasma and sera, monoclonal antibodies consist of identical immunoglobulin molecules with a single amino acid sequence and a single recognition domain for a specific structure (epitope) of a single specific target molecule (antigen). Monoclonal antibody medicinal products may also contain combinations of a small number of precisely specified monoclonal antibodies; this is indicated in the composition of the medicinal product.
How do the SARS-CoV-2 neutralising monoclonal antibodies work?
These antibodies work by binding to the spike protein on the surface of the SARS-CoV-2 coronavirus. In this way, they block the SARS-CoV-2 viruses from binding to the receptors on the surface of human cells. As a result, the viruses cannot penetrate the cells and infect them. As viruses reproduce in cells and are released by the infected cells, the neutralisation of viral entry and infection of the cells is also associated with the prevention of viral reproduction (replication).
What benefits may be expected from the administration of these monoclonal antibodies?
The SARS-CoV-2 neutralising monoclonal antibodies may help to restrict the amount of virus in the patient (reduction of viral load). So far, only limited information is available on the safety and efficacy of their use in the treatment of COVID-19. According to the results of one clinical trial, after treatment patients were less likely to be admitted to hospital or A&E. Indications of a possible or anticipated benefit of treatment refer to a specific point in time during the treatment and to the patient group being treated.
What monoclonal antibodies are available for use against SARS-CoV-2?
The Federal Minister of Health Jens Spahn had announced that from February 2021 certain monoclonal antibodies against the coronavirus SARS-CoV-2 can be used in Germany as soon as they are available in Germany. Currently these are the antibody Bamlanivimab, which was developed by the US pharmaceutical company Eli Lilly, and the other, RegnCoV-2, consisting of the two antibodies Casirivimab/Imdevimab from the Swiss pharmaceutical company Roche and the US company Regeneron.
See also information on treatment for immunosuppressed or immunocompetent people in the context of new SARS-SoV-2 virus variants in FAQ:
For which groups of people is treatment with bamlanivimab or casirivimab/imdevimab suitable?
These SARS-CoV-2 neutralising monoclonal antibodies can be used in patients who have proved to have COVID-19 (Corona), are not yet receiving oxygen for the treatment of COVID-19 (Corona), and show risk factors pointing to a serious course of the disease. Treatment should be carried out within three days after a positive SARS-CoV-2 test and within ten days of occurrence of the symptoms. Information on the risk factors can be found in the information for health care professions or in the patient information on bamlanivimab or casirivimab/imdevimab (as applicable).
Because of the new emerging SARS-CoV-2 virus variants, the COVRIIN specialist group at the Robert Koch Institute has specified the possible use of the available monoclonal antibodies. According to this, the use of monoclonal antibodies in monotherapy (only one monoclonal antibody) in immunosuppressed patients may not lead to complete virus elimination and promote the development of so-called escape mutations. Combination therapy with two monoclonal antibodies should therefore be preferred in this group of patients. In the case of immunocompetent patients, on the other hand, monotherapy with Bamlanivimab is possible, provided that it is not the worrying SARS-CoV-2 variants B.1.135 (South African variant) or P1 (Brazilian variant). If the status remains unclear, the local epidemiological situation should be taken into account.
How are bamlanivimab or casirivimab/imdevimab used?
These monoclonal antibodies are administered by single infusion into the vein. Treatment should be given under conditions where treatment of an infusion reaction/allergic reaction is possible.
Bamlanivimab/Etesivimab finished dosage forms are clear to slightly opalescent and colourless to slightly yellowish or brownish solutions that are free of visible particles. Bamlanivimab infusion solution should be prepared and administered by qualified healthcare professionals under aseptic conditions. During this process, the contents of the vial should be checked for particulate matter and discoloration and, if particulate matter is detected, the vial should be discarded. Compatibility of Bamlanivimab/Eteivimab with commonly used infusion sets has been demonstrated in studies with and without PES "in-line" filters. Therefore, an explicit recommendation to use PES filters during infusion is not considered mandatory, especially since the use of "in-line" filters is, to the knowledge of the Paul-Ehrlich-Institut, considered standard in clinical routine for the infusion of drugs containing monoclonal antibodies.
Why can bamlanivimab or casirivimab/imdevimab be used in Germany, even though they have not yet received marketing authorisation in Europe and thus in Germany?
Medicinal products that are to be placed on the market in Germany normally require marketing authorisation in accordance with medicinal product legislation. In Germany, the Ordinance Assuring the Supply of Products for Medical Needs (MedBVSV) permits a nationwide exception in the epidemic situation defined by the Bundestag on 28 March 2020. Medicinal products urgently needed in the SARS-CoV-2 epidemic can be procured and supplied by the Federal Ministry of Health. The Paul-Ehrlich-Institut’s assessment was included in the decision by the Federal Ministry of Health (BMG) on procurement and marketing. With regard to the aforementioned antibodies, the Paul-Ehrlich-Institut had determined, as specified in the Ordinance, that their quality was guaranteed and that, based on the findings of medical science, it was anticipated that their use would represent a positive risk-benefit ratio for the prevention or treatment of COVID-19.
Can bamlanivimab or casirivimab/imdevimab be used to treat patients who have been hospitalised for severe COVID-19?
In patients who were already treated in hospital for COVID-19, no benefit was observed for treatment with bamlanivimab or casirivimab/imdevimab. For this reason, these monoclonal antibodies should not be used in patients who
- are hospitalised because of a serious course of COVID-19;
- are receiving oxygen treatment for COVID-19;
- show a COVID-19 related increased requirement for oxygen during chronic oxygen therapy due to a pre-existing co-morbidity.
Can bamlanivimab or casirivimab/imdevimab be administered by GPs?
The application can be outpatient or inpatient in the hospital or outside the hospital (outreach treatment). Use in nursing homes or homes for the disabled may also be considered. It must be ensured that any severe allergic reactions and other side effects that may occur can be treated quickly.
What risks are associated with treatment with bamlanivimab or casirivimab/imdevimab?
Adverse reactions associated with any intravenous infusion, i.e. the administration of a medicinal product via a vein, may include short-term injection pain, bleeding, bruising, pain, swelling and possible infection at the infusion site. Monoclonal antibodies may cause allergic or infusion-related reactions.
The tolerability of bamlanivimab and casirivimab/imdevimab is currently being investigated in clinical trials. Apart from the infusion-related reactions mentioned above, no adverse drug reactions have so far been identified.
How should suspected adverse reactions to bamlanivimab or casirivimab/imdevimab be reported?
The Paul-Ehrlich-Institut receives reports of suspected adverse reactions online via www.nebenwirkungen.bund.de. Healthcare professionals can also contact the Paul-Ehrlich-Institut directly by email on firstname.lastname@example.org.
Suspension Vaccination AstraZeneca
Why is the COVID-19 Vaccine from AstraZeneca called Vaxzevria now?
The COVID-19 vaccine was given the permanent trade name Vaxzevria on 25 March 2021. This change was performed by the manufacturer, AstraZeneca, and this is normal in common trademark practice. The name change has no effect on the composition, nor the quality of the vaccine. The vaccine remains the same. The complete changeover to the name Vaxzevria (e. g. on the external package material) will take a few months.
The original name of the vector vaccine by AstraZeneca was ChAdOx1. ChAd stands for chimpanzee adenovirus, which serves as a vector. Ox is the abbreviation for the University of Oxford, which initially developed the vaccine. In spring 2020, Oxford University started a partnership with the manufacturer, AstraZeneca to develop this COVID-19 vaccine product. AstraZeneca gave the vaccine the name AZD1222 in accordance with its internal naming convention for vaccines under development. The vaccine was authorised under the name COVID-19 Vaccine AstraZeneca.
Can persons who previously received their first vaccination with the COVID-19 vaccine Vaxzevria by AstraZeneca now receive a different vaccine?
This depends on their age.
Persons of 60 years of age can also receive their second vaccination with Vaxzevria.
For persons under 60 years of age who received a dose of COVID-19 vaccine Vaxzevria by AstraZeneca, the STIKO (Ständige Impfkommission, Standing Vaccination Committee), currently recommends an mRNA vaccine for their second vaccination twelve weeks after the first one.
What must persons who received COVID-19 vaccine Vaxzevria pay attention to?
Those who develop continued headache or discover punctiform skin bleeding four to 16 days after a vaccination with COVID-19 vaccine Vaxzevria from AstraZeneca should seek medical treatment as soon as possible. This is important from the point of view of risk prevention, since this could be a very rare adverse effect. All persons vaccinated with Vaxzevria should pay attention to possible signs of this adverse effect, even if the likely-hood of such an adverse effect occurring is very low.
Why was vaccinating with the COVID-19 vaccine Vaxzevria from AstraZeneca temporarily put on hold in March 2021?
The vaccination with Vaxzevria was put on hold from 15 March 2021 to 19 March 2021, because, during its continued safety monitoring, the Paul-Ehrlich-Institut observed a particular type of vein thrombosis in the brain (sinus vein thrombosis, SVT) in temporal connection with the Vaxzevria vaccination combined with low platelet count (thrombocytopenia), and bleeding. These reactions occurred very seldom but statistically more frequently than to be expected when compared with the general incidence, if a vaccination had not been performed. The regular safety reports on the tolerability of the COVID-19 vaccines show the number of cases of SVT reported to the Paul-Ehrlich-Institut after a vaccination with Vaxzevria.
The Pharmacovigilance Risk Assessment Committee (PRAC) at the European Medicines Agency (EMA) has used these reports, including reports from other EU member states, for an EU-wide safety assessment and, as a result, has confirmed the favourable risk/benefit ratio of Vaxzevria. To minimise the risk, a warning was included in the Summary of Product Characteristics and the package leaflet that particular types of thromboses can occur in very rare cases during the period of up to 16 days after the vaccination.
Following this, the Standing Vaccination Committee (Ständige Impfkommission, STIKO) at the Robert Koch-Institut has adapted its recommendations for vaccinations with Vaxzevria.
Why did the Paul-Ehrlich-Institut recommend the temporary putting on hold of the use of this vaccine?
By 15 March 2021, the Paul-Ehrlich-Institut had received seven reports in which a particular type of serious vein thromboses of the brain in connection with low platelet count (thrombocytopenia), and bleeding ware found in temporal relation with a vaccination with the COVID-19 vaccine. This is a very serious medical condition, which is difficult to treat.
Out of the seven persons affected, three had died at that point. Six had a particular type of vein thrombosis of the brain, i. e. sinus vein thromboses. These six persons were young to middle-aged women (between 20 and 50 years of age). Another case with brain haemorrhage combined with low platelet count and thromboses was medically well comparable. All four cases occurred between four and 16 days after a vaccination with the COVID-19 vaccine Vaxzevria from AstraZeneca.
The number of these cases after a vaccination with Vaxzevria was statistically significantly higher than the number of vein thromboses of the brain, which normally occurs in the comparable number of persons in the unvaccinated population. These findings resulted in a so-called observed-versus-expected analysis, in which the number of cases within a period of 14 days expected without a vaccination was compared with the number of cases reported after 1.6 million Vaxzevria vaccinations in Germany. About one case would have been the number to be expected. However, seven were reported.
In addition to the experts of the Paul-Ehrlich-Institut, some additional experts for thromboses and haematology, and one adenovirus specialist were included in the analysis of cases reported. All experts agreed that, for these cases, a pattern was recognisable, and that a relationship of the above-mentioned cases reported with the Vaxzevria vaccination would be plausible.
Against the background of all findings and various discussions, the Paul-Ehrlich-Institut suggested to put vaccinations with the COVID-19 vaccine Vaxzevria temporarily on hold to analyse the cases further. The Federal Ministry of Health (Bundesministerium für Gesundheit, BMG) followed this suggestion.
Why have vaccinations with Vaxzevria from AstraZeneca been resumed in Germany?
After the indication of a risk of a particular type of serious vein thromboses of the brain combined with low platelet counts (thrombocytopenia), and bleeding, a safety assessment was performed by the Pharmacovigilance Risk Assessment Committee (PRAC) at the European Medicines Agency, EMA). The expert group confirmed the favourable risk/benefit ratio of Vaxzevria. To minimise the risk, a warning was included in the Summary of Product Characteristics and the package leaflet that particular thromboses were found in very rare cases during a period of up to 16 days after the vaccination. Based on the favourable safety assessment by the EMA, vaccinations with Vaxzevria were resumed on 19 March 2021. Persons willing to receive a vaccination were informed on the newly identified risk during the information talk.
On Friday 12 March 2021, the vaccination with COVID-19 vaccination Vaxzevria from AstraZeneca was not yet put on halt, but from 15 March 2021 to 19 March 2021. What had changed since that Friday?
On Friday, 12 March 2021, the frequency of thromboses of the brain among the vaccinated persons was still within a range to be expected among the unvaccinated population. An important tool in pharmacovigilance – drug safety – is to examine whether an assumed adverse effect occurs more frequently within vaccinated populations than within unvaccinated populations (so-called observed-versus-expected analysis). If the frequency of an event is within that expected, this is more likely to speak in favour of an adverse effect occurring accidentally in temporal relation to the vaccination. If, however, the adverse reaction occurs statistically more frequently in the group of vaccinated populations, the latter must be considered as a risk signal, i. e. an event pointing to a possible causal relationship with the vaccination.
On Monday, 15 March 2021, additional cases of vein thrombosis of the brain were reported after a vaccination with COVID-19 vaccine Vaxzevria by AstraZeneca. Due to the additional cases, the number of cases observed was significantly higher than the number to be expected. After consultation with other external experts, the Paul-Ehrlich-Institut, in an overall conclusion based on the facts available, recommended a temporary putting on hold of the vaccinations with COVID-19 vaccine Vaxzevria from AstraZeneca. The Federal Ministry of Health (Bundesgesundheitsministerium, BMG) followed this recommendation.
Thromboses can also occur with the contraceptive pill. So why the worry in the case of the COVID-19 vaccine Vaxzevria from AstraZeneca?
It is correct that thromboses are known as a very rare adverse effect of the contraceptive pill, which can also be of fatal outcome. This adverse effect is included in the Summary of Product Characteristics. The contraceptive pill requires a prescription. All women must be informed on this risk by the prescribing doctor.
Before the reports on the occurrence of the very rare vein thromboses of the brain in connection with the vaccination against COVID-19 from AstraZeneca, this risk was unknown. Accordingly, information on this risk could not be provided. Meanwhile, Section 4.8. of the Summary of Product Characteristics for Vaxzevria has been completed by a warning concerning the very rare adverse effect of a sinus vein thrombosis accompanied by low platelet counts. The Standing Vaccination Committee (Ständige Impfkommission, STIKO) at the Robert Koch-Institut has adjusted the vaccination recommendation corresponding to the finding. That way, vaccinating doctors can inform persons willing to receive a vaccination on the possible risks and alternatives during the information talk.
Safety and Efficacy (As of 31 March 2021)
Who is responsible for the evaluation and monitoring of vaccines (vaccine safety)?
In Germany, the Paul-Ehrlich-Institut is responsible for the authorisation of vaccines, i.e. the evaluation of quality, efficacy and safety 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.
The expertise for the assessment of individually occurring adverse reactions after vaccinations lies with the Paul-Ehrlich-Institut. After a vaccine has been licensed, all reports of suspected adverse reactions or vaccine complications are continuously recorded and evaluated. The Paul-Ehrlich-Institut publishes weekly safety reports on reported suspected cases in Germany following vaccination against COVID-19.
Specific questions beyond the safety report will be answered by the Paul-Ehrlich-Institut at email@example.com.
On how many people were the COVID-19 vaccines tested before they were granted the marketing authorisation in Europe?
At the time at which the COVID-19 mRNA vaccine Comirnaty and the COVID-19 Vaccine Moderna were authorised for use in Europe, 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 took part.
For the vector vaccine COVID-19 Vaccine AstraZeneca, data were available at the time of the marketing authorisation on the efficacy in around 6,000 vaccinated persons (around 12,000 study subjects) from the phase 2/3 studies.
For the analysis of safety after vaccination, data from more than 20,000 study participants (including around 10,000 vaccinated persons) was evaluated; this data covered a period of up to around two months after the second dose.
How is the efficacy of a COVID-19 vaccine determined?
During the clinical trial, the study participants are assigned randomly to one of two groups. 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.
At the time of marketing authorisation, Comirnaty had an efficacy of 95% against COVID-19 (95% confidence interval: 90.0% – 97.9%) based on 170 cases of COVID-19 (8 in the vaccine group, 162 in the placebo group) in study participants who tested positive for SARS-CoV-2 at least seven days after the second vaccination. An efficacy of 94 percent (95% confidence interval: 89.3 – 96.8%) against COVID-19 was calculated at the time of the marketing authorisation for COVID-19 Vaccine Moderna based on 196 COVID-19 cases tested positive for COVID-19, 14 days after the second vaccination. These particiants included 11 in the vaccine group and 185 in the placebo group.
The efficacy was comparable in all age groups, although the over 75-year-old group was small in both phase 3 studies (4.4%). There were also no indications in subgroup analyses of any differences in efficacy with regard to gender or ethnicity.
Have any safety steps been omitted during testing in order to speed up marketing authorisation?
For the marketing authorisation of Comirnaty and COVID-19 Vaccine Moderna, all the tests relevant to an assessment of the safety of the vaccines were carried out. For COVID-19 Vaccine AstraZeneca, experimental studies in animals on reproductive and developmental toxicity were not completed at the time of the marketing authorisation. A preliminary study on reproductive toxicity in mice did not show any signs of toxicity. Long-term data on vaccine safety will be collected in further clinical studies. The quality, safety and efficacy of every single vaccine product must be ensured before a vaccine can receive marketing authorisation.
The current approvals for Comirnaty, COVID-19 Vaccine Moderna and COVID-19 Vaccine AstraZeneca are conditional marketing authorisations (CMA). This means that on certain dates after the marketing authorisation, additional data (e.g. with reference to the follow-up monitoring of the vaccinated persons) 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 clear criteria with regard to which conditions must be met before marketing authorisation can be issued for a COVID-19 vaccine. This includes in particular a clinical efficacy significantly in excess of 50% with a lower confidence interval limit of 20 to 30, safety for at least six weeks after vaccination and the follow-up monitoring of safety and efficacy after marketing authorisation.
Are the COVID-19 vaccines safe, even though they have been developed so quickly?
The short development time for the current COVID-19 vaccine candidates was possible thanks to a number of factors:
- Knowledge of the potentially protective antigen from previous work on vaccines for SARS-CoV in 2002/2003 and MERS-CoV
- New vaccine technologies
- Some 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 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 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).
The clinical trials of the vaccines included at least 30,000 study participants. This allowed extensive information to be gained on the safety and efficacy of the vaccines.
Between 20,000 and up to more than 35,000 study participants were evaluated for the marketing authorisation of the COVID-19 vaccines. This has provided comprehensive information on the safety and efficacy of the vaccines.
When Comirnaty, COVID-19 Vaccine Moderna and COVID-19 Vaccine AstraZeneca received marketing authorisation, information on safety and tolerability was available for a period of at least two months after the second vaccination.
The follow-up monitoring of the study participants does not end with marketing authorisation. They will continue to be monitored for a period of up to two years. 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 potential or very rare adverse reactions can be recorded at the time of marketing authorisation. For this reason, the safety of vaccines, like that of other new 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.
Are all the adverse reactions to the COVID-19 vaccines known at the time of marketing authorisation?
Experience with a large number of vaccines over many years has shown that most adverse reactions occur shortly after vaccination. Thanks to the large number of participants in the clinical trials of the COVID-19 vaccines (> 10,000 vaccinated persons), we can assume that it would have been possible to detect even rare adverse reactions during the observation period. However, these medicinal products will continue to be actively monitored even after marketing authorisation so that ever more knowledge can be gained, including with regard to their long-term safety in the various population groups.
How high is the risk of mRNA vaccines becoming integrated into the genome?
There is no discernible risk of the mRNA becoming integrated into the human genome. The genome, which consists of DNA, is located in the cell nucleus, which the mRNA normally does not penetrate. In addition, the mRNA would first have to be transcribed into DNA in the cell, as RNA itself cannot integrate into the human genome, which is made up of DNA. This would only be possible if specific virus proteins were present at the same time; these proteins would have to transcribe the vaccine mRNA into DNA, then transport this DNA into the cell nucleus, where it would in turn be integrated into the genome by means of a virus protein. This is an extremely unlikely and hitherto unobserved sequence of reactions. In addition, the mRNA is only present in the cells of the vaccinated person temporarily, before being broken down intracellularly.
Why do the mRNA vaccines authorised contain lipid nanoparticles?
The currently authorised COVID-19 mRNA vaccines – Comirnaty and COVID-19 Vaccine Moderna – contain lipid particles in which the mRNA is encapsulated. On account of their size (< 100 nm), they are also referred to as lipid nanoparticles (LNPs). When using the term “particle”, however, it should be noted that these are not non-degradable solid particles (metals, plastics etc.), but rather fat globules that, like biological cell membranes, are made up of a phospholipid layer. They act as carriers and protect the otherwise unstable mRNA. Above all, however, they ensure that the mRNA is absorbed into the cells after vaccination (especially around the injection site) and is then released within the cell where the mRNA is to be transcribed.
What do we know about the safety of lipid nanoparticles in mRNA vaccines?
Lipid nanoparticles (LNPs) are similar to the liposomes (fat cells) that have been used for over 20 years as delivery mechanisms for medicinal products (e.g. Myocet liposomal, Caelyx pegylated liposomal, DaunoXome, AmBisome). In another authorised medicinal product, therapeutic RNA molecules are encapsulated in very similar LNPs (Onpattro). With these medicinal products, significantly higher amounts of lipids are administered intravenously compared to vaccination. There have also been authorised vaccines with a similar structure, called “virosomal vaccines”, e.g. Epaxal for hepatitis A or Inflexal for influenza. Virosomes are also phospholipid vesicles that carry viral envelope proteins on their surface. We have many years of experience with these vaccines and they have a good safety profile. At present, they are no longer on the market, but this is not the result of safety concerns.
As with biological membranes, the structure of LNPs is formed by phospholipids with cholesterol stored in them. The various LNPs also contain other lipid components that impart special characteristics. As all lipids are identical or very similar to the body’s own lipids, LNPs are considered to be “biodegradable”, i.e. it may be assumed that, similar to dietary lipids, they are broken down in the body enzymatically and are largely incorporated into the body’s own fat metabolism.
The potential toxicity of each of these novel vaccine preparations was tested in preclinical toxicity tests prior to marketing authorisation.
Are there any indications of the development of vaccine-associated enhanced COVID-19 disease (VAED)?
Clinical trials with mRNA vaccines suggest that there are no indications whatsoever of an enhanced COVID-19 disease in vaccinated persons. Studies of animals of various species that were infected with SARS-CoV-2 after vaccination have also shown no signs of a VAED.
The concern surrounding a potential VAED is based on animal experimental data for other betacoronaviruses, in which abnormal (pathological) immune phenomena were seen after vaccination with other (non-mRNA) vaccines and subsequent infection with SARS or MERS viruses, but without any SARS or MERS illness being detected in the animals. In the 1960s, enhanced illness with human respiratory syncytial virus (RSV) with signs of inflammation was also seen in young children who had been vaccinated with an inactivated vaccine against RSV.
Furthermore, in many COVID-19 vaccines the antigen has been optimised in such a way that it counteracts a theoretically possible VAED (optimised spike protein variant in the stabilised prefusion conformation).
Do the vaccines contain microchips/nanochips?
No. All ingredients are listed in the relevant Summary of Product Characteristics (SmPC).
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)
Are there any indications that the newly authorised COVID-19 vaccines trigger autoimmune diseases?
No. In the extensive clinical trials carried out prior to the marketing authorisation of the vaccines, there were no indications of autoimmune diseases. Nonetheless, special attention will also be devoted to this theoretical risk after marketing authorisation within the framework of pharmacovigilance.
How is the safety of the vaccines monitored after marketing authorisation?
At the time of the first marketing authorisation, our knowledge of the safety of the COVID-19 vaccines is naturally incomplete, because in clinical trials both the duration of the follow-up monitoring and the number of vaccinated persons are limited. It is possible that not all the rare or very rare adverse effects associated with administration of the vaccine have been identified in the clinical trials. They are, however, of great importance for the overall evaluation of a new vaccine. In general, new knowledge about the safety of vaccines, especially with regard to very rare occurrences, can be obtained even a long time after marketing authorisation – as is the case with all vaccines. For this reason, experts in the safety of medicinal products (pharmacovigilance) never stop monitoring the vaccines, even after marketing authorisation.
Routine pharmacovigilance measures after marketing authorisation include the recording and evaluation of reports of suspected vaccination complications or adverse reactions to vaccination. These reports are recorded and evaluated centrally both at the Paul-Ehrlich-Institut and in the EudraVigilance database for the whole of Europe. In this connection, the marketing authorisation holder must regularly prepare safety reports, which are assessed jointly by the various marketing authorisation agencies in the European Union. As part of marketing authorisation, the marketing authorisation holder must submit “risk management plans”, which summarise what is known – and what is not yet known – about the safety of the vaccines. In addition, it must describe precisely the measures that will be used to fill the remaining gaps in knowledge – e.g. further studies after marketing authorisation – and in what timeframe this will be achieved. These gaps in knowledge may, for example, relate to safety in particular groups of people who were not represented sufficiently in the clinical trials.
In the case of the COVID-19 vaccines, the Paul-Ehrlich-Institut is also carrying out additional studies. This includes a study using the SafeVac 2.0 smartphone app, which will be used to further investigate the tolerability of the individual COVID-19 vaccine products. Participation in the app-based study is voluntary.
When does vaccination protection begin with the authorised vaccines?
In the clinical trials for authorising the respective vaccines, the complete vaccination protection from a COVID-19 infection was established seven to fifteen days after the second vaccination. However, some vaccination protection was seen with all vaccines after the first vaccination.
It is not yet certain whether vaccination protection for vaccinated persons also means that they cannot transmit the virus to non-vaccinated people. Therefore, even after being vaccinated, you must still protect yourself and the people around you by observing the corona protection rules (maintain social distancing, wash your hands, wear a face covering, use the Corona Warning App, and ensure adequate ventilation).
What vaccination reactions may occur after a vaccination with the authorised COVID-19 vaccines?
After vaccination with the authorised COVID-19 vaccines, local and general symptoms may occur as the body is attempting to react to the vaccine. These reactions generally occur within two days of vaccination and rarely last for longer than one or two days. Based on different study designs, a direct comparison between the frequencies of reactions determined in clinical trials is very difficult. For this reason, observations for all authorised vaccines are presented separately.
In the clinical trials for the marketing authorisation of Comirnaty, vaccinated persons (> 16 years of age) very commonly reported pain at the injection site (> 80% of those vaccinated), fatigue (> 60%), headache (> 50%), muscle pain and chills (> 30%), joint pain (> 20%), swelling at the injection site and fever (> 10%). Vomiting was common (> 1%), swelling of the lymph nodes was uncommon (less than 1%).
For COVID-19 Vaccine Moderna, the reactions in vaccinated persons (>18 years) reported most frequently included pain at the injection site (>90%), fatigue (70%), head and muscle pain (>60%), joint ache and chills (>40%), malaise or vomiting (<20%), swelling of the lymph nodes in the arm pit, fever, swelling and redness at the injection site (each >10%). A general rash or rash and hives at the injection site were frequently reported. Occasionally (between 0.1% and 1%), itching occurred at the injection site.
For COVID-19 Vaccine AstraZeneca, the most frequently reported vaccination reactions in vaccinated persons (>18 years) included sensitivity to palpation at the injection site (> 60%), pain at the injection site, headache and fatigue (>50 %), muscle pain and malaise (> 40%), febrile sensations and chills (>30%), bone ache and sickness (>20%). Frequent adverse effects (between 1% and 10%) included fever > 38°C, swelling and redness at the injection site, sickness and vomiting. Occasionally (between 0.1% and 1%) were swelling of the lymph node, itching, or skin rash were reported.
Most of the reactions were slightly less common in older people than in younger people. The vaccination reactions were mostly mild or moderate in intensity. In the case of the COVID-19 mRNA vaccines, they occurred somewhat more frequently after the second vaccination. Contrary to this, in the clinical studies on COVID-19 Vaccine AstraZeneca, the adverse effects reported after the second dose (above all fever, malaise, chills) were significantly milder and less frequent than after the first.
In the extensive clinical trials prior to marketing authorisation, four cases or three cases of acute facial paralysis (Bell’s palsy) were observed after administration of Comirnaty and COVID-19 Vaccine Moderna, respectively (compared with 1 case in the control group of unvaccinated persons) (corresponding to a frequency between 0.1% and 0.01%). Whether there is a causal connection of this event with the vaccination is currently the subject of further investigation for each vaccine. Bell’s palsy generally resolves completely in 85% of affected patients.
Isolated cases of severe hypersensitivity reactions (anaphylaxis) after vaccinations with Comirnaty and COVID-19 Vaccine Moderna were reported shortly after marketing authorisation. There were no cases of anaphylaxis in the clinical trials.
As a precautionary measure, the vaccinating doctors should be equipped for any emergency measures. It is recommended that vaccinated persons should be monitored for at least 15 minutes after vaccination.
What is the risk of allergic reactions after vaccination with the authorised vaccines?
Allergic reactions can occur with vaccinations, as after the use of all medicinal products. These include both local hypersensitivity reactions and, in very rare cases, serious, potentially life-threatening immediate reactions (anaphylaxis), which require immediate medical attention. The incidence of anaphylactic reactions following vaccinations of children, adolescents and adults with vaccines other than COVID-19 is reported to be 1 to 10 per 100,000 vaccine doses, depending on the study and vaccine.
While isolated hypersensitivity reactions but no anaphylaxis were observed in the pivotal studies of Comirnaty, COVID-19 Vaccine Moderna, and Vaxzevria (formerly COVID-19 Vaccine AstraZeneca), cases of severe hypersensitivity reactions (anaphylaxis) have also been reported in Germany (as previously in the United Kingdom and the United States) after vaccination with all three vaccines since vaccination with COVID-19 vaccines began. This should be seen against the background that in Germany alone, a significantly higher number of people have already been vaccinated in a short time than in the studies for approval. Up to and including 12 March 2021, the Paul-Ehrlich-Institut has evaluated a total of 99 suspected cases from Germany on the basis of 8.9 million vaccinations according to the internationally recognised anaphylaxis definition of the Brighton Collaboration with levels 1 to 3 of diagnostic (safety. Information on the suspected cases reported from Germany can be found in the regular safety reports of the Paul-Ehrlich-Institut. For the fourth vaccine approved in the EU (COVID-19 Vaccine Janssen), one case of anaphylaxis has occurred so far in a still ongoing clinical trial. The vaccine has not yet been used in Germany.
It is unclear to date which component(s) of the COVID-19 vaccines could be responsible for the reported anaphylactic reactions. After the administration of Comirnaty and COVID-19 Vaccine Moderna, the lipid nanoparticles contained in the vaccine, especially the polyethylene glycol (PEG) contained therein in bound form, are considered as triggering agents for hypersensitivity reactions. The vector vaccines from AstraZeneca and Janssen-Cilag contain small amounts of polysorbate 80 as an adjuvant, which also has PEG moieties in the molecule. However, many other vaccines also contain polysorbate 80 as a stabiliser (e.g., influenza, hepatitis A, or HPV vaccines such as Fluarix, Havrix, Gardasil), and reports of IgE-mediated reactions to polysorbates in drugs are an absolute rarity overall.
In the summaries of product characteristics (SmPCs) of the mRNA vaccines and the vector vaccine COVID-19 vaccine Janssen, anaphylaxis is listed as a possible side effect. For AstraZeneca's vector vaccine (Vaxzevria), the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) has also recommended inclusion in the SmPC. For the vaccines to be administered twice (mRNA vaccines as well as Vaxzevria), there is an additional warning that a second dose of the vaccine should not be administered to individuals who have experienced anaphylaxis after the first dose. Only one vaccination is provided with the Janssen COVID-19 vaccine. The respective warning is thus not included for this product.
In the EU, there is no contraindication for people with allergies or a history of anaphylaxis for any of the four licensed COVID-19 vaccines. However, known allergies to ingredients contained in the vaccine are a contraindication to vaccination.
According to the technical information of all licensed COVID-19 vaccines, all vaccinated individuals should be followed up for at least 15 minutes after vaccination. Appropriate medical treatment and monitoring should always be available in the event of a severe allergic intolerance reaction following vaccine administration.
Anti-allergic premedication is not recommended, as possible initial symptoms of anaphylaxis may be masked and not noticed until after the follow-up period. In the worst case, treatment options for a life-threatening anaphylactic reaction are then not immediately available.
Specific recommendations for physicians on how to proceed in patients with a positive allergy history (known allergies in the past or an allergic reaction to the first COVID 19 mRNA vaccination) can be found in a flow chart prepared by the Paul-Ehrlich-Institut together with the Robert Koch Institute and in close cooperation with the allergological societies in Germany. It is available at the vaccination centers and can be accessed on the website of the Paul-Ehrlich- Institut.
As of 25 March 2021
Flowchart - Procedure in case of positive allergy history before COVID-19 mRNA vaccination (German only)
Statement by the Paul-Ehrlich-Institut – Recommendation on the coronavirus vaccination of allergy sufferers
Safety reports on COVID-19 vaccines
Meeting highlights from the Pharmakovigilance Risk Assessment Committee (PRAC) 8-11 March 2021
Can COVID-19 mRNA vaccines affect fertility?
There is no evidence from the non-clinical studies of the authorised mRNA-COVID-19 vaccines Comirnaty and COVID-19 Vaccine Moderna 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).
Is there a risk that the DNA from vector vaccines such as the COVID-19 vaccine from AstraZeneca can be integrated into the human genome?
The COVID-19 vaccine consists of an innocuous virus from the family of adenoviruses (cold viruses) from chimpanzees (adenoviral vectors). This virus does not replicate in humans. The genome of the vector was modified in such a way that it contains the gene with the blueprint for the production of an optimised surface protein of SARS Coronavirus-2, the spike protein. The human body has regular contact with adenoviruses – “common cold viruses”. Even in the case of a natural infection with adenoviruses, no genetic changes have so far been observed in human cells. 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 of infected cells.
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.
Can COVID-19 vaccination with an mRNA or a vector vaccine cause damaging cell fusions?
The answer is clearly no.
In the meantime, it is known that the spike protein of Coronavirus SARS-CoV-2, when in contact with human cells, causes the cells to fuse with neighbouring ones and partly die. Such fused cells were found in lungs of patients who had died of COVID-19.
With these findings, the question arose whether vaccines causing the formation of spike proteins might also cause such membrane fusions.
When the COVID-19 vaccines available in Germany (mRNA vaccines or vector vaccines) are used, few body cells receive foreign genetic information at one single time. This information consists of mRNA (mRNA vaccines) or DNA transmitted by harmless cold vaccines (vector vaccines). The genetic information is translated into protein by the cells affected. The cells generate the spike protein of Coronavirus SARS-CoV-2. Since the vaccines do not replicate, unlike the Coronavirus SARS-CoV-2, the amount of spike protein will remain small and local. No clinical effects can be expected, because the number of cells, into which the genetic information for the formation of the spike protein is inserted by the vaccination, is so small.
Clinical studies in tens of thousands of vaccinated study participants have proofed the safety of the vaccines. The regular public safety updates by the Paul-Ehrlich-Institut do not include any evidence of such vaccination complications either.
Membrane fusion is a natural process used by the cells to transport material such as hormones, neurotransmitters, and waste to the desired destination. Viruses also use this process to enter new cells.
SafeVac 2.0 App
What is the SafeVac 2.0 app?
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.
Who developed the SafeVac 2.0 app?
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.
Can a vaccinated person who does not wish to take part in the SafeVac 2.0 app survey also report adverse reactions?
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.
What does participation in the SafeVac 2.0 study look like?
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.
What are the particular benefits of the SafeVac 2.0 app?
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.
When will it be possible to start using the SafeVac 2.0 app?
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.
Where can I download the SafeVac 2.0 app?
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.
I didn't succeed in entering the batch number of the vaccine into the SafeVac 2.0 app. What can I do?
Please check whether you have a stable internet connection via LTE or WIFI. This is a requirement, enabling you to get feedback to your smartphone when 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.
Antibody and Antigen Testing
Can the vaccination with COVID-19-mRNA vaccines lead to positive test results after rapid antigen tests or PCR tests?
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.
Why are rapid SARS-CoV-2 antigen tests not tested and certified before they are marketed, as is done with HIV tests?
Pursuant to the currently applicable EU Directive for in vitro diagnostic devices (IVD), tests for the human immunodeficiency virus (HIV) rank among the category of high risk products, and are therefore subject to the certification by a Notified Body. COVID-19 tests are currently still categorised as “low-risk IVDs”, and as such, can be certified by the manufacturers themselves. They do not require independent testing before they can be marketed. SARS-CoV-2 self tests are an exception to this. For these tests, it is required that a Notified Body reviews certain aspects or that the Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM) grants a special authorisation (see below).
The future IVD Directive, the implementation of which will be compulsory as from May 2022, requires an EU reference laboratory and a Notified Body to be consulted for the testing of SARS-CoV-2 tests. For this purpose, a laboratory assay and an independent verification of the data will be required for the tests.
The Paul-Ehrlich-Institut is preparing to apply for its role of one of the EU reference laboratories in order to review high risk tests in the laboratory.
The Paul-Ehrlich-Institut welcomes the classification of tests such as SARS-Co-2 antigen tests and their independent review und evaluation, as planned as from May 2022. This will increase the safety of and confidence in these in vitro diagnostic devices.
Both the Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM) and the Paul-Ehrlich-Institut (PEI) are mentioned as the authorities responsible for antigen tests. Who has which role?
- The Paul-Ehrlich-Institut in agreement with the Robert Koch-Institut (RKI) has laid down minimum criteria, which antigen tests must fulfil.
- The BfArM provides a list of all tests which, on the basis of the manufacturer’s information, fulfil the minimum criteria for antigen tests laid down by the Paul-Ehrlich-Institut. This list includes only those antigen tests, which have been reported to the BfArM by the appropriate manufacturer or distributor for inclusion into the list.
- The Paul-Ehrlich-Institut performs comparative experimental studies on the sensitivity of rapid SARS-CoV-2 antigen tests. Sensitivity is an indicator of how many of the infected persons are recognised correctly by the rapid antigen test. 80 percent sensitivity for example means that 80 out of 100 persons infected with Corona receive a positive and 20 percent a false negative result although they are infected. The Paul-Ehrlich-Institut does not examine the specificity of the tests. The specificity shows how successful the test is in identifying only those persons who are in fact positive. A 95 percent specificity would mean that out of 100 non infected persons, 95 percent are tested correctly as negative and five persons as false positive.
- The Paul-Ehrlich-lnstitut provides a list of tests which have previously been included in the evaluation and have been assessed appropriately in accordance with the state of the art. These examinations are continued, and the table is updated and completed accordingly.
- The tests which have been evaluated by the Paul-Ehrlich-Institut and fulfil the required criteria are marked appropriately on the list of the BfArM. Tests which do not fulfil the critera are removed from the list of the BfArM. Those tests marked with “No” in the list, have not yet been valididated.
- A special case are SARS-CoV-2 antigen tests for personal use – so-called self tests. They are granted a special authorisation: The BfArM currently permits them to be marketed temporarily without the CE mark pursuant to Section 11 paragraph 1 of the German Medical Devices Act (Medizinproduktegesetz, MPG). In addition to the quality of clinical detectability, the special authorisation is granted by the BfArM on the basis of whether the drawing of the sample and the testing are plausible based on the instructions in the package leaflet and can be performed by a lay person (this is, among other things, based on a positive evaluation by the Paul-Ehrlich- Institut).
Can a Pneumococcal Vaccination Help in the Case of COVID-19?
As a rule, an up-to-date vaccination protection is important. This is especially true in times of a pandemic. In Germany, the German Standing Committee on Vaccination (Ständige Impfkommission, STIKO) makes recommendations on which groups of people should receive vaccinations against particular infectious diseases.
Pneumococci are the most frequent cause of bacterial pneumonia. A pneumococ-cal vaccination does not prevent a virus infection such as SARS-CoV-2. However, if a pneumococcal infection occurs on top of this virus infection, the patient's body, which is already weakened, must fight an additional lung infection caused by a bacterium. This additional risk can be minimised by a pneumococcal vaccination.
Furthermore, by preventing a bacterial pneumonia, pneumococcal vaccination can help to ensure that urgently needed capacities (such as ventilation sites) are available for patients with severe COVID-19 progression.
Who should Receive a Vaccination against Pneumococci?
The German Standing Committee on Vaccination (Ständige Impfkommission, STIKO) has adjusted their recommendations regarding the pneumococcal vaccination during the current pandemic. Seniors of 70 years and older as well as persons with particular underlying diseases have been requested to have themselves vaccinated against pneumococci, since persons in this age group have an increased risk of SARS-CoV-2 infection. Besides, the vaccination of infants and young children up to the age of 2 years is recommended.
Are Pneumococcal Vaccines Available or are there Supply Shortages?
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.
Where can I get Information about a Participation in the Clinical Trial of the COVID-19 Vaccine?
In Germany, the Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, authorises clinical trials of vaccines and approves the trials if the data situation is positive. The Paul-Ehrlich-Institut is not involved in the recruitment of study participants. This is the responsibility of the respective applicant, who has the relevant information (e.g. place of performance).
Is it possible to use Animal Vaccines against Corona Viruses in Humans?
No, it is not possible to use animal vaccines in humans.
The animal vaccines authorised against coronaviruses contain antigens of viruses that belong to the large family of coronaviruses, but are clearly different from the SARS-CoV-2 pathogen. Therefore, if administered, no protective effect against SARS-CoV-2 would be expected.
There are no data on the safety and efficacy of animal vaccines against coronaviruses when used in humans. Furthermore, the different types of coronaviruses show different clinical pictures and infect different species.
Veterinary medicinal products are not authorised for use in humans, which means that safety has not been assessed in this respect. The Paul-Ehrlich-Institut strongly advises against experimental use in humans.
Where do I Find Further Reliable Information on the Coronavirus?
If people base their behaviour in dealing with the Coronavirus on false information, disinformation and misinformation can become a risk. Especially social networks spread fake news. For this reason, it is important to obtain information from reliable sources.
- 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
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