FAQ - Frequently Asked Questions
Coronavirus SARS-CoV-2 / COVID-19
Development and Authorisation
Have any human mRNA vaccines already been granted a marketing authorisation?
Two vaccines against COVID-19 are currently authorised. In addition clinical trials are currently ongoing for several vaccine candidates, in particular for therapeutic vaccines against cancer diseases.
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.
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.
The current view of the Paul-Ehrlich-Institut is that a conditional marketing authorisation for COVID-19 vaccines will be possible in Europe.
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.
The current view of the Paul-Ehrlich-Institut is that a conditional marketing authorisation for COVID-19 vaccines will be possible in Europe. 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.
What are the steps in developing a vaccine against a new unknown virus?
At first, the pathogen is analysed. Besides, tests are carried out to identify the components of the virus to which the human immune system reacts so that it can confer protection (including antibodies) against the virus. After that, a vaccine design is developed – which vaccine platform is suitable and which excipients are required? The efficacy and tolerability of the vaccine candidate are then tested in cell cultures (e.g. with human immune cells) and in animal experiments. Only after extensive tests and providing proof that the vaccine can be manufactured reliably in good quality it will be tested in clinical trials of Phase 1 to Phase 3 after the healthy volunteers have given their informed consent. As soon as all results of the preclinical and clinical studies are available, a marketing authorisation can be submitted. For Europe, the co-ordinating body for the marketing authorisation of COVID-19 vaccines is the European Medicines Agency (EMA). The assessment for the EMA is performed by experts of national medicines authorities in Europe. If the vaccine fulfils all the requirements and its benefits both for individuals and for public health outweigh the risks, a recommendation for a marketing authorisation will be made by the European Commission after a successful marketing authorisation procedure, which takes several months. The vaccine can then be marketed for human use. Recommendations for the vaccination against an infectious disease are given by the Standing Vaccination Committee (STIKO) at the Robert Koch-Institute, in which the Paul-Ehrlich-Institut is represented as guest expert.
Will a clinical trial in germany also be followed by a marketing authorisation of germany?
mRNA 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 co-ordinated by the European Medicines Agency (EMA). Two member states can be chosen as rapporteur and co-rapporteur for preparing the assessment report. The Paul-Ehrlich-Institut often assumes such a role in the marketing authorisation procedure.
Batch Release Testing
What is the legal basis for batch testing in Germany?
In accordance with Section 32 of the German Medicinal Products Act (Arzneimittelgesetz, AMG) – "Official batch testing" – a batch (a production unit) of a vaccine may only be marketed in Germany if it has been tested and released by the competent higher federal authority, i.e. the Paul-Ehrlich-Institut, the Federal Institute for Vaccines and Biomedicines.
What is examined during the batch release?
Checks are carried out to determine whether the batch has been manufactured and tested according to methods of manufacture and control which comply with the prevailing standard of scientific knowledge and the requirements specified in the marketing authorisation. The tests that are required for batch testing are specific to each vaccine product and are defined by the European Directorate for the Quality of Medicines & HealthCare (EDQM).
Does batch release have to be carried out by the Paul-Ehrlich-Institut?
Yes, batch release in Germany must be carried out by the Paul-Ehrlich-Institut. However, the Paul-Ehrlich-Institut does not necessarily also have to perform the batch testing. A batch can also be released if the competent authority of another member state of the European Union has determined that the requirements for batch release have been met, after an experimental investigation and after checking the data submitted by the pharmaceutical company regarding the manufacture and testing of the batch.
How can the Paul-Ehrlich-Institut test batches of novel mRNA vaccines? Surely it does not have any experience in the batch testing of mRNA vaccines?
The marketing authorisation documents define how the manufacturing process of the authorised vaccine product must be carried out and what controls must be performed during manufacture. Batch testing includes checking the submitted batch documentation for compliance with the requirements of the marketing authorisation and checking whether the required criteria have been met in the corresponding control testing.
The Paul-Ehrlich-Institut also conducts its own experimental testing of the mRNA vaccines. Even if the actual RNA platform is in fact novel for vaccines, the methods for testing RNA vaccines are not fundamentally anything new for the Paul-Ehrlich-Institut. As a result, the RNA vaccine-specific methods only needed to be adapted on the basis of the experimental expertise already available at the Paul-Ehrlich-Institut.
The tests that are required for batch testing are specific to each vaccine product and are defined by the European Directorate for the Quality of Medicines & HealthCare (EDQM).
How, in concrete terms, are mRNA vaccines tested experimentally?
During batch testing, the identity, quantity, concentration and integrity of the RNA contained in the vaccine are all examined. In addition, the proportion of RNA that is encapsulated in lipid particles is determined.
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
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.
Have any human mRNA vaccines already been granted a marketing authorisation?
Two vaccines against COVID-19 are currently authorised. In addition clinical trials are currently ongoing for several vaccine candidates, in particular for therapeutic vaccines against cancer diseases.
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.
App SafeVac 2.0
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.
Safety and Efficacy (As of 21 January 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.
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.
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 6,800 vaccinated persons (around 13,000 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.
How high is the risk of allergic reactions after vaccination with the authorised vaccines?
At the start of vaccinations with Comirnaty and COVID-19 Vaccine Moderna, cases of hypersensitivity reactions were reported. None of the participants in the studies reported on immediate life-threatening reactions (anaphylaxis) after either one of the vaccine doses.
It is not yet clear which component of the vaccine could have been responsible for the reported anaphylactic reactions. Experts are debating whether the polyethylene glycol (PEG) component in the lipid nanoparticles of either vaccines might be responsible.
Based on the currently available data, the Paul-Ehrlich-Institut does not believe that a generally increased risk of serious adverse effects for people with known atopic-allergic disorders (e.g. asthma, neurodermatitis and allergic rhinitis with conjunctivitis (rhinoconjunctivitis), including hay fever and dust mite allergy) can be derived from vaccination with Comirnaty or COVID-19 Vaccine Moderna.
Other than in the United Kingdom, for Comirnaty, in the EU there is no contraindication for allergy sufferers or people with a history of anaphylaxis for either of the vaccines. A reaction to the first dose of a COVID-19 vaccine or a previously known allergy to the ingredients it contains does, however, represent a contraindication for a further vaccination. Test procedures that could either predict or rule out the likely occurrence of a (pseudo-)allergic intolerance reaction to a COVID-19 vaccination are not available.
It is therefore recommended in the Summaries of Product Characteristics in the EU marketing authorisation for Comirnaty and COVID-19 Vaccine that all vaccinated persons should be observed for at least 15 minutes after vaccination. Appropriate medical treatment and supervision should always be readily available in case of a severe allergic intolerance reaction following administration of the vaccine.
Statement by the Paul-Ehrlich-Institut – Recommendation on the coronavirus vaccination of allergy sufferers
Expert discussion on anaphylactic reactions – Castells and Phillips, Maintaining Safety with SARS-CoV-2 Vaccines (NEJM, Dec 30, 2020)
Evaluation of all allergic reactions including anaphylaxis after the first dose of Comirnaty from the American database of adverse reactions (Morbidity and Mortality Weekly Report (MMWR) of 06.01.2021)
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.
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.
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