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 on a regular basis 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 received marketing authorisation in Europe?
At the time that the COVID-19 mRNA vaccines Comirnaty and COVID-19 Vaccine Moderna were authorised for use in 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 per vaccine product took part in the pivotal (decisive) clinical trial.
At the time that the vector vaccine Vaxzevria (COVID-19 Vaccine AstraZeneca) was authorised for use, data on efficacy was available from around 6,000 vaccinated persons (around 12,000 study participants) from the phase 2/3 studies.
At the time that the vector vaccine COVID-19 Vaccine Janssen was authorised for use, data on efficacy was available from around 19,000 vaccinated persons (around 39,000 study participants).
For the analysis of safety after vaccination, for all the authorised vaccines data from more than 20,000 study participants (including at least 8,000 fully vaccinated persons) was evaluated; this data covered a period of up to two months after the final dose.
How is the efficacy of a COVID-19 vaccine determined?
During the authorisation-related clinical trial of the safety and efficacy of a COVID-19 vaccine candidate, normally phase 3 or 2/3, the study participants are assigned randomly to one of two groups. One group is vaccinated with the vaccine candidate (the “verum group”), while the control group is given a placebo or another vaccine. Care is taken to ensure that both groups have a similar composition (e.g., in terms of age, gender etc.) and that there is a comparable risk of infection with SARS-CoV-2. The occurrence of a laboratory-confirmed symptomatic SARS-CoV-2 infection, i.e., illness with COVID-19, with effect from a specific point in time after vaccination is then recorded in both groups and the frequency is compared. A calculated efficacy of 90% means that the number of COVID-19 cases that occurred in the vaccinated group was reduced by 90% within a certain time compared to a non-vaccinated control group (e.g. n = 10 vs. 100 cases with groups of the same size).
How great is the efficacy of the COVID-19 vaccines?
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 laboratory-confirmed symptomatic SARS-CoV-2 infections (8 in the vaccine group, 162 in the placebo group) at least seven days after the second vaccination. At the time of marketing authorisation, COVID-19 Vaccine Moderna had an efficacy of 94% against COVID-19 (95% confidence interval: 89.3% – 96.8%) based on 196 laboratory-confirmed symptomatic SARS-CoV-2 infections (11 in the vaccine group, 185 in the placebo group) at least 14 days after the second vaccination.
The efficacy of the mRNA vaccines was comparable in all age groups, although the over 75-year-old group was small in both phase 3 trials (4.4% of all study participants ≥ 16 or 18 years of age). There were also no indications in subgroup analyses of any differences in efficacy with regard to gender or ethnicity.
In the context of marketing authorisation, the vector vaccine from AstraZeneca (Vaxzevria; COVID-19 Vaccine AstraZeneca) had an efficacy of 59% (95% confidence interval: 45.8% – 69.7%) based on 218 laboratory-confirmed symptomatic SARS-CoV-2 infections at least 15 days after the second vaccination among all participants ≥ 18 years of age from four studies (64 in all vaccine groups, 154 in the in the control groups vaccinated with a meningococcal vaccine or placebo). The time interval between the two vaccinations with the full dose was four to 12 weeks in the evaluated groups.
Two observational studies from England and Scotland have now proven that Vaxzevria (COVID-19 Vaccine AstraZeneca) provides a good protective effect after the first vaccination even in older people: In the group of over 80-year-olds, a protective effect of 60% against COVID-19 was shown to exist four weeks after the first vaccination (95% CI: 41-73), and 83% (95% CI: 72-89) against COVID-19-related hospital admission.
The second vector-based vaccine authorised in the EU (COVID-19 Vaccine Janssen) had an efficacy of 67% against COVID-19 (95% confidence interval: 59.0% – 73.4%) based on 464 laboratory-confirmed symptomatic SARS-CoV-2 infections among all participants ≥ 18 years of age (116 in the vaccine group, 348 in the placebo group) at least 14 days after the vaccination. The efficacy was comparable in all age groups, although the number of over 75-year-old study participants included in the phase 3 trial was small (3.8%).
The data presented are based on the authorisation data for the respective vaccines. Since then, new virus variants have arisen for which the efficacy of the vaccines may deviate from these data.
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. In the case of Vaxzevria (COVID-19 Vaccine AstraZeneca), animal studies on reproductive and developmental toxicity had not yet been completed at the time of marketing authorisation. A preliminary study on reproductive toxicity in mice showed no toxicity. Long-term data on vaccine safety will be collected in further clinical studies, which is one of the requirements for the conditional marketing authorisations (see below). The quality, safety and efficacy of every single vaccine product must be ensured before a vaccine product can receive marketing authorisation.
The current approvals for Comirnaty, COVID-19 Vaccine Moderna, Vaxzevria (COVID-19 Vaccine AstraZeneca) and COVID-19 Vaccine Janssen are conditional marketing authorisations. 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
- Application and further development of new vaccine technologies
- Some otherwise preclinical trials were carried out in parallel to clinical trials
- Performance of overlapping phase 1/2 and phase 2/3 trials
- Regulatory guidance through intensive and in some cases repeated scientific advice
- Rolling review at the Paul-Ehrlich-Institut and at the European Medicines Agency (EMA)
- High level of focus and generous financial support from the German Federal Government, the European Commission and global charitable foundations which also enabled large-scale manufacture to commence prior to marketing authorisation
- Worldwide cooperation, e.g. at the level of the WHO and the International Coalition of Medicines Regulatory Agencies (ICMRA)
- For the marketing authorisation of the COVID-19 vaccines, data was evaluated from between 20,000 and almost 40,000 study participants. This allowed extensive information to be gained on the safety and efficacy of the vaccines.
When Comirnaty, COVID-19 Vaccine Moderna, Vaxzevria (COVID-19 Vaccine AstraZeneca) and COVID-19 Vaccine Janssen 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 be actively monitored over a period of up to two years as part of the ongoing pivotal clinical trials. 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.
Do we need to fear long-term effects of vaccines that occur years after vaccination?
No. Side effects that occur years after a vaccination are not known with vaccines.
We know from decades of experience that most side effects occur within a few hours or a few days after a vaccination. In rare cases, vaccine side effects occur or are recognised only after weeks or a few months.
The COVID-19 vaccines currently authorised in Europe have been approved and in general use since late 2020 or early 2021. The first clinical trials were started 1.5 years ago. Since then, they have been vaccinated millions or even billions of times. These vaccines and their side effects are now well known - including very rare side effects.
What are long-term effects anyway?
There are two possibilities of what is meant by the term "long-term effects". Something that only occurs after a long time, or something that lasts over a long period of time.
A desirable long-term consequence of vaccination in the sense of a long-lasting effect is protection against infection or serious illness. For some people, this protection even lasts for life - for example, with the measles vaccination. For other vaccinations, such as against influenza - and according to the current status also against COVID-19 - booster vaccinations are necessary. Together, however, the vaccinations lead to continuous protection against the pathogen.
In individual cases, even very rare vaccination complications can last a long time, possibly years. However, this is the absolute exception. An example of such an extremely rare side effect with a long-term effect is the very rare occurrence of narcolepsy after vaccination against swine flu in 2009/2010 and is an absolute exception. Here, too, the first indications of this vaccination complication occurred only a few months after the start of the vaccinations.
Concerned citizens understand long-term consequences - often also called late effects - to mean side effects that occur only after a delay of many months or years after vaccination. These concerns are unjustified. We are not aware of such very late-onset side effects of vaccines.
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.
Do the vaccines contain microchips/nanochips?
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 COVID-19 vaccines?
In the clinical trials for the marketing authorisation of the respective vaccines, complete vaccination protection against COVID-19 was detected seven to fifteen days after the second vaccination or two weeks after the single vaccination with COVID-19 Vaccine Janssen. However, with all the vaccines a certain level of protection against COVID-19 was already evident after the first vaccination.
What vaccination reactions may occur after a vaccination with the authorised COVID-19 vaccines?
The safety of the vaccines has been examined intensively as part of the authorisation process. Information on the frequency and type of side-effect(s) observed and vaccine complications can be found in the relevant technical information (section 4.8).
The safety of vaccines is continually monitored even after authorisation. If new findings arise, the technical information is updated accordingly. Possible expected vaccine reactions and knowledge about possible rare vaccine complications are also stated in the information leaflet that is given to people receiving the vaccine before vaccination for the respective vaccine as part of the information they receive (see further information).
Should allergy sufferers be vaccinated?
According to current knowledge, allergy sufferers or people who have already experienced a severe allergic reaction (anaphylaxis) can be vaccinated against COVID-19 with all authorised vaccines. There is no increased risk of serious adverse effects. An exception is a pre-existing allergy to an ingredient of the specific COVID-19 vaccine or a severe intolerance reaction to previous administration of the COVID-19 vaccine. In this case, allergological clarification is recommended and it is usually possible to switch to another COVID-19 vaccine.
As a general rule, severe allergic reactions can occur in very rare cases with all vaccines. Therefore, each person should be observed for 15 minutes after vaccination so that they can receive appropriate medical treatment in the event of an allergic reaction. If the person to be vaccinated has a history of anaphylaxis or severe allergic reactions following administration of medication or other vaccines, the observation time will be increased to 30 minutes if necessary.
It is not recommended to take anti-allergic drugs before vaccination, as a possible allergic reaction could be delayed and occur outside the monitoring period of 15 or 30 minutes.
In the rare case of a severe anaphylactic reaction after the first or second dose of vaccine, a further dose should not be administered.
Can COVID-19 mRNA vaccines affect fertility?
There is no evidence from the non-clinical studies of the authorised mRNA-COVID-19 vaccines 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.
What are infection-dependent antibodies (ADE)?
Infection-enhancing antibodies (Antibody-Dependent Enhancement, ADE) bind to the surface of viruses but do not neutralise them. Instead, they facilitate the uptake of the virus into the cell and enhance the infection.
The possibility of ADE formation is generally addressed early in vaccine development in both non-clinical trials and clinical trials.
One viral infection in which ADE is occasionally observed is the dengue virus infection. After an initial infection that usually runs uncomplicatedly, the second infection occasionally leads to a severe course that is attributed to ADE. Such amplifications of infection by antibodies can also be induced by the dengue vaccine Dengvaxia when vaccinating people who have no previous immunity to dengue viruses. Therefore, the vaccine is only authorised for use in people who have been infected with dengue virus in the past and live in endemic areas.
Are infection-amplifying antibodies (ADE) a potential problem with COVID-19 vaccines?
So far, there is no evidence of the presence of ADE-induced amplification of infection, either in animal models of SARS-CoV-2 infection, in COVID-19 recovered people or in SARS-CoV-2 infected people. Scientists, including those in the clinical field, continue to closely monitor SARS-CoV-2 infections in vaccinated and recovered individuals. From the beginning of COVID-19 vaccine development, the question of ADE development has been under intense investigation, as there was evidence of ADE development in the preclinical development of vaccines against other beta coronaviruses - SARS-CoV-1 and MERS. There has been no evidence of ADE in any of the COVID-19 vaccines authorised in Europe, either in preclinical development, clinical trials or post-market use.
What is VAED?
VAED stands for Vaccine-Associated Enhanced Disease. On the one hand, it can be caused by the occurrence of so-called infection-enhancing antibodies (Antibody-Dependent Enhancement, ADE). On the other hand, it can be caused by vaccine-associated hypersensitivity (VAH). These processes involve a shift in the balance between different immune cells, the so-called type 1 and type 2 T helper cells, which in turn has consequences for the release of important messenger substances of the immune system.
VAED arose in context with the development of a vaccine candidate against pneumonia in children caused by the respiratory syncytial virus (RSV) more than 50 years ago (1967). There, increased RSV disease with signs of inflammation in vaccinated individuals was noticed in the clinical trials. The development of the vaccine was stopped early for these reasons.
Is there any evidence for the development of VAED (Vaccine associated enhanced disease) with the COVID-19 vaccine?
No. There is no evidence of enhanced COVID-19 disease in vaccinated individuals, either in clinical trials with COVID-19 vaccines or in the context of the now widespread use of COVID-19 vaccines in the general population. Also, studies in animals of different species infected with SARS-CoV-2 after vaccination have shown no evidence of VAED.