Who is responsible for the evaluation and monitoring of vaccines (vaccine safety)?
In Germany, the Paul-Ehrlich-Institut is responsible for the authorisation of vaccines, i.e. the evaluation of quality, efficacy and safety as well as pharmacovigilance (drug safety) after authorisation.
The Standing Commission on Vaccination (Ständige Impfkommission, STIKO), located at the Robert Koch Institute (RKI), prepares vaccination recommendations based on data on the efficacy and safety of the respective approved vaccines so that vaccines can be used optimally. For this purpose, the STIKO incorporates the assessments of the Paul-Ehrlich-Institut on the safety of vaccines.
The expertise for the assessment of individually occurring adverse reactions after vaccinations lies with the Paul-Ehrlich-Institut. After a vaccine has been licensed, all reports of suspected adverse reactions or vaccine complications are continuously recorded and evaluated. The Paul-Ehrlich-Institut publishes weekly safety reports on reported suspected cases in Germany following vaccination against COVID-19.
Specific questions beyond the safety report will be answered by the Paul-Ehrlich-Institut at email@example.com.
On how many people were the COVID-19 vaccines tested before they were granted the marketing authorisation in Europe?
At the time at which the COVID-19 mRNA vaccine Comirnaty and the COVID-19 Vaccine Moderna were authorised for use in Europe, data on efficacy was available from around 14,000 to 18,000 people who had been vaccinated with the respective vaccine in the phase 2/3 trials. In total, more than 30,000 study participants took part.
For the vector vaccine COVID-19 Vaccine AstraZeneca, data were available at the time of the marketing authorisation on the efficacy in around 6,000 vaccinated persons (around 12,000 study subjects) from the phase 2/3 studies.
For the analysis of safety after vaccination, data from more than 20,000 study participants (including around 10,000 vaccinated persons) was evaluated; this data covered a period of up to around two months after the second dose.
How is the efficacy of a COVID-19 vaccine determined?
During the clinical trial, the study participants are assigned randomly to one of two groups. Care is taken to ensure that both groups have a similar composition (e.g. in terms of age, gender etc.) and that there is a comparable risk of infection with SARS-CoV-2. The occurrence of a laboratory-confirmed symptomatic SARS-CoV-2 infection, i.e. illness with COVID-19, with effect from a specific point in time after vaccination is then recorded in both groups and the frequency is compared.
At the time of marketing authorisation, Comirnaty had an efficacy of 95% against COVID-19 (95% confidence interval: 90.0% – 97.9%) based on 170 cases of COVID-19 (8 in the vaccine group, 162 in the placebo group) in study participants who tested positive for SARS-CoV-2 at least seven days after the second vaccination. An efficacy of 94 percent (95% confidence interval: 89.3 – 96.8%) against COVID-19 was calculated at the time of the marketing authorisation for COVID-19 Vaccine Moderna based on 196 COVID-19 cases tested positive for COVID-19, 14 days after the second vaccination. These particiants included 11 in the vaccine group and 185 in the placebo group.
The efficacy was comparable in all age groups, although the over 75-year-old group was small in both phase 3 studies (4.4%). There were also no indications in subgroup analyses of any differences in efficacy with regard to gender or ethnicity.
Have any safety steps been omitted during testing in order to speed up marketing authorisation?
For the marketing authorisation of Comirnaty and COVID-19 Vaccine Moderna, all the tests relevant to an assessment of the safety of the vaccines were carried out. For COVID-19 Vaccine AstraZeneca, experimental studies in animals on reproductive and developmental toxicity were not completed at the time of the marketing authorisation. A preliminary study on reproductive toxicity in mice did not show any signs of toxicity. Long-term data on vaccine safety will be collected in further clinical studies. The quality, safety and efficacy of every single vaccine product must be ensured before a vaccine can receive marketing authorisation.
The current approvals for Comirnaty, COVID-19 Vaccine Moderna and COVID-19 Vaccine AstraZeneca are conditional marketing authorisations (CMA). This means that on certain dates after the marketing authorisation, additional data (e.g. with reference to the follow-up monitoring of the vaccinated persons) must be submitted by the marketing authorisation holder.
The Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMA) has formulated clear criteria with regard to which conditions must be met before marketing authorisation can be issued for a COVID-19 vaccine. This includes in particular a clinical efficacy significantly in excess of 50% with a lower confidence interval limit of 20 to 30, safety for at least six weeks after vaccination and the follow-up monitoring of safety and efficacy after marketing authorisation.
Are the COVID-19 vaccines safe, even though they have been developed so quickly?
The short development time for the current COVID-19 vaccine candidates was possible thanks to a number of factors:
- Knowledge of the potentially protective antigen from previous work on vaccines for SARS-CoV in 2002/2003 and MERS-CoV
- New vaccine technologies
- Some preclinical trials were carried out in parallel to clinical trials
- Performance of overlapping phase 1/2 and phase 2/3 trials
- Regulatory guidance through intensive and in some cases repeated scientific advice
- Rolling review at the Paul-Ehrlich-Institut and the European Medicines Agency (EMA)
- High level of focus and generous financial support from the German Federal Government, the European Commission and global charitable foundations which enabled large-scale manufacture to commence prior to marketing authorisation
- Worldwide cooperation, e.g. at the level of the WHO and the International Coalition of Medicines Regulatory Agencies (ICMRA).
The clinical trials of the vaccines included at least 30,000 study participants. This allowed extensive information to be gained on the safety and efficacy of the vaccines.
Between 20,000 and up to more than 35,000 study participants were evaluated for the marketing authorisation of the COVID-19 vaccines. This has provided comprehensive information on the safety and efficacy of the vaccines.
When Comirnaty, COVID-19 Vaccine Moderna and COVID-19 Vaccine AstraZeneca received marketing authorisation, information on safety and tolerability was available for a period of at least two months after the second vaccination.
The follow-up monitoring of the study participants does not end with marketing authorisation. They will continue to be monitored for a period of up to two years. One of the reasons for doing this is to evaluate how long the efficacy of the vaccination will last.
In general, however, it is the case with COVID-19 vaccines, as with all other new vaccines and therapeutic medicinal products, that not all potential or very rare adverse reactions can be recorded at the time of marketing authorisation. For this reason, the safety of vaccines, like that of other new medicinal products, continues to be checked after marketing authorisation. One element of this follow-up monitoring (surveillance) is, for example, the analysis of spontaneous reports of suspected adverse reactions or vaccination complications. For the pandemic COVID-19 vaccines, other studies are also being carried out, including active safety studies.
Are all the adverse reactions to the COVID-19 vaccines known at the time of marketing authorisation?
Experience with a large number of vaccines over many years has shown that most adverse reactions occur shortly after vaccination. Thanks to the large number of participants in the clinical trials of the COVID-19 vaccines (> 10,000 vaccinated persons), we can assume that it would have been possible to detect even rare adverse reactions during the observation period. However, these medicinal products will continue to be actively monitored even after marketing authorisation so that ever more knowledge can be gained, including with regard to their long-term safety in the various population groups.
How high is the risk of mRNA vaccines becoming integrated into the genome?
There is no discernible risk of the mRNA becoming integrated into the human genome. The genome, which consists of DNA, is located in the cell nucleus, which the mRNA normally does not penetrate. In addition, the mRNA would first have to be transcribed into DNA in the cell, as RNA itself cannot integrate into the human genome, which is made up of DNA. This would only be possible if specific virus proteins were present at the same time; these proteins would have to transcribe the vaccine mRNA into DNA, then transport this DNA into the cell nucleus, where it would in turn be integrated into the genome by means of a virus protein. This is an extremely unlikely and hitherto unobserved sequence of reactions. In addition, the mRNA is only present in the cells of the vaccinated person temporarily, before being broken down intracellularly.
Why do the mRNA vaccines authorised contain lipid nanoparticles?
The currently authorised COVID-19 mRNA vaccines – Comirnaty and COVID-19 Vaccine Moderna – contain lipid particles in which the mRNA is encapsulated. On account of their size (< 100 nm), they are also referred to as lipid nanoparticles (LNPs). When using the term “particle”, however, it should be noted that these are not non-degradable solid particles (metals, plastics etc.), but rather fat globules that, like biological cell membranes, are made up of a phospholipid layer. They act as carriers and protect the otherwise unstable mRNA. Above all, however, they ensure that the mRNA is absorbed into the cells after vaccination (especially around the injection site) and is then released within the cell where the mRNA is to be transcribed.
What do we know about the safety of lipid nanoparticles in mRNA vaccines?
Lipid nanoparticles (LNPs) are similar to the liposomes (fat cells) that have been used for over 20 years as delivery mechanisms for medicinal products (e.g. Myocet liposomal, Caelyx pegylated liposomal, DaunoXome, AmBisome). In another authorised medicinal product, therapeutic RNA molecules are encapsulated in very similar LNPs (Onpattro). With these medicinal products, significantly higher amounts of lipids are administered intravenously compared to vaccination. There have also been authorised vaccines with a similar structure, called “virosomal vaccines”, e.g. Epaxal for hepatitis A or Inflexal for influenza. Virosomes are also phospholipid vesicles that carry viral envelope proteins on their surface. We have many years of experience with these vaccines and they have a good safety profile. At present, they are no longer on the market, but this is not the result of safety concerns.
As with biological membranes, the structure of LNPs is formed by phospholipids with cholesterol stored in them. The various LNPs also contain other lipid components that impart special characteristics. As all lipids are identical or very similar to the body’s own lipids, LNPs are considered to be “biodegradable”, i.e. it may be assumed that, similar to dietary lipids, they are broken down in the body enzymatically and are largely incorporated into the body’s own fat metabolism.
The potential toxicity of each of these novel vaccine preparations was tested in preclinical toxicity tests prior to marketing authorisation.
Are there any indications of the development of vaccine-associated enhanced COVID-19 disease (VAED)?
Clinical trials with mRNA vaccines suggest that there are no indications whatsoever of an enhanced COVID-19 disease in vaccinated persons. Studies of animals of various species that were infected with SARS-CoV-2 after vaccination have also shown no signs of a VAED.
The concern surrounding a potential VAED is based on animal experimental data for other betacoronaviruses, in which abnormal (pathological) immune phenomena were seen after vaccination with other (non-mRNA) vaccines and subsequent infection with SARS or MERS viruses, but without any SARS or MERS illness being detected in the animals. In the 1960s, enhanced illness with human respiratory syncytial virus (RSV) with signs of inflammation was also seen in young children who had been vaccinated with an inactivated vaccine against RSV.
Furthermore, in many COVID-19 vaccines the antigen has been optimised in such a way that it counteracts a theoretically possible VAED (optimised spike protein variant in the stabilised prefusion conformation).
Do the vaccines contain microchips/nanochips?
Are there any indications that the newly authorised COVID-19 vaccines trigger autoimmune diseases?
No. In the extensive clinical trials carried out prior to the marketing authorisation of the vaccines, there were no indications of autoimmune diseases. Nonetheless, special attention will also be devoted to this theoretical risk after marketing authorisation within the framework of pharmacovigilance.
How is the safety of the vaccines monitored after marketing authorisation?
At the time of the first marketing authorisation, our knowledge of the safety of the COVID-19 vaccines is naturally incomplete, because in clinical trials both the duration of the follow-up monitoring and the number of vaccinated persons are limited. It is possible that not all the rare or very rare adverse effects associated with administration of the vaccine have been identified in the clinical trials. They are, however, of great importance for the overall evaluation of a new vaccine. In general, new knowledge about the safety of vaccines, especially with regard to very rare occurrences, can be obtained even a long time after marketing authorisation – as is the case with all vaccines. For this reason, experts in the safety of medicinal products (pharmacovigilance) never stop monitoring the vaccines, even after marketing authorisation.
Routine pharmacovigilance measures after marketing authorisation include the recording and evaluation of reports of suspected vaccination complications or adverse reactions to vaccination. These reports are recorded and evaluated centrally both at the Paul-Ehrlich-Institut and in the EudraVigilance database for the whole of Europe. In this connection, the marketing authorisation holder must regularly prepare safety reports, which are assessed jointly by the various marketing authorisation agencies in the European Union. As part of marketing authorisation, the marketing authorisation holder must submit “risk management plans”, which summarise what is known – and what is not yet known – about the safety of the vaccines. In addition, it must describe precisely the measures that will be used to fill the remaining gaps in knowledge – e.g. further studies after marketing authorisation – and in what timeframe this will be achieved. These gaps in knowledge may, for example, relate to safety in particular groups of people who were not represented sufficiently in the clinical trials.
In the case of the COVID-19 vaccines, the Paul-Ehrlich-Institut is also carrying out additional studies. This includes a study using the SafeVac 2.0 smartphone app, which will be used to further investigate the tolerability of the individual COVID-19 vaccine products. Participation in the app-based study is voluntary.
When does vaccination protection begin with the authorised vaccines?
In the clinical trials for authorising the respective vaccines, the complete vaccination protection from a COVID-19 infection was established seven to fifteen days after the second vaccination. However, some vaccination protection was seen with all vaccines after the first vaccination.
It is not yet certain whether vaccination protection for vaccinated persons also means that they cannot transmit the virus to non-vaccinated people. Therefore, even after being vaccinated, you must still protect yourself and the people around you by observing the corona protection rules (maintain social distancing, wash your hands, wear a face covering, use the Corona Warning App, and ensure adequate ventilation).
What vaccination reactions may occur after a vaccination with the authorised COVID-19 vaccines?
After vaccination with the authorised COVID-19 vaccines, local and general symptoms may occur as the body is attempting to react to the vaccine. These reactions generally occur within two days of vaccination and rarely last for longer than one or two days. Based on different study designs, a direct comparison between the frequencies of reactions determined in clinical trials is very difficult. For this reason, observations for all authorised vaccines are presented separately.
In the clinical trials for the marketing authorisation of Comirnaty, vaccinated persons (> 16 years of age) very commonly reported pain at the injection site (> 80% of those vaccinated), fatigue (> 60%), headache (> 50%), muscle pain and chills (> 30%), joint pain (> 20%), swelling at the injection site and fever (> 10%). Vomiting was common (> 1%), swelling of the lymph nodes was uncommon (less than 1%).
For COVID-19 Vaccine Moderna, the reactions in vaccinated persons (>18 years) reported most frequently included pain at the injection site (>90%), fatigue (70%), head and muscle pain (>60%), joint ache and chills (>40%), malaise or vomiting (<20%), swelling of the lymph nodes in the arm pit, fever, swelling and redness at the injection site (each >10%). A general rash or rash and hives at the injection site were frequently reported. Occasionally (between 0.1% and 1%), itching occurred at the injection site.
For COVID-19 Vaccine AstraZeneca, the most frequently reported vaccination reactions in vaccinated persons (>18 years) included sensitivity to palpation at the injection site (> 60%), pain at the injection site, headache and fatigue (>50 %), muscle pain and malaise (> 40%), febrile sensations and chills (>30%), bone ache and sickness (>20%). Frequent adverse effects (between 1% and 10%) included fever > 38°C, swelling and redness at the injection site, sickness and vomiting. Occasionally (between 0.1% and 1%) were swelling of the lymph node, itching, or skin rash were reported.
Most of the reactions were slightly less common in older people than in younger people. The vaccination reactions were mostly mild or moderate in intensity. In the case of the COVID-19 mRNA vaccines, they occurred somewhat more frequently after the second vaccination. Contrary to this, in the clinical studies on COVID-19 Vaccine AstraZeneca, the adverse effects reported after the second dose (above all fever, malaise, chills) were significantly milder and less frequent than after the first.
In the extensive clinical trials prior to marketing authorisation, four cases or three cases of acute facial paralysis (Bell’s palsy) were observed after administration of Comirnaty and COVID-19 Vaccine Moderna, respectively (compared with 1 case in the control group of unvaccinated persons) (corresponding to a frequency between 0.1% and 0.01%). Whether there is a causal connection of this event with the vaccination is currently the subject of further investigation for each vaccine. Bell’s palsy generally resolves completely in 85% of affected patients.
Isolated cases of severe hypersensitivity reactions (anaphylaxis) after vaccinations with Comirnaty and COVID-19 Vaccine Moderna were reported shortly after marketing authorisation. There were no cases of anaphylaxis in the clinical trials.
As a precautionary measure, the vaccinating doctors should be equipped for any emergency measures. It is recommended that vaccinated persons should be monitored for at least 15 minutes after vaccination.
What is the risk of allergic reactions after vaccination with the authorised vaccines?
Allergic reactions can occur with vaccinations, as after the use of all medicinal products. These include both local hypersensitivity reactions and, in very rare cases, serious, potentially life-threatening immediate reactions (anaphylaxis), which require immediate medical attention. The incidence of anaphylactic reactions following vaccinations of children, adolescents and adults with vaccines other than COVID-19 is reported to be 1 to 10 per 100,000 vaccine doses, depending on the study and vaccine.
While isolated hypersensitivity reactions but no anaphylaxis were observed in the pivotal studies of Comirnaty, COVID-19 Vaccine Moderna, and Vaxzevria (formerly COVID-19 Vaccine AstraZeneca), cases of severe hypersensitivity reactions (anaphylaxis) have also been reported in Germany (as previously in the United Kingdom and the United States) after vaccination with all three vaccines since vaccination with COVID-19 vaccines began. This should be seen against the background that in Germany alone, a significantly higher number of people have already been vaccinated in a short time than in the studies for approval. Up to and including 12 March 2021, the Paul-Ehrlich-Institut has evaluated a total of 99 suspected cases from Germany on the basis of 8.9 million vaccinations according to the internationally recognised anaphylaxis definition of the Brighton Collaboration with levels 1 to 3 of diagnostic (safety. Information on the suspected cases reported from Germany can be found in the regular safety reports of the Paul-Ehrlich-Institut. For the fourth vaccine approved in the EU (COVID-19 Vaccine Janssen), one case of anaphylaxis has occurred so far in a still ongoing clinical trial. The vaccine has not yet been used in Germany.
It is unclear to date which component(s) of the COVID-19 vaccines could be responsible for the reported anaphylactic reactions. After the administration of Comirnaty and COVID-19 Vaccine Moderna, the lipid nanoparticles contained in the vaccine, especially the polyethylene glycol (PEG) contained therein in bound form, are considered as triggering agents for hypersensitivity reactions. The vector vaccines from AstraZeneca and Janssen-Cilag contain small amounts of polysorbate 80 as an adjuvant, which also has PEG moieties in the molecule. However, many other vaccines also contain polysorbate 80 as a stabiliser (e.g., influenza, hepatitis A, or HPV vaccines such as Fluarix, Havrix, Gardasil), and reports of IgE-mediated reactions to polysorbates in drugs are an absolute rarity overall.
In the summaries of product characteristics (SmPCs) of the mRNA vaccines and the vector vaccine COVID-19 vaccine Janssen, anaphylaxis is listed as a possible side effect. For AstraZeneca's vector vaccine (Vaxzevria), the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) has also recommended inclusion in the SmPC. For the vaccines to be administered twice (mRNA vaccines as well as Vaxzevria), there is an additional warning that a second dose of the vaccine should not be administered to individuals who have experienced anaphylaxis after the first dose. Only one vaccination is provided with the Janssen COVID-19 vaccine. The respective warning is thus not included for this product.
In the EU, there is no contraindication for people with allergies or a history of anaphylaxis for any of the four licensed COVID-19 vaccines. However, known allergies to ingredients contained in the vaccine are a contraindication to vaccination.
According to the technical information of all licensed COVID-19 vaccines, all vaccinated individuals should be followed up for at least 15 minutes after vaccination. Appropriate medical treatment and monitoring should always be available in the event of a severe allergic intolerance reaction following vaccine administration.
Anti-allergic premedication is not recommended, as possible initial symptoms of anaphylaxis may be masked and not noticed until after the follow-up period. In the worst case, treatment options for a life-threatening anaphylactic reaction are then not immediately available.
Specific recommendations for physicians on how to proceed in patients with a positive allergy history (known allergies in the past or an allergic reaction to the first COVID 19 mRNA vaccination) can be found in a flow chart prepared by the Paul-Ehrlich-Institut together with the Robert Koch Institute and in close cooperation with the allergological societies in Germany. It is available at the vaccination centers and can be accessed on the website of the Paul-Ehrlich- Institut.
As of 25 March 2021
Flowchart - Procedure in case of positive allergy history before COVID-19 mRNA vaccination (German only)
Statement by the Paul-Ehrlich-Institut – Recommendation on the coronavirus vaccination of allergy sufferers
Safety reports on COVID-19 vaccines
Meeting highlights from the Pharmakovigilance Risk Assessment Committee (PRAC) 8-11 March 2021
Can COVID-19 mRNA vaccines affect fertility?
There is no evidence from the non-clinical studies of the authorised mRNA-COVID-19 vaccines Comirnaty and COVID-19 Vaccine Moderna that vaccination could lead to impairment of female or male fertility (fertility).
As required for any drug approval in the EU, various animal toxicity studies were conducted prior to human use. Potential adverse effects of repeated vaccinations on fertility, pregnancy and embryonic development were each investigated in a special, very large study in female rats conforming to international guidelines (so-called ‘DART(Developmental and Reproductive Toxicity) study’). These studies show no evidence of impairment of female fertility caused by the vaccines. Furthermore, in the toxicity studies with repeated administration of an increased vaccine dose (so-called ‘repeat-dose toxicity study’), no vaccine-related changes in female or male reproductive organs (ovaries or testicles) were observed in the subsequent comprehensive fine-tissue (histopathological) examinations.
With this data situation, the best possible safety for the exclusion of damage to reproductive organs and of an impairment of reproduction in humans is guaranteed within the framework of a drug marketing authorisation.
The studies conducted and their evaluation can be found in the published European public assessment report (EPAR) of the European Medicines Agency (EMA).
Is there a risk that the DNA from vector vaccines such as the COVID-19 vaccine from AstraZeneca can be integrated into the human genome?
The COVID-19 vaccine consists of an innocuous virus from the family of adenoviruses (cold viruses) from chimpanzees (adenoviral vectors). This virus does not replicate in humans. The genome of the vector was modified in such a way that it contains the gene with the blueprint for the production of an optimised surface protein of SARS Coronavirus-2, the spike protein. The human body has regular contact with adenoviruses – “common cold viruses”. Even in the case of a natural infection with adenoviruses, no genetic changes have so far been observed in human cells. Adenoviral vectors are generally considered as non-integrating vectors. This means that they do not integrate their genome into the cell genome. Like the genome of other adenoviruses, the genome of the COVID-19 vector vaccines on the basis of non-replicable adenoviruses will remain outside the human DNA (extrachromosomal) in the cell nucleus of infected cells.
Also, against the background that the adenoviral vectors – unlike natural cold viruses – cannot replicate in the vaccinated person, due to genetic changes, and are rapidly eliminated in the body, there is – based on the current state of the art – no risk of the adenovirus vector DNA integrating into the human genome.
Can COVID-19 vaccination with an mRNA or a vector vaccine cause damaging cell fusions?
The answer is clearly no.
In the meantime, it is known that the spike protein of Coronavirus SARS-CoV-2, when in contact with human cells, causes the cells to fuse with neighbouring ones and partly die. Such fused cells were found in lungs of patients who had died of COVID-19.
With these findings, the question arose whether vaccines causing the formation of spike proteins might also cause such membrane fusions.
When the COVID-19 vaccines available in Germany (mRNA vaccines or vector vaccines) are used, few body cells receive foreign genetic information at one single time. This information consists of mRNA (mRNA vaccines) or DNA transmitted by harmless cold vaccines (vector vaccines). The genetic information is translated into protein by the cells affected. The cells generate the spike protein of Coronavirus SARS-CoV-2. Since the vaccines do not replicate, unlike the Coronavirus SARS-CoV-2, the amount of spike protein will remain small and local. No clinical effects can be expected, because the number of cells, into which the genetic information for the formation of the spike protein is inserted by the vaccination, is so small.
Clinical studies in tens of thousands of vaccinated study participants have proofed the safety of the vaccines. The regular public safety updates by the Paul-Ehrlich-Institut do not include any evidence of such vaccination complications either.
Membrane fusion is a natural process used by the cells to transport material such as hormones, neurotransmitters, and waste to the desired destination. Viruses also use this process to enter new cells.