COVID-19 Vaccination

A synthesis review of current status and proposal of a registry study to overcome social polarization tendencies and answer open research questions

The original German version of the article will appear in Der Merkurstab 2021, Volume 74, Issue 2.

Abstract

Clinical and epidemiological management of the COVID-19 pandemic requires a comprehensive assessment of the vaccination issue. The development of such an impressive variety of effective COVID-19 vaccines in a very short time can be considered an extraordinary achievement. The following synthesis review outlines the innovative vaccines and discusses their potential social and scientific implications. This includes discussion of changing vaccination practices by establishing vaccination centers. There is currently no basis for recommending vaccination in childhood. It is likely that the current vaccines are contributing to a reduction in viral transmission. The extent to which “herd immunity” can be achieved in this way is an open question. This is also the case when evaluating the extent and duration of vaccine protection in different age groups, as well as rare and very rare serious adverse events. It applies even more to the question of vaccine protection against mutations of the SARS-CoV-2 virus (1). Lastly, it is currently not possible to comparatively evaluate the different vaccines and vaccine types in terms of efficacy and risks. This is also the case if the second dose of a vaccine is given at different intervals from the first dose. The crucial observation period for rare, serious adverse events or those that manifest themselves only in a longer follow-up period is the one in which a vaccine is used broadly in a population for the first time – and at the same time a sufficient number of people have not or not yet been vaccinated who have sufficiently comparable biological and sociological characteristics to those vaccinated. Indirect compulsory vaccination or compulsory vaccination of medical personnel for specific occupational groups are discussed against this background. A centralized immunization registry with reliable pseudonymization of individual vaccination decisions without overt or covert discrimination could provide a solid basis for the social integration of citizens with different vaccination choices and for generating optimized scientific evidence.

Preliminary remark and personal statement

With their proposal of a pseudonymized COVID-19 vaccination registry, the authors hope to contribute to countering the polarization that threatens to arise when a society does not readily tolerate different positions on controversial medical issues. At the same time, nonjudgmental, scientific monitoring of the population’s personal COVID-19 vaccination decisions offers the best means of providing credible answers to outstanding questions about COVID-19 vaccination in as short a time as possible.

Vaccination history and requirements

Safe and well-tolerated, effective vaccination in a pandemic can be considered a desirable preventive measure. This also applies if severe symptoms only affect a small proportion of those infected, as with COVID-19 (2). It is helpful to recall the polio pandemic in the middle of the 20th century, which also caused severe disease and deaths in an even smaller proportion of those infected. In that case, the main risk groups were children of kindergarten and early school age (3). Polio infection leads to paralytic polio in approximately 0.1% of infected individuals and, depending on severity, can be lethal in 5–60% of these severely affected individuals, i.e., in approximately 0.01% of all infected individuals (4). In the survivors, mild to very severe symptoms of paralysis may remain, and post-polio syndrome may occur decades later. To live in a polio-free country can be considered to be a great step forward. (At this point, the authors would like to commemorate the Italian doctor and long-time president of the International Association of Anthroposophic Medical Societies (IVAA) Giancarlo Buccheri (4), who lived with the consequences of paralytic poliomyelitis throughout his life. He died of COVID-19 in Milan in April 2020.)

This comparison with polio highlights another aspect of the COVID-19 pandemic that is relevant to the vaccination issue and often discussed, namely the modest rate of morbidity and mortality relative to the total number of infections and the total population. COVID-19 requires considerable special efforts on the part of the health system (especially intensive care) in order to provide adequate facilities for seriously ill patients, which was also the case during the polio pandemic until vaccination programs took effect (i.e., “iron lungs”, special departments, extensive rehabilitation programs and the care of post-polio syndromes).

Oral vaccination against polio (OPV) proved to be a very effective tool for ending this pandemic; not only does it prevent infection, but it also prevents the transmission of the virus by infected individuals. This vaccine nevertheless causes paralytic “vaccination polio” in one in 2.7 million people vaccinated, and much more frequently in those with immunodeficiency. This extremely rare but serious “side effect” of the oral polio vaccine with attenuated live viruses has led to it being considered too risky in polio-free countries such as Germany today, where it was thus replaced by a “dead vaccine” with inactivated virus material (IPV). A worldwide eradication of poliomyelitis has not yet been achieved, any more than it has for measles. Political and religious difficulties in the implementation of global polio immunization (Afghanistan, Pakistan) have contributed to this. In addition, mutated polioviruses (cVDPVs) derived from orally administered live vaccines are now circulating in Africa (6, 7). The example of measles viruses also shows how difficult it is to implement global elimination programs: in 2019, the number of reported infections reached the level of that of 1996, with a worldwide mortality rate of more than 20% (8). These examples suggest that elimination of SARS-CoV-2 by blanket vaccination is unlikely in the near future, especially since, unlike measles, many infected persons do not develop symptoms of the disease and the measles vaccine with attenuated measles viruses may provide “sterile immunity”, whereas current COVID vaccines are more likely to reduce but not completely prevent viral transmission by vaccinated persons (9). It is likely that SARS-COV-2 may become endemic in the long term, possibly then in the form of a primary childhood infection that is usually harmless.

Regarding vaccine safety, the example of “vaccine polio” resulting from OPV illustrates that studies with approximately 30,000 to 40,000 participants, such as those now submitted to regulatory authorities in the United States, the United Kingdom, and the European Medicines Agency (EMA) (11, 12, 13, 14, 15), are by no means adequately large to capture with sufficient reliability rare but globally highly relevant serious vaccine risks. On the other hand, since approval studies with, e.g., 30 million participants are not feasible, the example of the oral polio vaccine shows that post marketing surveillance is needed for serious side effects to become apparent. The best time for this is when a population is vaccinated for the first time and a biological and sociological comparable population is not vaccinated: it is then possible to determine undesirable effects of a vaccine that are very rare, serious or that manifest themselves only after a longer follow-up period, as well as determine their frequency and impact.

Specific and non-specific effects of vaccines

Vaccines have a specific protective effect as well as non-specific effects. The latter can either weaken or strengthen the immune system. Aaby’s studies (16, 17, 18) in very poor countries show that vaccines using inactivated viruses in the first six months of life increase the overall mortality of small children and, conversely, that live vaccines, such as the measles vaccine, can disproportionately reduce overall mortality. A large Japanese study of more than 100,000 children recently found that the prevalence of asthma, wheeze and eczema among children at 12 months of age might be related to the amount of inactivated vaccine exposure before 6 months of age (19). This is in line with other studies, some as yet unpublished. Even with the newly developed SARS-CoV-2 vaccines, non-specific vaccination effects are to be expected, which can be very different due to the variety of vaccination technologies used. Both undesired and desired effects (e.g., cross immunity to other pathogens) are possible. The recording of non-specific effects, which can lead to surprises, usually requires longer observation periods than in the present approval studies, as well as sufficiently large collectives, with comparative recording where possible (20).

What could be achieved by combining a vaccination registry with freedom of choice on vaccination?

From the previous considerations, it is clear, when assessing the sustainable optimization of the effectiveness and safety of COVID-19 vaccines, that this point in time would present the ideal conditions for the introduction of a vaccination registry and scientific tracking system. This should encompass both the vaccination group and those who cannot (yet), or do not (yet), want to be vaccinated. The political and legal debate about general or job-specific vaccination requirements, as well as mandates for so-called risk groups, appears to be premature, not only because of the limited knowledge regarding safety and effectiveness of the various vaccines and their juridical problems but also from the perspective of establishing a long-term vaccination strategy. An objective, comparative recording of vaccinated and non-vaccinated individuals forms an essential basis for sustainable, evidence-based vaccination recommendations in the medium term, to which an informed public in a democratic state is entitled. This is even more the case if the currently circulating virus mutants differ significantly from the conditions at the time of the approval studies and if experts fear decreasing vaccination protection against mutations of SARS-CoV-2 in the medium term (21).

The registry must be absolutely trustworthy in terms of data protection and data security. A vaccination registry as suggested by the German Society for Epidemiology is suitable for this, with the pseudonymized registration of the vaccinated and the non-vaccinated. By linking them to health insurance data via a trust center, vaccinated and non-vaccinated individuals can be compared with respect to the occurrence of serious events. In contrast, experts have questioned whether the separate data collection planned by the German Ministry of Health at the Robert Koch Institute is suitable for this (22, 23, 24).

In our opinion, high – albeit not absolute (25) – legal protection of freedom of choice on vaccination is advantageous. A securely and reliably managed vaccination registry for SARS-CoV-2 vaccinations , which also covers the challenge of various vaccines of different technologies, therefore also appears to us as the best solution, both scientifically and socially, for achieving a satisfactory level of evidence as quickly as possible with regard to the effectiveness and safety of the various SARS-CoV-2 vaccines. In the light of limited vaccine supplies a third arm of this registry study could be considered in which indecisive or science-supportive citizens could be randomized to vaccines from different companies or timing. Such a broadly based scientific approach would have a socially integrating effect and help to counteract polarization with regard to the vaccination issue. Reliable pseudonymization of this registry should be a central requirement; data breaches could have serious consequences and the risk of discrimination against non-vaccinated people cannot be ruled out, especially with this vaccination. The necessary trust of the population could be created and optimized on all sides with this approach.

What are the prerequisites for SARS-CoV-2 vaccinations?

The weekly safety report of the Paul Ehrlich Institute (PEI) and the European Medicines Agency (EMA) (26) publishes the side effects of the mRNA vaccines approved in Germany. In it, apart from allergic reactions and flu-like symptoms, no serious adverse reactions of the newly licensed Sars-CoV-2 vaccines in the U.S. and Europe are causally attributed to the vaccine. This also applies to the more than 100 deaths reported to PEI by the end of January 2021 after vaccination, even if they occurred only one hour after vaccination. Statistically, “the observed number of deaths after vaccination does not exceed the expected number of deaths without vaccination.” (27) However, in the pivotal trials facial paresis occurs more frequently with both vaccines than with placebo (28). In general, the authors gain the impression from the multitude of published reports and oral communications on this subject that the mRNA vaccines used so far in Germany require sufficient vital reactivity from the organism. The German Standing Commission on Vaccination (STIKO) formulates: “Even the very elderly, and people with progressive diseases who are in poor general health must be able to be vaccinated. These groups should be medically evaluated to see if vaccination can be recommended for them.” (29) At the same time, STIKO warns of possible exaggerated vaccination reactions after a COVID infection.    

Effectiveness and side effects vary according to both the vaccine and the vaccinated person. There are no vaccines without side effects (16). However rare statistically, every vaccination also carries a risk for the vaccinated person. It is a legal requirement that adequate information be provided to the person to be vaccinated – or to their legal representative – and their conscious consent must be obtained (30).

Written educational material alone is not considered to be sufficient from a legal point of view; there must also be an opportunity to ask questions. Clarification is particularly difficult when

  • the vaccine uses a technology that has never been widely used in humans, and
  • the effectiveness and side effects of the vaccine in humans have only been recorded for a few months.

In addition, the exclusion of contraindications based on an individual medical history is not dispensable for any vaccination. This is clear from the relevant case law. To date, there has been little mention of adequate physical examination of these patients before vaccination is administered (31). Mere “education” is not sufficient to properly carry out a vaccination. The principle of reversing the burden of proof should also be highlighted here, as this applies to the vaccinator or doctor responsible for carrying out the vaccination, should there be reasonable suspicion that the vaccinated person has not been fully informed and examined (32, 33).

The pandemic reality is that for COVID-19 vaccination, patient histories and examinations are considered irrelevant except for the question of rare allergic reactions to the ingredients of the vaccine solution (PEG at BioNTech-Pfizer, unknown at AstraZeneca). The physical examination is also considered expendable because it is an infection transmission opportunity. This is the only way that 40 patients per hour can be vaccinated by one physician. 

Regulatory studies to date

What do we know today about the effectiveness of the SARS-CoV-2 vaccines?

What about the effectiveness of the new SARS-CoV-2 vaccines? The following questions need to be answered:

Will the vaccine reduce the number of or prevent serious COVID-19 cases and COVID-related deaths, especially in high-risk groups?

Does it interrupt virus transmission (i.e., is the vaccinated person no longer contagious)?

The fact is that these are not the primary endpoints of the Phase III pivotal trials. The endpoints were “COVID events”, i.e., a positive PCR Test as evidence of infection and a clinical symptom that can be attributed to a SARS-CoV-2 infection, e.g., a new cough (34)! The reasons for this are obvious: the infection rate was not very high during the studies and serious COVID-19 cases are rare even among infected people. For study sizes of, e.g., approx. 30,000 (Moderna) to 43,000 participants (BioNTech-Pfizer), this involves an order of magnitude of 95 (Moderna) or 170 (BioNTech-Pfizer vaccine) COVID-19 cases in the sense of the above definition, i.e., small numbers of cases in short observation periods (2 months). P. Doshi (32), associate editor of the British Medical Journal, comments on this as follows: “Let’s put this in perspective. First, a relative risk reduction is being reported, not absolute risk reduction, which appears to be less than 1%. Second, these results refer to the trials’ primary endpoint of COVID-19 of essentially any severity, and importantly not the vaccine’s ability to save lives, nor its ability to prevent infection, nor its efficacy in important subgroups (e.g., frail elderly). Those still remain unknown. Third, these results reflect a time point relatively soon after vaccination, and we know nothing about vaccine performance at 3, 6, or 12 months, so cannot compare these efficacy numbers against other vaccines like influenza vaccines (which are judged over a season). Fourth, children, adolescents, and immunocompromised individuals were largely excluded from the trials, so we still lack any data on these important populations.” Doshi has now updated his criticism with arguments and calls for the full publication of the study data at an early stage, since from his point of view the question of the relative effectiveness of the vaccines cannot yet be answered as clearly from the published data as stated by the manufacturer (36).

In both mRNA vaccine trials, according to data supplied by the manufacturers, far fewer (94 to 95%) vaccinated individuals had a “COVID-19 case”, as well as a less severe disease progression (9 vs. 1 in the BioNTech-Pfizer trial). These are very low numbers (37), so studies such as the one by Dagan et al. from Israel are important, which looked at 596,618 vaccinated and unvaccinated (matched pairs) and essentially confirmed the results of the pivotal study, showing a reduction of 92% in the severity of illness requiring intensive care from day 7 after the second vaccination in both outpatients and clinically treated patients (38). The results of the phase III study for the Russian Sputnik V vector vaccine also show efficacy, particularly of over 90% against severe courses (39). AstraZeneca’s vector vaccine has also shown very clear efficacy against severe courses (40), although this will only be fully assessable after the second vaccination, which for this vaccine should ideally be after 8-12 weeks (41, 42). The Beijing Institute of Biological Products reported an efficacy after 2 injections of approximately 79.34% “against the disease caused by the new coronavirus infection (COVID-19)” and a “conversion rate of the neutralizing antibody of 99.52%” (43) for Sinopharm’s vaccine with inactivated virus material. Further details have not yet been published.

Who has been vaccinated in previous and ongoing studies?

  •  There are still comparatively few elderly people (>85 years) from the high-risk group (44, 45, 46). In contrast to the EMA authorization of AstraZeneca’s viral-vector-based vaccine (47) – with the EMA acknowledging insufficient data in persons older than 55 years – the German Standing Committee on Vaccinations (STIKO) does not recommend this vaccine for people older than 64 years (48).
  •  With a few exceptions, no children.
  •  No pregnant women.

This statement initially applies globally to all the various SARS-CoV-2 vaccines under development. It should be noted that, especially in the age group between 60 and 80 years, individuals’ state of health can vary greatly. According to the initial publications, there is insufficient knowledge about how these vaccines are tolerated by the elderly, particularly by those with multiple pre-existing health conditions and correspondingly complex ongoing (poly)medication.

With regard to the effectiveness of the vaccines, this, as well as the severity of acute side effects, tends to decrease with age because the reaction of the organism to the vaccine is weaker (49, 50). It is to be expected that this factor will vary with different vaccine technologies. It is an open question whether the mRNA vaccine performs better in older patients than conventional vaccine technologies, such as the inactivated vaccines developed and already widely used in China.

Thus, from the ongoing phase III studies (approval studies) we can only make a limited assessment of the efficacy of the new vaccines in relation to vulnerable groups. This applies even more in situations where the gap between the administration of the first and the second dose deviates markedly from that applied in the approval studies, a policy that is currently being considered due to shortages of available vaccines (51). In particular, it should be emphasized:

  • No vaccine has yet demonstrated that it can also interrupt virus transmission and thus prevent the SARS-CoV-2 virus being passed on (“sterile immunity”) – a crucial question for pandemic control (52).
  •  It is still too early to tell for how long the vaccines so far developed can reduce or even prevent the likelihood of COVID-19 infection. A booster vaccination is only possible for some of the vaccines; for the time being, the question remains open as to whether and, if so, when, follow-up vaccination will be necessary after the primary immunization. This question is also highly relevant for assessing the costs and complexity of a vaccination program – and this is a question that will take some time to answer.
  • With mutations of the SARS-CoV-2 virus now circulating worldwide, it is becoming more likely that the efficacy of vaccines developed to date against new mutations of SARS-CoV-2 may weaken (21).

Which vaccines have been developed so far?

If we consider the global spectrum of around 200 SARS-CoV-2 vaccines (53) currently in development, the following vaccines are currently at the forefront:

  • Classic “dead” vaccines with inactivated viral material and varying adjuvants (e.g., from the Chinese companies Sinovac, Sinopharm, etc.)
  • mRNA vaccines (e.g., BioNTech-Pfizer, Moderna, Curevac, etc.)
  • Vector vaccines (54) (e.g., National Gamaleya Research Center for Epidemiology and Microbiology (Russia) (55), AstraZeneca and Oxford University, CanSino Biologics (Beijing), Janssen (Johnson & Johnson) and others, with different vector viruses)
  • Peptide vaccines (Novavax) showing differential efficacy against different mutations of SARS-CoV-2 (56).
  • DNA vaccines (e.g., Inovio (U.S.), Genexine/BINEX/GenNBio/Int. Vaccine Inst. (Korea))

It goes beyond the scope of this article to cover the variety of vaccines under development, but it is clear that a longer period of comparative scientific evaluation will be required to answer the question as to which vaccines are suitable for which patients and under which circumstances. The OPV (oral polio vaccine; see above) example shows that with a high incidence of disease, vaccines that reliably reduce transmission and curtail severity of illness progression can be acceptable even if they have a comparatively higher risk of side effects (e.g., paralysis in very rare cases such as OPV). If the incidence is lower, however, vaccines with reduced effect on transmission but better tolerance (like the IPV polio vaccine today) may be preferable. All these questions can only be answered if a blanket commitment, made early on to a particular vaccine, for example by means of an indirect mandate, is avoided. Rather a variety of vaccines should be given a chance – which can also be logistically expedient – provided that a suitable vaccination registry is kept covering all the recipients of the different vaccines (once available) and which, at the same time, enables a comparison with non-vaccinated persons. At the same time, this would provide the opportunity for individually differentiated choices, beyond a simple yes/no, addressing the question as to which particular vaccine the individual or their doctor may prefer as soon as several different vaccines are logistically available. An important prerequisite for the benefit and acceptance of such a registry is a freedom of choice to vaccinate, along with secure pseudonymization, not only with regard to governmental requirements, but also the lived realities in companies and society at large. Waiving a state vaccination mandate does not imply that workers and consumers will not be put under the social pressures of indirect vaccination mandates. We will go into this in more detail below.

How are vaccines (the “verum”) compared to “placebos” in the approval studies?

It should first be emphasized and positively acknowledged that the manufacturer of the mRNA vaccine from BioNTech-Pfizer compared it with a “real” placebo, namely a 0.9% saline solution, in its approval study (57). Normally there would be an ethical imperative for members of the placebo group to be offered the “verum” or the actual vaccine, if available on the market, after completion of the emergency approval study. However, this would endanger the long-term follow-up observation within the study . “In view of the short follow-up time, it is extremely important that study participants remain in their groups for as long as possible and ethically justifiable, even after approval (which is not a regular, but a conditional or emergency one) in order to be able to generate further data on safety and efficacy”, writes arznei-telegramm®, stating that BioNTech-Pfizer plans to “offer unblinding and immunization as part of the study upon request” if a national vaccination recommendation is given (45). This applies particularly to the question of whether this vaccine can trigger autoimmune diseases, which usually only manifest after a certain time interval.

It is otherwise quite common (e.g., in the approval studies of vector vaccines known to us) to use vaccines und substances with relatively frequent effects as a “placebo”, e.g. a vaccine against meningitis or simply adjuvants like aluminum hydroxide (58). On the one hand this is because in vaccination studies, which often have to be carried out on young children, it is considered “unethical” to vaccinate a toddler with a placebo only for study purposes, so it has become common to vaccinate using a known vaccine as a “placebo” – an otherwise hardly acceptable procedure in pharmaceutical research. On the other hand, there are concerns that the “verum group” will be unblinded in the comparative study if they manifest significantly more severe side effects than the control group. However, it needs to be pointed out that from a medical-scientific point of view, such studies do not meet the conditions for a transparent assessment of the risk of acute and long-term vaccine side effects. The same applies if – as in HPV vaccine studies – the “placebo” group is injected with the adjuvant of the “verum” and only the inactivated, immunogenic viral material is missing in the “placebo”. This is because we know that adjuvants in particular can have problematic side effects. In summary, it can be asserted that a careful individual examination of each licensing study is required and many of these studies – e.g. on the Russian vector vaccine or the AstraZeneca vector vaccine – are not real “placebo” studies.

mRNA and vector vaccines

Risks and consequences associated with the new vaccine technologies (45, 59)

At this point we would particularly like to examine the novel mRNA and vector vaccines. These are so-called platform technologies that have been newly developed over the past 30 years and, with one exception in the case of Ebola, have not yet led to vaccines approved for humans. It is also the case that manufacturers such as BioNTech, Curevac or Moderna have yet to bring onto the market either a medicine or a vaccine approved under normal licensing procedures.

The principle common to both mRNA and the current vector vaccines can be summarized as follows: it is not the antigen itself that is inoculated, but its genetic blueprint, either as mRNA “packaged” in liponanoparticles (see below) or as information genetically integrated into the genome of a vector virus, which changes the protein synthesis of the human organism intracellularly in such a way that

  • the antigen (e.g., coronavirus spike protein) is produced by the organism itself and thereby
  • triggers the activation of the cellular and humoral response of the immune system.

According to current understanding, both are essential for achieving an adequate immune response to SARS-CoV-2. Thereby the organism itself becomes the producer of the actual vaccine.

The risk that DNA vaccines, DNA-transporting vector vaccines or mRNA-based vaccines will lead to an insertion of additional nucleotides or DNA sequences into human DNA (using reverse transcriptase, as is typical for retroviruses and found in humans as human telomerase reverse transcriptase (hTERT) to counteract the shortening of telomeres) is currently assessed as “extremely unlikely”, even in the presence of HIV infection, in which a reverse transcriptase (60) is available to the virus.

In principle, mRNA and viral vector vaccines (VVV) as platform technologies allow a specific vaccine to be produced quickly in the event of a new pandemic as soon as the genetics (or relevant parts) of the pathogenic virus are known. In that case, only the genetic information contained in the vaccine has to be adapted accordingly. This also applies should a pandemic-causing virus mutate. Thus, these vaccines have basically opened a new chapter in pharmaceutical history. To be sure, although this expectation is, to date, still awaiting clinical verification, it no doubt represents a powerful technological and economic incentive in vaccine development.

Advantages and disadvantages of mRNA vaccines (59)

Advantages:

  • The production of mRNA on a DNA template is easily scalable industrially and enables the rapid production of large quantities. At the same time, efforts are being made to minimize the amount of mRNA used in the absence of reliable knowledge as to the optimal dose of an mRNA vaccine.
  • There is no requirement to use cell cultures in order to obtain inactivated viral material or attenuated live viruses, thus eliminating any contamination or problematic adjuvants in such cell cultures.
  • No (problematic) adjuvants to stimulate the immune response.
  • No risk from pathogens capable of reproducing.
  • No administration of insertable DNA (61).
  •  mRNA is generally only very short-lived in the organism. The residence time of the mRNA can in principle be manipulated (replicable mRNA).
  •  In contrast to vector vaccines, mRNA vaccines can be boosted when the vaccine effect decreases.

However, there are also disadvantages:

·      A major disadvantage is the instability of the mRNA vaccine, which is only effective if the mRNA has the correct spatial structure. In vector vaccines, this is stabilized by the viral vector itself, while liponanoparticles (LNP) stabilize the biologically effective “packaging” of the mRNA in “pure” mRNA vaccines. Knowledge about these particles and their effect in the organism is still very limited. Since the acute side effects of mRNA vaccinations, according to previous approval studies, can be considerable, albeit mostly of limited duration (headache, fatigue, muscle pain, fever), it is not unlikely that the LNPs play a role here. In this sense, the problems of the LNPs are similar to those of an adjuvant, even though their strictly biological function is different. Another stabilizer in the BioNTech-Pfizer vaccine is polyethylene glycol (PEG), which, among other effects, is suspected of causing reactions ranging from allergic to anaphylactic (62).

  • The tolerability of these vaccines is poor, especially in younger people: in a Berlin hospital, 12% were unable to work after the 2nd vaccination of the BioNTech/Pfizer vaccine and 36% complained of severe discomfort, including a strong feeling of cold and shivering in addition to muscle pain and headache; some also developed fever (63). In other clinics, similar reports resulted from vaccination with the AstraZeneca vaccine.
  • The complex logistics (see below), especially of the BioNTech-Pfizer vaccine, are directly related to the low stability of the LNP-packaged mRNA.
  • The transferability between animal experiments and humans seems to be less with these than with conventional vaccines.
  • To date the duration of efficacy remains an open question and may also depend on the route of administration.
  • Studies of earlier mRNA vaccines, such as the rabies vaccine from CureVac in 2017, showed safety issues in the form of massive side effects, including systemic inflammatory processes, autoimmune phenomena (64), changes in blood clotting, etc.
  • The manipulation of protein biosynthesis harbors the particular risk of undesirable systemic immune reactions in the form of severe allergic reactions (anaphylaxis) and autoimmune reactions.

Advantages and disadvantages of viral-vectored vaccines

Viral-vectored vaccines (VVV) share the basic properties of mRNA vaccines in their principle of action, in so far as they are based on the “transport” of genetic information for antigen synthesis through the human organism. The “blueprint” of the vaccine antigen is transported by a carrier virus (already “correctly” folded) and is effective in protein biosynthesis in the cell infected by the carrier virus. In this case, if DNA viruses are used as “gene ferries”, as in the Astra-Zeneca VVV or the vector vaccine developed in Russia, the vaccine contains essentially foreign DNA (we are not addressing DNA vaccines in the narrower sense here). Common problems of all VVV are:

  • Inevitably developing or pre-existing immunity to the vector virus . Commonly used vector viruses are animal-specific DNA viruses, e.g., adenoviruses. Human-specific viruses are not used because of the risk of pre-existing immunity. But also, animal-specific viruses, as soon as they are used as VVVs, provoke a specific immunity, which can in principle make booster VVVs ineffective.
  • The extent of a possible, pre-existing immunity to the vector can vary considerably internationally.
  • Viruses alien to humans in principle also harbor risks for the human organism.
  • There is a residual risk of possible insertional mutagenesis of viral DNA into the human genome (65).

The AstraZeneca vaccine currently in use shows similar poor tolerability to the Biontech/Pfizer mRNA vaccine, although here the first dose tends to be worse tolerated (66).

How is vaccination practice changing due to the complex logistics required for mRNA vaccines?

Particularly the first mRNA vaccine from the German company BioNTech, developed in cooperation with the large pharmaceutical company Pfizer, requires complex logistics and, to put it mildly, unusual procedures regarding handling and administering the vaccine, thereby precluding its use in many kinds of outpatient medical practices. It is worth taking a look at the details (67). This vaccine has the following special properties:

  • Long-term storage is only possible in ultra-low freezers (–70°C or –94°F).
  • Delivery to vaccination centers requires appropriate refrigeration logistics.
  • In a vaccination center, the vaccine thaws in the vaccination refrigerator at +2°C to +8°C (35.6°F to 46.4°F) in 30 minutes and can then be kept for 5 days.
  • In order to be able to administer the vaccine, the thawed vaccine must be reconstituted by diluting it with a NaCl solution. To do this, the stopper of the vial must be disinfected with an antiseptic swab, the contents mixed with 1.8 ml 0.9% NaCl solution, removed once only from the 10 ml plastic vial with a syringe with a cannula (the rest must be discarded), and added to the vaccine. Mixing is then carried out by inverting the vial 10 times (!). Now 6 vaccination doses can be withdrawn per vial, whereby a new disposable syringe with a Luer connector must be used for each withdrawal.
  • After reconstitution, the vaccine can only be kept for a maximum of 6 hours at 2°C to 25°C (35.6°F to 77°F). This also means that, even from the point of view of the packaging, the vaccine is already a product designed for mass vaccination, not for individual vaccination decisions.

It is essentially the BioNTech-Pfizer vaccine that triggered the establishment of large vaccination centers in Germany. In our opinion, this is threatening to lead to a degree of militarization of vaccination itself (68), precluding prior knowledge of the patient on the part of the administering doctor.

In contrast, the mRNA vaccine from Moderna has a shelf life at refrigerator temperatures of 30 days and of six months at –20°C (–4°F). The vector vaccine from AstraZeneca, which can be kept at regular refrigerator temperatures of 2°C to 8°C (35.6°F to 46.4°F), is also supplied in multi-dose vials, each vial containing 10 vaccine doses and remaining viable for 12 hours at room temperature (67).

This format, which is not unproblematic in terms of hygiene and handling requirements, underlines its character as a vaccine designed for mass inoculation and restricts its applicability, e.g., in general practice, where individual assessment and advice can take place. This aspect is currently not being discussed publicly.

Questions currently remaining to be answered

With COVID-19, the significance of antibodies in the blood, in terms of protection against infection, the severity of potential disease, and how long they persist, remains unknown. This is also indicated by the publication on the Sinopharm vaccine cited above, which contrasts a response rate of 99.52% at the level of antibody formation with a protection rate of 79.34% against COVID-19 disease (69). Antibodies usually serve as surrogate markers of vaccination success in terms of successful immunization, e.g., with measles. With COVID-19 in particular, there are still ambiguities (70) because cellular (difficult to measure) immunity is of particular significance here . Clinical observations over years are of decisive importance. The quality and duration of potential vaccination protection cannot be assessed at the time of approval.

We do not know how many people in the population have background or cross immunity to SARS-CoV-2 (71, 72) (for whom the vaccination would therefore only mean a risk, with no additional gain). This risk applies in particular to children, who seem to be more protected against symptomatic COVID-19 disease through previous contact with coronaviruses, as well as by the robust response of their unspecific immune system (73).

In principle, SARS-CoV-2 raises the question of whether vaccinating children is ethically justifiable, since, according to the current state of knowledge, there is not only a very low risk of serious illnesses (74) such as MIS-C syndrome (75, 76), but also because children rarely to very rarely infect adults (77, 78, 79, 80). A current Australian meta-analysis reaches the following conclusions: “Only 8 (3.8%) transmission clusters were identified as having a pediatric index case [...] The secondary attack rate in pediatric household contacts was lower than in adult household contacts (RR, 0.62; 95% CI, 0.42–0.91).” (81) A Scottish study even shows that children appear to reduce COVID-19 disease risk in households (82)!

  • Rare, serious side effects can only be recorded after a large number of individuals have been vaccinated. The weekly safety reports of the German Paul Ehrlich Institute (PEI), e.g., currently show a rate of 0.1/1000 suspected unexpected severe side effects (83). The OPV example illustrates that potential risks of a vaccine may only become apparent after millions of doses have been administered. In the case of the Pandemrix® vaccine against so-called “swine flu”, Sarkanen et al. refer retrospectively to a possible vaccination risk of 1 : 18,400 of developing narcolepsy after vaccination (84). This example also illustrates the length of follow up required to recognize such autoimmune reactions to vaccines. It is evident that only the recording of very high numbers – possibly eight-digit numbers of vaccinated versus non-vaccinated individuals – will enable the recording of such side effects. The risk of allergic and autoimmune diseases, which can lead to serious neurological diseases (e.g., transverse myelitis), cannot currently be assessed with the SARS-CoV-2 vaccines, nor can the question of which patients are particularly at risk. It should always be remembered that the approval studies reflect an unrepresentatively healthy patient cohort.

The vaccination decision process

Arguments in favor of COVID-19 vaccination

In a pandemic of the magnitude of COVID-19, action must be taken and decisions made before all the details are clear. This also applies to the question of vaccination and it is inherently justified. The COVID-19 vaccination issue is not addressing extremely small risks like measles in Germany, but a large number of patients with severe illness whom we encounter every day in primary care and hospital settings and whose condition is sometimes terminal. At the same time, we are facing enormous dilemmas as well as secondary repercussions of the pandemic in educational, social, cultural, economic and medical fields.

Medicine is a science of action. This means continually having to make decisions and act before all desirable evidence is on the table, in a situation of uncertainty, without conclusive statistical evidence. This applies in principle to doctors as well as to citizens, patients, care recipients and, if applicable, their relatives or caregivers. This makes the call for a registry study all the more important. Even without answers to the still unanswered questions about safety, duration of vaccination protection, sterile immunity and possible contraindications, there are already some arguments in favor of vaccination today, which we would like to briefly summarize here:

  • Avoiding becoming ill oneself is a high value per se. However, some older people also want to be vaccinated so that they can continue to be there for their spouse who needs care. Both motives apply especially to medical personnel.
  •  To date, we see post-COVID syndromes , up to and including long-COVID (85), with persistent fatigue, neurologic deficits, persistent exertional dyspnea, and inability to work for many months in approximately 2 to 10% of manifestly ill patients. These cases are likely to be prevented or reduced by vaccination. Even in the case of side effects that have not yet been comprehensively statistically recorded, it is currently not to be expected that they will reach an order of magnitude comparable to the number of post-COVID syndromes.
  • Recommending vaccination seems relatively evident in nursing/care homes and homes for the elderly , not only because of the risk of disease and infection, but also in order to better enable the social contacts of the residents that are so necessary and to be able to relieve the staff both physically and psychologically. However, the STIKO restriction already cited above must be taken into account: “Even the very elderly, and people with progressive diseases who are in poor general health must be able to be vaccinated. These groups should be medically evaluated to see if vaccination can be recommended for them.” (29)
  • High demands are placed on the issue of participatory vaccination decision-making in social therapy facilities , where adults of all ages are involved, some with neurological or psychiatric pre-existing conditions, and where currently many who serve in a caregiver role are being asked to consent to vaccination. Specific risk factors must be taken into account. For example, adults with trisomy 21 (Down’s syndrome) have a significantly increased risk of mortality with COVID-19 (86). A comprehensive statement on this issue was published by the American Academy of Developmental Medicine & Dentistry, which summarizes the specific risks of people with assistance needs related to COVID-19, and accordingly calls for fair access to COVID-19 vaccines, while at the same time emphasizing that the autonomy of those affected should be respected, and while clearly opposing mandatory vaccination (87).

Health care workers are under particularly high pressure during the pandemic, which also results from the tight staffing situation as a consequence of one-sided economization of the health care system. Both nurses and physicians are well aware of how much patient care in the coming months will depend not least on their own health and ability to work. This applies particularly to secondary care, where anthroposophic hospitals in Germany and Switzerland are also involved in the care of COVID-19 patients experiencing all degrees of severity. Equally important for good care of the many COVID-19 patients is the outpatient setting, where specific anthroposophic therapy concepts have been clinically experienced as helpful, especially when they are used in the first week of illness (88). It is reasonable that COVID-19 vaccination of hospital and ambulatory practice staff can further minimize the risk of infection (possibly also the risk of transmission) beyond the known protective measures, thus preventing serious staff absences and contributing to stabilizing and securing patient care during the pandemic. At the same time, this argument must be handled sensitively, because especially employees in the health care system, including nursing homes, want to be taken seriously in exercising freedom of decision. According to both surveys and our personal experience, quite differing attitudes towards COVID-19 vaccinations prevail in this sector.

The issue of compulsory and indirect compulsory vaccination

Let us return to the discussion of a SARS-CoV-2 vaccination requirement. In this regard, representatives of Leopoldina, the German Ethics Council, and the Standing Commission on Vaccination STIKO (89) commented in the following vein on November 9, 2020: vaccination should be voluntary; the guiding principle for the planned vaccination campaign should be “the informed, voluntary consent of citizens willing to be vaccinated”. An undifferentiated, general vaccination obligation should therefore be ruled out. An obligation could at most be justified for a “precisely defined group,” in which case there would have to be “compelling reasons” (90).

It is not difficult to see that medical personnel in particular are being considered here – who, of course, due to their exposure, belong to the “threatened segments of the population” referred to in the current Infection Protection Act and whose activities are “necessary for the system”: “The Federal Ministry of Health is authorized to order by ordinance, with the consent of the Federal Counsel (Bundesrat), that threatened segments of the population must participate in protective vaccination or other measures of specific prophylaxis if a communicable disease with clinically severe progression occurs and is expected to spread epidemically.” (IfSG § 20,6) Several statements by members of the Ethics Council, as well as a variety of other voices in the media, suggest that, at the latest, when SARS-CoV-2 vaccines prove effective against transmission of the virus – i.e., when vaccinated individuals can no longer pass on the disease – mandatory vaccination of medical personnel would be warranted. However, such “sterile immunity” from a vaccine is unlikely. The chairman of the German Drug Commission W. D. Ludwig commented in an interview, according to the Frankfurter Rundschau of December 3, 2020: “We don’t know anything about how long that immunity lasts. We can state relatively confidently that so-called sterile immunity is probably not even achievable at the moment.” (91) This is supported by the fact that no vaccine has yet been able to demonstrate that it is capable of completely eliminating the risk of symptomatic COVID-19 disease. This also means that a reduction, but not a complete elimination, of the transmission risk is more likely for the time being. However, random sampling of physicians and nurses, i.e., those who bear the highest risk of exposure (92), shows that a significant proportion currently do not (yet) wish to be vaccinated. “Among the group practicing in a health profession, vaccination readiness [...] is by far the lowest,” RKI and media reported in December 2020 (93).

Since the health care system is working at the edge of its breaking point in terms of personnel, it is difficult to imagine the consequences if such a vaccination requirement were to trigger a substantial exodus of vaccine-averse “system-relevant” professionals from the health care systems in Germany, Austria, Switzerland and other countries. This seems quite conceivable in view of the general frustration of nursing professionals in particular, around one-fifth of whom are currently considering changing careers, according to studies in Germany (94, 95, 96).

The fact is that a considerable proportion of well-informed, professional medical personnel are currently skeptical about SARS-CoV-2 vaccination. Information campaigns are not likely to change this attitude, but only hard data resulting from comparative registry studies conducted free from direct or indirect vested interests, e.g., of the pharmaceutical industry, such as would be possible with an immunization registry as proposed in this paper.

While a general government vaccination requirement for adults seems unlikely, a system of indirect vaccination requirements is the much more likely and highly problematic scenario. Already the “Measles Protection Act” (MSG) passed in Germany in 2019 (97), which has contributed significantly to the polarization of general vaccination supporters and vaccination critics in a bureaucratically costly manner, represents at its core an interlocking system of indirect vaccination obligations , insofar as it excludes young children who are not immunized against measles from daycare centers and kindergartens, creates financial obstacles for parents who are unwilling to have their children vaccinated at school age, and potentially provides for even more far-reaching interventions, including the involvement of the youth welfare office. On February 4, 1921, the German Ethics Council expressed opposition to special rules for vaccinated individuals (98), as did the Council of Europe in its Resolution 2361 of January 27, 2021: “Ensure that citizens are informed that the vaccination is NOT mandatory and that no one is politically, socially, or otherwise pressured to get themselves vaccinated, if they do not wish to do so themselves.” (99)

If now the Australian airline Qantas intends to carry only vaccinated passengers as soon as vaccines are available and other airlines are considering similar arrangements, if companies are already now threatening their employees, indicating that in the future anyone unwilling to be vaccinated will no longer be tolerated in the company – even outside the health care sector – if there is public debate about making concert visits etc. dependent on “proof of immunity”, then it must first be said that there is no reliable factual evidence for this, since, according to current knowledge, no “proof of immunity” for SARS-CoV-2 has a sound scientific basis. Even with “95% efficacy”, the current approval studies already show that COVID-19 disease is possible in vaccinated people even after vaccination, including severe progression requiring hospitalization – and thus probably also the infection of others. Case reports show that in very rare cases, illness may recur after recovery from COVID-19 (100). Similarly, it has not yet been possible to determine immunity with sufficient reliability by simple antibody measurements: “The detection of antibodies to SARS-CoV-2 does not indicate directly protective immunity and correlates of protection for COVID-19 have not yet been established.” (101)

A system of indirect vaccination obligations threatens to discriminate against the non-vaccinated, which would de facto restrict this group of people in fundamental rights guaranteed by the German constitution, with respect to civil society if not the State. This argument is exacerbated by the fact that

  • from a medical ethics perspective, it is completely unclear whether children can and should be vaccinated, since no data on the safety and efficacy of SARS-CoV-2 vaccines in children are available to date, and all evidence to date points to a fundamentally different benefit-risk analysis for SARS-CoV-2 vaccination in children. The draft STIKO recommendation from the first week of December does not include vaccination of children. Martin Terhardt, a pediatrician and a member of the Standing Committee on Vaccination, told the rbb evening show that children under 16 are likely to be excluded (102, 103, 104).
  •  It is also to be expected that relative and absolute contraindications – possibly vaccine-specific for SARS-CoV-2 vaccination – will emerge in the coming months, which would lead to special discrimination against those affected. Immediately after mass vaccination began in the United Kingdom, two severe allergic reactions to the BioNTech-Pfizer vaccine occurred, so people who have already had more severe allergic reactions to foods, vaccines, or medications are now being advised against vaccination.
  • Given the diversity of SARS-CoV-2 vaccines with their varying efficacy, duration of efficacy, etc., a uniform “immunity pass” would be far less likely to be medically credible based on vaccination-only data than, say, measles vaccines.

Informed consent to vaccination as a basis for social acceptance and comparative research of SARS-CoV-2 vaccines

Realistically, 2021 will be characterized by the fact that a portion of the population will be vaccinated against SARS-CoV-2 infections with various vaccines and another portion will not or will not yet be vaccinated. Children are likely to remain excluded for the time being, if only because of the lack of data. Individual preferences, systematic prioritization, and logistical limitations are likely to play a role in who gets vaccinated. Whether indirect or direct vaccination obligations will be added is still an open question.

In this situation, we believe that informed consent to vaccinate is the only legal and evidence-based solution to the vaccination question with respect to COVID-19 . Given the limited knowledge, we believe physicians are obligated to involve all adults in the vaccination decision in a participatory manner, analogous to newly established surgical procedures with time-limited evaluations. In our view, this should apply especially to medical personnel themselves. The history of vaccination has always shown that even the best vaccines can, in rare or very rare cases, confer permanent damage to the organism in previously healthy individuals. Although this fact is as little of a counterargument as are the very rare complications of caesarean section or appendectomy, it does require informed consent, which has become as commonplace in surgical specialties as exploratory physical examinations (see (31)). The legal situation must be at least as strict in the area of protective vaccinations, which, in contrast to surgical interventions, are often performed on healthy individuals.

To be specific, this means that in every vaccination consultation, and not just in writing, information must be provided about the disease, the vaccine, its efficacy and its possible side effects, and the opportunity must be given for follow-up questions. Any consultation where the outcome is predetermined has no legal standing. In view of this legal situation – which is quite effective in vaccination damage lawsuits – it is a scandal that the German health care system currently does not reimburse for open-ended vaccination counseling. Up to now, vaccination counseling as a medical service has only been reimbursed by health insurance companies and in private practice after vaccination has taken place. Such a system is legally unacceptable, because it raises the strong suspicion that the physician has provided one-sided information.

In our view, the combination of freedom of choice on whether to vaccinate, in conjunction with a transparent and manufacturer-independent registry study to record all COVID-19 vaccinations, currently offers the best possible solution from a legal, scientific and social acceptance point of view. The vaccination registry study now planned in Bavaria under the direction of STIKO member Prof. Klaus Überla of the University of Erlangen may be a step in this direction (105, 106). To what extent this will be the case remains to be assessed when more details become known.

Freedom of thought – willingness to learn – flexibility of judgment

With regard to collegial dialogue within the medical profession, we uphold the principle originally put forward by Rosa Luxemburg: those who want freedom must want the freedom of those who think differently. Anyone who strives for human rights must stand by them, especially in times of crisis. The German constitution was created in response to an extreme exceptional situation, to serve as a reliable foundation of the constitutional state in stormy times. Neither the state nor civil society must be allowed to arbitrarily undermine the fundamental principles of the German constitutional state, as laid down in Articles 1-20 of the Constitution (and for other countries these principles may apply in a related way and in a different legal form).

Conclusion

A viable prevention through effective and safe vaccines can make a significant contribution to rapidly overcoming COVID-19. Moreover, in the context of the vaccination programs currently being rolled out, some of the questions regarding efficacy and safety can only be answered in the presence of adequate scientific monitoring, conducted independently of the vested interests of SARS-CoV-2 vaccine manufacturers. At this point, a democratic society faces the challenge of how far it wants to and can combine a safe, pseudonymized vaccination registry with individual vaccination choice free from overt or covert discrimination. Clearly, such a solution could allow for the social integration of citizens making diverse vaccine choices, while optimizing the gathering of scientific evidence.

The assessment of the currently developed SARS-CoV-2 vaccines with all their related questions is first and foremost a medical-scientific question, the answer to which will be based on the results of studies as well as practical clinical experience in managing the vaccination. However, the third pillar of evidence-based medicine, according to its founder David Sackett, is patient preference, which is nowhere of greater importance than in preventive interventions. Scientists, medical practitioners, patients and all members of society need to have the freedom space to develop their judgment about SARS-CoV-2 vaccines in the context of this pandemic in the same flexible way that politicians rightly claim for themselves.

Acknowledgements

The authors would like to thank their colleagues Dr. med. Marion Debus, Dr. med. Thomas Breitkreuz, Prof. Dr. med. Harald Matthes, Dr. med. Tido von Schoen-Angerer, Dr. med. Steffen Rabe, Dr. med. Martin Hirte for valuable suggestions and corrections.

Georg Soldner
Pediatrician
Josef-Retzer-Str. 36
81241 Munich, Germany
Deputy Head of the Medical Section
at the Goetheanum
4143 Dornach, Switzerland
georg.soldner@medsektion-goetheanum.ch

Prof. Dr. med. David Martin
Pediatrician, Pediatric Oncologist, Diabetologist and Endocrinologist
Holder of the Gerhard Kienle Chair of Medical Theory, Integrative and Anthroposophic Medicine at
Witten/Herdecke University
Alfred-Herrhausen-Str. 50
58488 Witten, Germany
david.martin@uni-wh.de

1 Eckert N, Fischer-Fels J. SARS-CoV-2: Wettlauf mit dem Virus. Deutsches Ärzteblatt 2021:118(7):A342/B-345.

2 Cf. the daily situation report of the Robert Koch Institute (RKI) of October 21, 2020. Available at https://www.rki.de/DE/Content/InfAZ/N/Neuartiges_Coronavirus/Situationsberichte/Okt_2020/2020-10-20-de.pdf;jsessionid=172A7681A1228B9DA3E2D06798534A47.internet081 (29.12.2020). The RKI speaks here of a mortality rate of well below 1% of all infected people. However, the mortality rates differ considerably, depending on the recording of asymptomatic cases and the average age of the infected people (which is 17 years in Africa, with a correspondingly low mortality) and the population.

3 In the case of the “Spanish flu”, it was the 20–40-year-olds, which clearly shows the central importance of the aspect of age in viral pandemics – and thus also for vaccination issues with COVID-19.

4 Kliegman RM, Stanton BF, Geme JS, et al. (ed.). Nelson Textbook of Pediatrics. 20th ed. Philadelphia: Elsevier; 2016: 1555–1560.

5 Gasperi S, Mulder F, Soldner G, Winkler M, Zimmermann P. Im Gedenken an Dr. med. Giancarlo Buccheri. Der Merkurstab 2020;73(4):275. Available at https://www.anthromedics.org/DMS-21247-DE (29.12.2020).

6 On Pakistan and Afghanistan available at http://polioeradication.org/wp-content/uploads/2020/12/weekly-polio-analyses-WPV-20201222.pdf (02.01.2021). 

7 WHO. Circulating vaccine-derived poliovirus type 2 – Sudan. Disease outbreak news 1 September 2020. Available at https://www.who.int/csr/don/01-september-2020-polio-sudan/en/ (19.12.2020).

8 CDC. Progress toward regional measles elimination – Worldwide, 2000–2019. Weekly 2020;69(45):1700–1705. Available at         https://www.cdc.gov/mmwr/volumes/69/wr/mm6945a6.htm (31.12.2020).

9 Levine-Tiefenbrun M, Yelin I, Katz R, Herzel E, Golan Z, Schreiber L, Wolf T, Nadler V, Ben-Tov A, Kuint J, Gazit S, Patalon T, Chodick G, Kishony R. Decreased SARS-CoV-2 viral load following vaccination. medRxiv Feb 8, 2021  DOI: https://doi.org/10.1101/2021.02.06.21251283. [Crossref]

10 Lavine JS, Bjornstad ON, Antia R. Immunological characteristics govern the transition of COVID-19 to endemicity. Science 2021;371(6530):741-745. DOI: https://doi.org/10.1126/science.abe6522. [Crossref]

11 Regarding the BioNTech-Pfizer vaccine, whose phase III trial included 43,998 participants, cf. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. The New England Journal of Medicine 2020;NEJMoa2034577. DOI: https://doi.org/10.1056/NEJMoa2034577. [Crossref]

12 Available at https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-conclude-phase-3-study-covid-19-vaccine (15.12.2020).

13 For the Moderna vaccine, whose phase III trial included 30,000 participants, cf. https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-primary-efficacy-analysis-phase-3-cove-study/ (15.12.2020).

14 For AstraZeneca’s vaccine, in whose phase III trials more than 23,000 participants were enrolled and 11,636 were included in the interim analysis, see: Voysey M, Costa Clemens SA, Madhi SA, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: An interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. The Lancet 2020. DOI: https://doi.org/10.1016/S0140-6736(20)32661-1. [Crossref]

15 Available at https://www.astrazeneca.com/media-centre/press-releases/2020/azd1222hlr.html (15.12.2020).

16 Kristensen I, Aaby P, Jensen H. Routine vaccinations and child survival: Follow up study in Guinea-Bissau, West Africa. The BMJ 2000;321(7274):1435–1438. DOI: https://doi.org/10.1136/bmj.321.7274.1435. [Crossref]

17 Aaby P, Kollmann TR, Benn CS. Nonspecific effects of neonatal and infant vaccination: Public-health, immunological, and conceptual challenges. Nature Immunology 2014;15(10):895–899. DOI: https://doi.org/10.1038/ni.2961. [Crossref]

18 Aaby P, Ravn H, Benn CS. The WHO review of the possible nonspecific effects of diphtheria-tetanus-pertussis vaccine. The Pediatric Infectious Disease Journal 2016;35(11):1247–1257. DOI: https://doi.org/10.1097/INF.0000000000001269. [Crossref]

19 Yamamoto-Hanada K, Pak K, Saito-Abe M, et al. Cumulative inactivated vaccine exposure and allergy development among children: A birth cohort from Japan. Environmental Health and Preventive Medicine 2020;25:27. DOI: https://doi.org/10.1186/s12199-020-00864-7. [Crossref]

20 The Standing Committee on Vaccination at the Robert Koch Institute (STIKO) emphasizes the need for “intensified surveillance” in its recommendation on COVID-19 vaccination: Beschluss der STIKO für die Empfehlung der COVID-19-Impfung und die dazugehörige wissenschaftliche Begründung. STIKO-Empfehlung zur COVID-19-Impfung. Epidemiologisches Bulletin 2021;2:60. Available at https://www.rki.de/DE/Content/Infekt/EpidBull/Archiv/2021/Ausgaben/02_21.pdf?__blob=publicationFile (25.01.2021).

21 Collier DA, De Marco A, Ferreira IATM et al. SARS-CoV-2 B.1.1.7 escape from mRNA vaccine-elicited neutralizing antibodies. Reprint. medRxiv February 3, 2021. DOI: https://doi.org/10.1101/2021.01.19.21249840. [Crossref]

22 Sieber U, Pohl M. Datenchaos nach der Corona-Impfung? Available at https://www.tagesschau.de/investigativ/kontraste/corona-impfung-nachbeobachtung-101.html (29.12.2020).

23 Available at https://www.dgepi.de/assets/Stellungnahme-zum-Referentenentwurf-der-Coronavirus-Impfverordnung_CoronaImpfV.pdf (29.12.2020).

24 Available at https://www.dgepi.de/assets/Stellungnahmen/COVID19_Impfung_Routinedaten.pdf (29.12.2020).

25 The frequently cited ruling of the Federal Administrative Court on smallpox vaccination in 1959 is explicitly limited to that extraordinarily severe infectious disease, with which neither measles nor COVID-19 can be compared: BVerwG, Urt. v. 14.07.1959 – IC 170.56 – VerwGE 9,78 = NJW 1959, 2325. Available at https://www.urteilsbesprechungen.de/2020/08/31/bundesverwaltungsgericht-urteil-vom-14-07-1959-c-17056/ (31.12.2020).

26 European Medicines Agency. First COVID-19 vaccine safety update. 29.01.2021. Available at https://www.ema.europa.eu/en/news/first-covid-19-vaccine-safety-update-published (08.02.2021).

27 Paul-Ehrlich-Institut. Verdachtsfälle von Nebenwirkungen und Impfkomplikationen nach Impfung zum Schutz vor COVID-19 seit Beginn der Impfkampagne am 27.12.2020 bis zum 31.01.2021. 04.02.2021, p. 7. Available at  https://www.pei.de/SharedDocs/Downloads/DE/newsroom/dossiers/sicherheitsberichte/sicherheitsbericht-27-12-bis-31-01-21.pdf?__blob=publicationFile&v=5 (05.02.2021).

28 COVID-19-Impfstoff von Moderna. arznei-telegramm 2021;52(1):3.

29 Robert-Koch-Institut: Epidemiologisches Bulletin 2021;5:5. Available at  https://www.rki.de/DE/Content/Infekt/EpidBull/Archiv/2021/Ausgaben/05_21.pdf?__blob=publicationFile (05.02.2021).

30 Hirte M. Impfen – Pro & Contra. Munich: Knaur; 2018.

31 Bütikofer J. Schutzimpfungen: Aufklärungspflicht aus juristischer Sicht. Deutsches Ärzteblatt 1997;94(26):A-1794–1796. Available at https://www.aerzteblatt.de/archiv/6914/Schutzimpfungen-Aufklaerungspflicht-aus-juristischer-Sicht (29.12.2020). p. A 1794: “From a legal perspective, physicians should not conceal the fact that vaccinations are by no means a harmless intervention in the immune system [...] An opportunity for comprehensive information through a discussion with the vaccinator must be provided at every vaccination appointment. Oral education is the method of choice for individual vaccinations in the office of the general practitioner. The Federal Court of Justice strongly advocates clarification in personal doctor-patient discussions, the responsible conduct of which it gives to the doctor – without being restricted by legal regulations. [...] In 20 years of professional experience with vaccine injury, I have had to deal with very few cases in which vaccine injury was fated to occur; most of the serious vaccine injury cases with which I have been professionally involved would probably have been avoidable if contraindications to vaccination had been more carefully observed and if children in particular had been routinely vaccinated only after careful examination. If the vaccinator did not provide education – or at least not in a timely manner – or cannot prove such education, he or she may face significant criminal and also civil difficulties.”

32 The corresponding STIKO publication also lacks any reference to a physical examination before administering the vaccine: STIKO-Empfehlung zur COVID-19-Impfung. Epidemiologisches Bulletin 2021;2. Available at https://www.rki.de/DE/Content/Infekt/EpidBull/Archiv/2021/Ausgaben/02_21.pdf?__blob=publicationFile (29.12.2020).

33 Bütikofer J. Schutzimpfungen: Aufklärungspflicht aus juristischer Sicht. Deutsches Ärzteblatt 1997;94(26):A-1794–1796. Available at https://www.aerzteblatt.de/archiv/6914/Schutzimpfungen-Aufklaerungspflicht-aus-juristischer-Sicht (29.12.2020). p. A 1796: “If the duty to inform is violated, the vaccinator is liable – which is far too little known – in addition to the state, for breach of contract and for tort, which leads, among other things, to a claim for damages for pain and suffering by the vaccinated person against the vaccinator. In civil proceedings against the physician, the vaccinated person only has to prove that he or she was vaccinated and that the damage was based on the vaccination. The physician, on the other hand, must prove that there was effective consent, and that means above all that he had provided sufficient information. If he fails to prove this, then he will be ordered to pay damages and, if necessary, compensation for pain and suffering. Since severe vaccination damage not only causes unimaginable human suffering to those affected, but also enormous financial burdens on health insurance companies, pension funds, those directly affected by the vaccination damage and, under certain circumstances, also the vaccinator, care should be taken not only for human but also for economic reasons to ensure that vaccinations are only carried out after careful information and consideration of contraindications.”

34 Doshi P. Will COVID-19 vaccines save lives? Current trials aren’t designed to tell us. The BMJ 2020:371. DOI: https://doi.org/10.1136/bmj.m4037. [Crossref]

35 Doshi P. Pfizer and Moderna’s “95% effective” vaccines – let’s be cautious and first see the full data. The BMJ Opinion 2020. Available at https://blogs.bmj.com/bmj/2020/11/26/peter-doshi-pfizer-and-modernas-95-effective-vaccines-lets-be-cautious-and-first-see-the-full-data/ (29.12.2020).

36 Doshi P. Pfizer and Moderna’s “95% effective” vaccines – let’s be cautious and first see the full data. The BMJ Opinion 2020. https://blogs.bmj.com/bmj/2021/01/04/peter-doshi-pfizer-and-modernas-95-effective-vaccines-we-need-more-details-and-the-raw-data/ (07.01.2021).

37 STIKO recommendation for COVID-19 vaccination, p. 25: “An efficacy of 75% was determined [...] against the secondary endpoint of ‘severe COVID-19 disease’, but this was not statistically significant.” Epidemiologisches Bulletin 2021;2:28. Also noteworthy is STIKO’s critical statement on risk of bias and trustworthiness of evidence, which notes, among other things, that “in the analysis of efficacy, approximately 4000 subjects in both study arms were not considered” and “parts of the study personnel were apparently not blinded.” The quality of evidence was judged to be low in the age group >75 years because of the wide confidence interval: in the highest age group (≥75 years), a statement about the effectiveness of vaccination is therefore subject to high uncertainty. STIKO-Empfehlung zur COVID-19-Impfung. Aktualisierung vom 14. Januar 2021. Epidemiologisches Bulletin 2021;2:28. Available at https://www.rki.de/DE/Content/Infekt/EpidBull/Archiv/2021/Ausgaben/02_21.pdf?__blob=publicationFile (25.01.2021).

38 Dagan N, Barda N, Kepten E, Miron O, Perchik S, Katz MA, Hernán MA, Lipsitch M, Reis B, Balicer RD. BNT162b2 mRNA Covid-19 vaccine in a nationwide mass vaccination setting. New England Journal of Medicine 2021, Feb 24. DOI: https://doi.org/10.1056/NEJMoa2101765. [Crossref]

39 Logunov D et al. Safety and efficacy of an rAd26 and rAd5-vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. The Lancet 2021; 397(10275):671-681. DOI: https://doi.org/10.1016/S0140-6736(21)00234-8. [Crossref]

40 COVID-19-Impfstoff von AstraZeneca. arznei-telegramm® 2021;2:9–12.

41 Lopez Bernal J, Andrews N, Gower C, Stowe J, Robertson C, Tessier E, Simmons R, Cottrell S, Roberts R, O’Doherty M, Brown K, Cameron C, Stockton D, McMenamin J, Ramsay M. Early effectiveness of COVID-19 vaccination with BNT162b2 mRNA vaccine and ChAdOx1 adenovirus vector vaccine on symptomatic disease, hospitalisations and mortality in older adults in England. medRixv 2021, March. DOI: https://doi.org/10.1101/2021.03.01.21252652. [Crossref]

42 Voysey M et al. Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials. The Lancet 2021, Feb. 19. DOI: https://doi.org/10.1016/S0140-6736(21)00432-3.

43 Available at http://www.bjbpi.com/news_list.asp?id=787 (31.12.2020).

44 Doshi P. Will COVID-19 vaccines save lives? Current trials aren’t designed to tell us. The BMJ 2020:371. DOI: https://doi.org/10.1136/bmj.m4037. [Crossref]

45 For the BioNTech-Pfizer vaccine, 4% of those vaccinated were over 75 years of age in the pivotal trial; with very small numbers of cases, no statistically significant efficacy was detectable with 5 vs. 0 symptomatic SARS-CoV-2 infections. Cf.: arznei-telegramm® 2020;51(12). Available at https://www.arznei-telegramm.de/01index.php3 (29.12.2020).

46 The study of the Moderna mRNA vaccine included 7,000 people over the age of 65: Available at https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-primary-efficacy-analysis-phase-3-cove-study/ (30.12.2020). More detailed information on this is not yet available.

47 European Medicines Agency. EMA recommends COVID-19 Vaccine AstraZeneca for authorisation in the EU. 29.01.2021. Available at https://www.ema.europa.eu/en/news/ema-recommends-covid-19-vaccine-astrazeneca-authorisation-eu (06.01.2021).

48 Robert Koch Institut. Beschluss der STIKO zur 2. Aktualisierung der COVID-19-Impfempfehlung. Epidemiologisches Bulletin 2021; 5. 04.02.2021. Available at https://www.rki.de/DE/Content/Infekt/EpidBull/Archiv/2021/Ausgaben/05_21.pdf?__blob=publicationFile (06.02.2021).

49 Andrew MK, McElhaney JE. Age and frailty in COVID-19 vaccine development. The Lancet, 2020;396(10267):1942–1944. DOI: https://doi.org/10.1016/S0140-6736(20)32481-8. [Crossref]

50 Ramasamy MN, Minassian AM, Ewer KJ, et al. Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): A single-blind, randomised, controlled, phase 2/3 trial. The Lancet 2020;396(10267):1979–1993. DOI: https://doi.org/10.1016/S0140-6736(20)32466-1. Andrew and McElhaney comment positively in principle on Ramasamy’s study of the Oxford University and AstraZeneca vaccine, but state: “The main study limitations were its single-blind design, the inclusion of few participants older than 80 years, and exclusion of people with substantial underlying chronic illnesses and frailty” (p. 1943).

51 Iacobucci G, Mahase E. COVID-19 vaccines: What’s the evidence for extending the dosing interval? BMJ 2021; 372 DOI: https://doi.org/10.1136/bmj.n18. [Crossref]

52 Editorial. COVID-19 vaccines: No time for complacency. The Lancet 2020;396(10263):1607. DOI: https://doi.org/10.1016/S0140-6736(20)32472-7. [Crossref]

53 Available at https://www.vfa.de/de/arzneimittel-forschung/woran-wir-forschen/impfstoffe-zum-schutz-vor-coronavirus-2019-ncov (30.12.2020).

54 Afrough B, Dowall S, Hewson R. Emerging viruses and current strategies for vaccine intervention. Clinical & Experimental Immunology 2019;196(2):157–166. DOI: https://doi.org/10.1111/cei.13295. [Crossref]

55 Logunov DY, Dolzhikova IV, Shcheblyakov DV et al. Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. The Lancet, Feb. 2, 2021, DOI: https://doi.org/10.1016/S0140-6736(21)00234-8. [Crossref]

56 Mahase E. Covid 19: Novavax vaccine efficacy is 86% against UK variant and 60% against South African variant. British Medical Journal 2021;372. DOI:  https://doi.org/10.1136/bmj.n296. [Crossref]

57 That is according to Pfizer’s 53-page FDA briefing document for the Dec. 10, 2020 Vaccines and Related Biological Products Advisory Board Meeting with the FDA: Pfizer and BioNTech. Vaccines and Related Biological Products. Advisory Committee Meeting, December 10, 2020, p. 12. Available at https://www.fda.gov/media/144245/download (30.12.2020).

58 Such is the case with a Chinese inactivated SARS-CoV-2 vaccine: Zhang Y, Zeng G, Pan H, et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18–59 years: A randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. The Lancet Infectious Diseases 2020. DOI: https://doi.org/10.1016/S1473-3099(20)30843-4. [Crossref]

59 Rabe S. mRNA- und Virus-Vektor-Impfstoffe. Available at https://impf-info.de/pdfs/mRNA_VV_Impfstoffe_201202.pdf (30.12.2020).

60 Liu MA. A comparison of plasmid DNA and mRNA as vaccine technologies. Vaccines (Basel) 2019;7(2):37. DOI: https://doi.org/10.3390/vaccines7020037. [Crossref]

61 But there is an insertion risk in the presence of a reverse transcriptase.

62 Paul-Ehrlich-Institut. Verdachtsfälle von Nebenwirkungen und Impfkomplikationen nach Impfung zum Schutz vor COVID-19 seit Beginn der Impfkampagne am 27.12.2020 bis zum 31.01.2021. 04.02.2021, S. 13. Available at  https://www.pei.de/SharedDocs/Downloads/DE/newsroom/dossiers/sicherheitsberichte/sicherheitsbericht-27-12-bis-31-01-21.pdf?__blob=publicationFile&v=5 (05.02.2021).

63 Data unpublished, in-clinic survey data available to authors.

64 Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines – A new era in vaccinology. Nature Reviews 2018;17:261–279. Available at https://www.nature.com/articles/nrd.2017.243.pdf?origin=ppub (30.12.2020): “A possible concern could be that some mRNA-based vaccine platforms induce potent type I interferon responses, which have been associated not only with inflammation but also potentially with autoimmunity. Thus, identification of individuals at an increased risk of autoimmune reactions before mRNA vaccination may allow reasonable precautions to be taken.” (p. 275)

65 Jötten F. Wird Adenovirus-DNA ins Genom eingebaut? Spektrum der Wissenschaft 2021;2. Available at https://www.spektrum.de/news/vektor-impfstoff-wird-adenovirus-dna-ins-genom-eingebaut/1835725 (03.03.2021).

66 Available at https://www.aerzteblatt.de/nachrichten/121263/COVID-19-Die-Datenlage-zum-Astrazeneca-Impfstoff-auf-einen-Blick (03.03.2021).

67 Hüttemann D. Was genau müssen Apotheker und PTA tun? Pharmazeutische Zeitung 02.12.2020. Available at https://www.pharmazeutische-zeitung.de/was-genau-muessen-apotheker-und-pta-tun-122284 (30.12.2020).

68 Regardless of the extent to which the Armed Forces are involved in this form of care, which is planned at a number of immunization centers.

69 Available at http://www.bjbpi.com/news_list.asp?id=787 (31.12.2020).

70 A Berlin laboratory provides information on the measurement of SARS-CoV-2 IgG antibodies: “According to current data, false positive results must be expected in about 12–14% of cases across manufacturers [...] Does antibody detection also mean immunity? The long-term studies needed to make this statement cannot currently exist.” IMD Labor Berlin. Indikation und Interpretation der SARS-CoV-2-Antikörperdiagnostik. Available at https://www.imd-berlin.de/fachinformationen/diagnostikinformationen/indikation-und-interpretation-der-sars-cov-2-antikoerperdiagnostik.html (30.12.2020).

71 Ng KW, Faulkner N, Cornish GH, et al. Preexisting and de novo humoral immunity to SARS-CoV-2 in humans. Science 2020;370(6522):1339–1343. DOI: https://doi.org/10.1126/science.abe1107. [Crossref]

72 The STIKO recommendation for COVID-19 vaccination indicates that “preexisting SARS-CoV-2 reactive CD4+ memory T cells [...] may be involved in both control and pathology of COVID-19.” STIKO-Empfehlung zur COVID-19-Impfung. Epidemologisches Bulletin 2021;2:12. Available at https://www.rki.de/DE/Content/Infekt/EpidBull/Archiv/2021/Ausgaben/02_21.pdf?__blob=publicationFile (25.01.2021).

73 Pierce CA, Preston-Hurlburt P, Dai Y, et al. Immune responses to SARS-CoV-2 infection in hospitalized pediatric and adult patients. Science Translational Medicine 2020;12(564):eabd5487. DOI: https://doi.org/10.1126/scitranslmed.abd5487. [Crossref]

74 Ludvigsson JF. Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults. Acta Paediatrica 2020;109(6):1088–1095. DOI: https://doi.org/10.1111/apa.15270. [Crossref]

75 Zeichner SL, Cruz AT. Multisystem inflammatory syndrome in children and SARS-CoV-2 Serology. Pediatrics 2020;146(6):e2020032888. DOI: https://doi.org/10.1542/peds.2020-032888. [Crossref]

76 Rabe S. mRNA- und Virus-Vektor-Impfstoffe, available at https://impf-info.de/pdfs/mRNA_VV_Impfstoffe_201202.pdf (30.12.2020), points out an important statement in the publication by Zeichner and Cruz related to the fact that MIS-C syndrome appears to be associated with highly elevated antibody titers to the receptor-binding region (RBD) of corona spike virus: “Close attention to vaccines eliciting anti-RBD antibodies may be advisable, if dysregulated or aberrant responses against RBD or parts of RBD contribute to hyperinflammation. Many candidate vaccines aim to elicit responses against the entire S, including RBD. Some aim to specifically elicit antibodies against RBD. Although a COVID-19 vaccine is urgently needed, leading vaccinologists have cautioned against deploying vaccines without thorough safety evaluations, recalling unfortunate past tragedies involving candidate vaccines, with vaccination yielding increased morbidity and mortality when vaccine recipients were later infected with circulating virus. If strong anti-RBD responses are associated with an increased risk of inflammatory disorders, it may then be advantageous to develop vaccines that, while eliciting excellent anti-SARS-CoV-2 neutralizing activity, preferentially avoid eliciting strong anti-RDB immune responses.” In principle, there is a risk of infection-enhancing antibodies (antibody-dependent enhancement) with coronaviruses. The extent to which – possibly not only corona-specific – vaccinations can increase the susceptibility of such immunological dysregulation has not yet been clarified.

77 Lee B, Raszka WV. COVID-19 transmission and children: The child is not to blame. Pediatrics 2020;146(2):e2020004879. DOI: https://doi.org/10.1542/peds.2020-004879. [Crossref]

78 Gilliam WS, Malik AA, Shafiq M, et al. COVID-19 transmission in US child care programs. Pediatrics 2020:e2020031971. DOI: https://doi.org/10.1542/peds.2020-031971. [Crossref]

79 Schwarz S, Jenetzky E, Krafft H, et al. Corona in children: The Co-Ki study. Monatsschrift Kinderheilkunde 2020:1–6. DOI: https://doi.org/10.1007/s00112-020-01050-3. [Crossref]

80 Isphording IE, Lipfert M, Pestel N. School re-openings after summer breaks in Germany did not increase SARS-CoV-2 cases. IZA DP 2020;No. 13790. Available at http://ftp.iza.org/dp13790 (30.12.2020).

81 Zhu Y, Bloxham CJ, Hulme KD, et al. A meta-analysis on the role of children in SARS-CoV-2 in household transmission clusters. Clinical Infectious Diseases 2020:ciaa1825. DOI: https://doi.org/10.1093/cid/ciaa1825. [Crossref]

82 Wood R, Thomson EC, Galbraith R, et al. Sharing a household with children and risk of COVID-19: A study of over 300,000 adults living in healthcare worker households in Scotland. medRxiv preprint 2020. DOI: https://doi.org/10.1101/2020.09.21.20196428. [Crossref]

83 Paul-Ehrlich-Institut. Sicherheit von COVID-19-Impfstoffen. Available at https://www.pei.de/DE/newsroom/dossier/coronavirus/coronavirus-inhalt.html?nn=13577266&cms_pos=5 (06.02.2021).

84 Sarkanen TO, Alakuijala APE, Dauvilliers YA, Partinen MM. Incidence of narcolepsy after H1N1 influenza and vaccinations: Systematic review and meta-analysis. Sleep Medicine Reviews 2018;38:177–186. DOI: https://doi.org/10.1016/j.smrv.2017.06.006. [Crossref]

85 Sudre CH, Murray B, Varsavsky T, et al. Attributes and predictors of Long-COVID: Analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App. medRxiv preprint 2020. DOI: https://doi.org/10.1101/2020.10.19.20214494. [Crossref]

86 Clift AK, Coupland CAC, Keogh RH, et al. COVID-19 mortality risk in Down syndrome: Results from a cohort study of 8 million adults. Annals of Internal Medicine 2020; DOI: https://doi.org/10.7326/M20-4986. [Crossref]

87 American Academy of Developmental Medicine & Dentistry. Joint position statement on equity for people with intellectual and developmental disabilities (IDD) regarding COVID-19 vaccine allocation and safety. Updated December 9, 2020. Available at https://ddi.wayne.edu/aucd/covid19vaccine-idd-statement.pdf (14.01.2021).

88 Soldner G, Breitkreuz T. COVID-19. Der Merkurstab 2020;73(4):225–234. DOI: https://doi.org/10.14271/DMS-21241-DE. [Crossref]

89 Positionspapier der STIKO, Leopoldina und des Deutschen Ethikrats zur Verteilung eines COVID-19-Impfstoffes. Available at https://www.rki.de/DE/Content/Infekt/Impfen/ImpfungenAZ/COVID-19/Positionspapier.html (30.12.2020).

90 Positionspapier der STIKO, Leopoldina und des Deutschen Ethikrats zur Verteilung eines COVID-19-Impfstoffes. Available at https://www.rki.de/DE/Content/Infekt/Impfen/ImpfungenAZ/COVID-19/Positionspapier.html (30.12.2020), p. 2: “Undifferentiated, general mandatory vaccination should therefore be ruled out. If at all, mandatory vaccination could only be justified by serious reasons and for a precisely defined group of people. This would particularly affect employees who, as potential multipliers, are in constant contact with members of a high-risk group, when only vaccination could prevent serious harm to this group of people. The necessary legislative specifications and their concrete application would also have to be made and reviewed in the light of the evolving knowledge on the efficacy and risk profiles of the new vaccines. In this respect, an area-specific vaccination requirement in the context of vaccines against COVID-19 in particular would only come into consideration once sufficient observation of the mode of action of the vaccine has taken place over time. At the same time, the ethical principle of non-injury or integrity protection is implicated.”

91 Available at https://www.fr.de/ratgeber/gesundheit/corona-covid-19-coronavirus-impfstoff-impfen-impfpflicht-experte-zulassung-warnung-90117382.html (31.12.2020).

92 According to survey results, the SARS-CoV-2 infection risk of long-term care workers is increased 6-fold compared to the general population: Betsch C, Korn L, Felgendreff L, et al. COVID-19 Snapshot Monitoring (COSMO Germany) – Wave 26. PsychArchives 2020. DOI: https://doi.org/10.23668/PSYCHARCHIVES.4356.

93 Betsch C, Korn L, Felgendreff L, et al. COVID-19 Snapshot Monitoring (COSMO Germany) – Wave 24. PsychArchives 2020. DOI: http://dx.doi.org/10.23668/psycharchives.4317. The current STIKO recommendation for COVID-19 vaccination also points to the same study: STIKO-Empfehlung zur COVID-19-Impfung. Epidemologisches Bulletin 2021;2:58. Available at https://www.rki.de/DE/Content/Infekt/EpidBull/Archiv/2021/Ausgaben/02_21.pdf?__blob=publicationFile (25.01.2021): “...among medical personnel the willingness to vaccinate is the lowest.”

94 Jacobs K, Kuhlmey A, Greß S, Klauber J, Schwinger A (ed.). Pflege-Report 2016. Schwerpunkt: Die Pflegenden im Fokus, Stuttgart: Schattauer; 2016.

95 Nolting HJ, Grabbe Y, Genz HO, Kordt M. Beschäftigtenfluktuation bei Pflegenden: Ein Vergleich der Bedeutung von arbeitsbedingtem Stress, organisationalen und individuellen Faktoren für die Absicht zum Berufswechsel und zum innerberufIichen Arbeitsplatzwechsel. Pflege 2006;19:108–115. DOI: https://doi.org/10.1024/1012-5302.19.2.108. [Crossref]

96 Redaktion Rechtsdepesche. Wieso ein Ausstieg aus der Pflege? 24.04.2018. Available at https://www.rechtsdepesche.de/wieso-ein-berufsausstieg-aus-der-pflege/ (30.12.2020).

97 Bundesgesetzblatt 2020, Teil I, no. 6, Bonn, 13.02.2020.

98 Deutscher Ethikrat. Besondere Regeln für Geimpfte? Ad-hoc-Empfehlung. Berlin, 04.02.2021.

99 Parliamentary Assembly. Covid-19 vaccines: ethical, legal and practical considerations. Resolution 2361. January 27, 2021. Available at https://pace.coe.int/en/files/29004/html (06.02.2021).

100 Tillet RL, Sevinsky JR, Hartley PD, et al. Genomic evidence for reinfection with SARS-CoV-2: A case study. The Lancet Infectious Diseases 2020;21(1):52–58. DOI: https://doi.org/10.1016/S1473-3099(20)30764-7. [Crossref]

101 European Centre for Disease Prevention and Control. Immune responses and immunity to SARS-CoV-2. Available at https://www.ecdc.europa.eu/en/covid-19/latest-evidence/immune-responses (31.12.2020).

102 Available at https://www.aerzteblatt.de/nachrichten/119116/STIKO-Impfempfehlungen-liegen-vor-Medizinisches-Personal-wird-nicht-gleichermassen-priorisiert. (30.12.2020).

103 See also: https://www.aerzteblatt.de/nachrichten/119069/Schwangere-und-Kinder-wahrscheinlich-von-Impfung-auf-SARS-CoV-2-ausgeschlossen (31.12.2020). The Guardian reported on Dec. 9, 2020, that vaccination should only be administered in facilities where resuscitation is available.

104 Available at https://www.theguardian.com/world/2020/dec/09/pfizer-covid-vaccine-nhs-extreme-allergy-sufferers-regulators-reaction (30.12.2020).

105 Studie begleitet Corona-Impfungen. Süddeutsche Zeitung, 27.12.2020, 16:17 pm. Available at https://www.sueddeutsche.de/bayern/gesundheit-muenchen-studie-begleitet-corona-impfungen-dpa.urn-newsml-dpa-com-20090101-201227-99-824198 (02.01.2021).

106 Corona begegnen. Eine Million Euro für Impfstudie CoVAKo 2021. Available at https://www.virologie.uk-erlangen.de/aktuelles/nachrichten/detail/corona-begegnen/ (31.12.2020).