Know more – make informed decisions

Impfsituation: Eine Spritze im Oberarm einer Person

The largest targeted vaccination campaign of the last 50 years has begun – but there is still widespread uncertainty and a considerable need for information: How effective is vaccination against COVID-19? And how safe is it? Science can offer information on many issues on an independent and broad basis.

Rarely has so much information become available through such markedly intense political debate fuelled by the media. And yet in spite of this – or indeed for this very reason – there is still great uncertainty and a considerable need for information among large parts of the population as the vaccination campaign against SARS-CoV-2 now gets underway.

According to a recent survey conducted by the University of Erfurt, almost three quarters of the German population obtain information about the new coronavirus fairly frequently to very frequently. However, more than half of the respondents feel poorly or fairly poorly informed about vaccination against the virus. There are also considerable gaps in information regarding the disease itself and its transmission. This has consequences: people who do not know that COVID-19 is transmitted by aerosols are less likely to adhere to basic social distancing and hygiene rules. So when it comes to getting vaccinated against SARS-CoV-2, it is likewise to be expected that lower levels of knowledge leads to a lower level of vaccine acceptance.

This is all the more worrying in view of the fact that there all kinds of myths and misinformation circulating to fill in the blanks. One particular factor fuelling reservations is the fact that the vaccines now being used for the first time use a new, gene-based technology. It is already becoming apparent that people who are critical of genetic engineering are also more likely to be vaccine hesitant. In view of this, knowledge is needed about vaccination, its possible benefits and its possible side effects, especially for those sections of the population with a significant need for information and a critical view of vaccination.

Every new vaccination and every individual decision to get vaccinated involves a weighing up of risks, often following similar criteria and questions: How likely is it that I will get sick? How bad will it be? Does vaccination provide safe protection? And will there be side effects? These and others like it are the obvious questions. Each individual asks them first of all for themselves, but often with a view to family and friends, too, as well as society and the common good. Ultimately, the potential benefits must clearly outweigh the potential harm.

In terms of this fundamental consideration, we do not have to start from scratch with COVID-19. One example that illustrates this well is the measles vaccination. Measles is a so-called RNA virus, comparable to SARS-CoV-2. It is so contagious that without vaccination it usually leads to infection even in childhood – this is the real reason why measles is known as a “children’s disease”, not because it is harmless.

In 20 to 30 percent of those infected with measles, complications such as pneumonia and encephalitis – i.e. inflammation of the brain – occur, in rare cases also sterility in men or bilateral deafness. Long-term effects can often occur even years later and result in death. The mortality rate is between 0.01 and 0.2 percent in industrialised countries, but can be as high as 25 percent in developing countries. There is no antiviral therapy available for manifest measles infection.

The introduction of vaccination reduced the death rate from measles worldwide by 74 percent between 2000 and 2010. Two vaccinations provide lifelong protection from a measles infection. As this is a live vaccine, people may experience an “attenuated”" measles infection with a mild rash and some fever after vaccination. In addition, the usual vaccination reactions such as swelling or pain at the puncture site are to be expected. And: as compared to other infectious diseases, the measles vaccination not only protects those who have been vaccinated, but also – through community protection (herd immunity) – infants and people who do not respond to the vaccination for various reasons or who cannot receive it – providing a sufficient number of people have been vaccinated. Conclusion: Comparing the complications and benefits of vaccination, the benefits undoubtedly outweigh the risks.

The example of measles infection allows many parallels to be drawn with the current pandemic: the new coronavirus can also lead to severe progressions in some cases, including complications during acute illness as well as long-term complications.

COVID-19 is caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome-Coronavirus-2). The infection triggers an acute respiratory illness with a systemic inflammatory reaction, which can be severe in some cases. Severe progressions are accompanied by pneumonia and damage to the lung tissue, potentially even acute lung failure. Of the cases reported in Germany up to the beginning of December, 7 percent had to be hospitalised. A total of 1.6 percent of those who were SARS-CoV-2-positive died, 87 percent of whom were 70 years and older. All in all, the frequency of contracting the disease severely correlates with age, so high age is the most important risk factor for a contracting a severe case of COVID-19 – along with other conditions such as obesity and arterial hypertension (high blood pressure). An analysis of the total mortality resulting from the first coronavirus wave in 34 geographical regions worldwide reflects this age dependency impressively. Among the patients who tested positive, the correlation between age and case fatality was striking: it was 0.4 percent at age 55, 1.4 percent at age 65, 4.6 percent at age 75 and 15 percent at age 85.

Regardless of the severity of the onset of the disease, COVID-19 can have significant long-term effects, both from the infection itself and from the known complications of intensive care treatment. Consequential symptoms also occur in very mild forms of the initial COVID-19 disease and are currently summarised under the term “Long COVID syndrome”. The symptoms are long-lasting and include fatigue, fever, shortness of breath, chronic cough, headache or depression. But even after mild progressions, i.e. without treatment in hospital, a British survey shows that COVID-19 symptoms affected a total of one in ten patients for longer than four weeks.

In terms of a comparison with measles, no specific effective therapy is yet available for the SARS-CoV-2 infection and the resulting COVID-19 disease. For this reason, vaccination is a target-oriented strategy to control the disease.

Several hundred vaccination strategies have been developed in response to the virus and tested worldwide since the start of the SARS-CoV-2 pandemic. This is unique in medical history. The development of any vaccine is a complex process consisting of several phases. At the beginning, there is the phase of identifying suitable antigens of the pathogen and developing a potential vaccine. This is followed by preclinical testing in the test tube and in animal experiments. The data is reviewed by regulatory authorities and promising potential vaccines can be approved for human trials. In order for this to happen, detailed findings regarding the mode of action must have already been presented, as well as on toxicity, i.e. the capacity of the vaccine to exert undesirable effects on human beings. Human testing then proceeds in three phases. In phase 1, it is primarily the ability of the vaccine to elicit an immune response (immunogenicity) that is investigated, while initial data on tolerability and safety are collected in healthy volunteers. In phase 2, a larger number of test subjects (usually 100-1000) are used for in-depth tolerability testing. In phase 3, the efficacy and safety of the vaccination are tested in a large number of subjects (>10 000), i.e. protection against infection as well as the frequency and severity of vaccination reactions and side effects. In order to receive approval from the drug authorities, each vaccine must successfully pass through all phases. For each authorisation, an assessment is made of whether the benefit of a vaccination clearly exceeds the actual and potential risks. Economic factors such as the cost of vaccination are not included in the assessment.

All SARS-CoV-2 vaccine candidates approved in Europe undergo the same rigorous development and testing processes as other vaccines. Normally, this development takes many years, sometimes even decades. With the SARS-CoV-2 vaccines, the process was completed in a much shorter time. This was possible due to a number of favourable factors and by making testing processes more efficient, though without compromising diligence.

SARS-CoV-2 vaccine development was able to build on years of prior experience with similar coronaviruses, such as the SARS coronavirus and the MERS coronavirus. As such, the spike protein – a characteristic surface protein of SARS-CoV-2 – was already known as a promising vaccine antigen. To some extent it was possible to draw on existing successful vaccine candidates against other viruses after appropriate adaptation to SARS-CoV-2. This saved years of development work. Ongoing consultation with the regulatory authorities took place at a very early stage, enabling vaccine developers and companies to prepare more specifically to meet the stipulations and requirements for the clinical trials and the approval procedures through direct dialogue. The combination and parallel planning of the three clinical trial phases was another factor that saved time. This enabled numerous organisational processes – such as the recruitment of test persons – to be clustered. Normally, these phases occur in sequence, i.e. one after the other, sometimes with long intervals in between. The combination of these phases was also largely made possible by the high level of financial commitment shown by governments, companies and foundations. In addition, it was possible to use a so-called rolling review process which allowed vaccine manufacturers to submit individual data packages to the regulatory authorities even during the phase 3 clinical trials. This resulted in faster processing and verification of the data. All in all, therefore, it was possible to significantly accelerate the entire vaccine development, testing and approval process without compromising the diligence of testing efficacy and safety. Ultimately, the positive benefit-risk ratio is a fundamental prerequisite for the granting of a marketing authorisation.

On this basis, the first SARS-CoV-2 vaccine to be approved in Europe since 21 December 2020 was that of the Mainz-based company BioNTech (jointly developed with the pharmaceutical company Pfizer). On 6 January 2021, the vaccine produced by the American company Moderna was also approved in Europe. Both vaccines are nucleic acid-based, so-called messenger RNA vaccines (mRNA vaccines). Messenger RNA is a transcript of genetic information and forms the blueprint for proteins. Our body’s own mRNA also serves as a blueprint for proteins in every cell. In the course of a viral infection, viruses introduce their genetic information into our cells and viral mRNA molecules and viral proteins derived from them are formed. In the case of the SARS-CoV-2 vaccine, artificially designed mRNA molecules are used that contain a blueprint for a stabilised form of the spike protein of SARS-CoV-2. In order to introduce the mRNA into the cells, the mRNA molecules are packaged in a lipid envelope. These small mRNA-containing particles (particles) thus resemble an enveloped virus such as the coronavirus. This stimulates cells in our body to produce the viral protein themselves. Our immune system can now develop targeted defence reactions against the protein, establishing a very robust immune response against the spike protein – and therefore against the virus. So live vaccine is not used in this case. Other mRNA vaccines are currently being tested, for example a vaccine developed by the Tübingen-based company CureVac.

This already provides a sound basis on which to answer many of the widespread questions regarding the benefit and safety of COVID-19 vaccination. For example, one of the most common fears surrounding vaccination can be clearly denied and refuted – namely that the mRNA vaccines used can change our genetic make-up. mRNA vaccines do not contain any genetic material, as mRNA is only a relatively short-lived transcript of genetic information. RNA is roughly comparable to the working memory (RAM) of a computer, while the genetic information itself lies safely on the hard drive – the latter being the DNA stored in the cell nucleus in humans and animals. Every cell in the body constantly produces mRNA: each body cell contains some 360,000 mRNA molecules on average. The formation of extrinsic RNA in our cells happens with every viral infection – also in the case of a mild cold or coronavirus infection. Moreover, since mRNA differs from DNA in its molecular structure, it can by no means be directly incorporated into the human genome. What is more, the mRNA of the vaccines does not reach the cell nucleus, i.e. the place where the genetic material is located. For this reason, there is a consensus among physicians and bioscientists that there is no danger of mRNA vaccines being integrated in our DNA in a way that damages genetic material.

For other questions, it is at least possible to make educated guesses based on the evidence to date, such as for possible vaccine protection against asymptomatic SARS-CoV-2 infection and against transmission of the virus. It is true that only symptomatic SARS-CoV-2 infections have been systematically recorded in the approval studies carried out to date. But animal studies suggest that vaccination can also significantly reduce and shorten viral shedding. However, this has not yet been sufficiently investigated in human clinical trials. Such studies are very costly, as they require regular smears and PCR tests of all study participants as well as the involvement of the social environment of the test persons. Numerous studies accompanying the vaccination programmes that are now starting will provide this information in the months to come.

There is a lot that can be said about the most common concern, namely the potential side effects of vaccination. This is possible based on the vaccinations carried out in the development and testing phase. In this study, 21,621 subjects vaccinated with the BioNTech vaccine BNT162b2 were observed and compared with 21,621 subjects who received a placebo. Such an approval trial involving over 40,000 study participants is unusually large for a drug trial. At the time of analysis, a total of 19,067 study participants (9,531 vaccinated and 9,536 placebo vaccinated) were assessed for tolerability at least two months after the second dose of vaccine. The mRNA vaccines used showed a very good reaction of the immune system, triggering a vaccination reaction in a relatively large number of vaccinated persons. Vaccine reactions include symptoms of a desired natural confrontation of the immune system with the vaccine, which is ultimately intended to result in the production of protective antibodies and specific immune cells. These include local pain at the injection site, redness and overheating as well as systemic symptoms such as fatigue, headache, muscle and limb pain and, more rarely, fever. These symptoms are similar to those of a mild viral infection. Such vaccination reactions usually lasted one to two days. Depending on age, up to 80 percent of those vaccinated report local or systemic vaccine reactions after a SARS-CoV-2 vaccination, with younger people showing more frequent and somewhat more severe vaccine reactions than older people. It has not yet been possible to show any severe side effects of the SARS-CoV-2 vaccinations according to the findings published to date.

Long-term safety data is not yet available, as the first human clinical trials of the SARS-CoV-2 vaccines did not begin until April 2020. However, most vaccination side effects occur within one year. All study participants will therefore continue to be monitored. In general, vaccines are among the safest medicines available. The vaccination programmes now starting worldwide are being closely tracked by so-called pharmacovigilance studies (monitoring of vaccine safety), and further data is being collected relating to aspects such as the duration of vaccination protection. The mRNA vaccines can therefore be said to exhibit a very good safety profile to date. The residual risk of any late effects is considered low, as with other vaccinations, but must be monitored very thoroughly.

Shortly after the introduction of the BioNTech/Pfizer mRNA vaccine, reports of severe allergic reactions in individuals caused a stir – and further concern. These mostly occurred in individuals who were already known to have a predisposition to severe allergic shock reactions. These people probably reacted to additives in the lipid envelope of the mRNA vaccine. So far, these allergic reactions have occurred in about 1:100 000 of vaccinated people and effective treatment was possible in all cases. So these are very rare side effects that occur much more frequently with other vaccines and medicines such as antibiotics or painkillers. People with mild allergies such as a grass pollen allergy can therefore definitely get vaccinated. If a person is prone to severe allergic shock reactions, vaccination should only be administered under close medical supervision.

It is not yet possible to make any reliable statements regarding the frequently asked question of how long vaccination protection against SARS-CoV-2 lasts. From experience with other vaccines, it is known that vaccines that are highly effective can usually provide protection for several years and even decades. This is not yet known for the SARS-CoV-2 vaccines yet, however, as the studies so far have only observed vaccinated individuals for a few weeks on average. Likewise, it is not yet known how long a person is protected from COVID-19 after surviving SARS-CoV-2 infection. So far, Moderna’s mRNA vaccine has been shown to maintain stable antibody levels in the blood for at least four months. Further studies will now have to show whether vaccination protection is maintained over a longer period of time.

However, there is broad consensus on the most recently discussed question of whether the vaccination provides protection against new variants of SARS-CoV-2, too. Viruses can change during reproduction and form new variants through mutations (changes) in their genetic material. Most recently, two variants of SARS-CoV-2 have been described in the UK, which may have acquired higher contagiousness through multiple mutations. This usually happens through the exchange of individual building blocks in the proteins, in this case also in the spike protein. However, small changes in individual building blocks do not usually prevent the entire immune response, consisting of antibodies and T cells, from continuing to recognise and neutralise coronaviruses. The immune response is directed against many different points of the coronavirus, making it difficult for the virus to escape the immune response. Some viruses, such as influenza viruses, are known to be able to escape vaccine protection completely due to far-reaching changes in their surface proteins. In principle, coronaviruses are not as variable as influenza viruses. Scientists do not generally expect SARS-CoV-2 to undergo change to such an extent in the near future as to render the vaccines ineffective. After some time, when large numbers of people have been vaccinated, variants could possibly develop against which the vaccinations no longer provide such effective protection. In this case, the vaccines could be adjusted, as is done annually in the case of influenza vaccination. The mRNA vaccines in particular are excellently suited to adaptation, as they allow a rapid technological adjustment of the sequence of mRNA molecules.

The best possible knowledge concerning these and other issues will be relevant to large sections of the population in Germany, especially in the medium and long term. The development of the vaccination strategy is based on ethical considerations that vaccination is the primary way to avert health damage as a result of the COVID-19 pandemic. This means that in the first phase, people who are particularly at risk due to age or co-morbidities (concomitant diseases) must be protected. Due to the limited availability of vaccines, it is particularly important to prevent the number of deaths and severe progressions. As shown above, the studies available to date indicate that older people in particular are subject to a significantly increased risk of dying from the disease. In addition, it is important to prevent disease from the outset in persons who are at a particularly high occupational risk of exposure and who are crucial to the maintenance of medical care. In further steps, the next youngest and other risk groups are to be vaccinated – organ transplant patients and people with trisomy 21 are subject to a high mortality risk, for example.

In the final phase, the aim is to interrupt the transmission of the virus and, if possible, end the pandemic. This is achieved when the vaccine is equally available to everybody and a very large number of people get vaccinated. This can lead to the much-cited community protection (herd immunity). Current surveys show that 50 to 60 percent of people in Germany are willing to be vaccinated against COVID-19. In order to ensure the highest possible level of vaccine acceptance, a sound – and effectively communicated – knowledge of the scientific background can make a crucial contribution in the months that follow.

Editorial status: 13 January 2021

  • Susanne Herold is Professor of Infectious Diseases of the Lung at Justus Liebig University in Giessen and Head of Department of the Infectious Diseases Unit at the University Hospital in Giessen-Marburg.
  • Britta Siegmund is Director of the Medical Clinic for Gastroenterology, Infectiology and Rheumatology at Charité – Universitätsmedizin Berlin, Vice-President of the DFG and Chair of the DFG Senate Commission on Basic Questions in Clinical Research.
  • Leif-Erik Sander is Professor of Infectiology and Pneumology and Head of the Infection Immunology and Vaccine Research Group at Charité – Universitätsmedizin Berlin.
  • Cornelia Betsch is Heisenberg Professor of Health Communication at the University of Erfurt.

Susanne Herold, Britta Siegmund and Cornelia Betsch are members of the DFG’s interdisciplinary Commission for Pandemic Research. The Commission thanks Leif-Erik Sander for his collaboration on this document.

Further information is also available on the website of the Commission for Pandemic Research

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