Preparations for a SARS-CoV-2 program are also underway in Halle. However, this is not about obtaining donor serum and supplying Covid 19 sufferers with it. The Halle physicians around Dr. Rather, Hanni Bartels from the Diakoniekrankenhaus want to examine the quality of existing antibody tests. As Dr. Bartels in an interview with MDR Wissen stated that in May forty ex-Covid 19 sufferers are participating in a preliminary study. Since these people have developed antibodies against the virus, antibody tests can be tried on them.
Three test kits already on the market are to be examined. The aim is to find out which test determines the antibodies most safely and precisely. The “winner test” is then tried again on all forty participants in order to determine the reliability, ie the reliability of the results. If this is the case, the test will later be used to investigate the development and spread of infections in Halle in a large-scale study. The current preliminary study is financed from third-party funds. It is created in close cooperation with the city of Halle and researchers from the medical faculty of the Martin Luther University Halle-Wittenberg.
In addition to projects at local and federal level, some countries are also active. For example, Lower Saxony is scarce due to a supplementary budget in early April ten million euros also invested in corona research. In particular, research projects at the Hannover Medical School, which also participates in the CAPSID program through the Institute for Transfusion Medicine, are supported here. In addition to issues related to disease development, the money will primarily go to antibody research and vaccine testing.
It is currently difficult to discern that the Central German federal states are following the example of Lower Saxony. An inquiry to the responsible ministry in Saxony-Anhalt remained unanswered. According to the Ministry of Science, there is no independent state program for the development of active substances or vaccines in Thuringia. Nevertheless, the universities and research institutions there are involved in numerous other corona projects. This also applies to Saxony, but there are no special state programs here either. Upon request, the Saxon Ministry of Science and Art (SMWK) announced that there are currently no antibody or vaccine projects in which SMKW is directly or indirectly involved. However, at least the university hospitals in Leipzig and Dresden are involved in ongoing research via the CAPSID program.
What CAPSID wants, what it can do and where the limits are
The study has several goals. Basically, the principle of action and the effectiveness of serum therapy in seriously ill Covid-19 patients should be researched. The focus here is on reducing the mortality rate and alleviating serious illnesses. Possible side effects are also the goal of the investigation. In general, immune serum therapy is viewed as a low-risk treatment approach based on historical experience. The two Covid-19 studies from China also found no side effects. The EU, which is currently building a database for immune serum and published therapy guidelines in early April, also speaks of one “therapy with low risk”.
Nevertheless, the simple serum therapy as used in the CAPSID program has some general weak points, because the quantity and quality of the antibodies differ from donor to donor. This is not only due to the general individuality of every person, but also to the fact that every donor has developed very specific antibodies as a result of his Covid 19 disease. In other words, each donor serum contains an individual medical history and is itself used for an individual medical history. The problem: Since the donations can vary well or be more or less suitable for the respective patient, the effectiveness in individual cases is not always easy to decide. This also makes it more difficult to determine the overall effectiveness of serum therapy.
The CAPSID study wants to work on the problem in such a way that the antibody concentration of each donor is recorded individually. The so-called neutralizing effectiveness should also be measured, because antibodies are not just antibodies. Normal antibodies only dock onto the virus, mark it and thus make it visible to the immune system as an attacker. Neutralizing antibodies, on the other hand, do the work themselves and render the virus ineffective by preventing it from entering the cell.
The researchers are therefore primarily targeting neutralizing antibodies. However, people with many antibodies do not automatically have many neutralizing antibodies. People with a strong cellular immune response in particular often have few neutralizing antibodies. The same applies to those whose innate immune response has responded well to SARS-CoV-2. That means: The fact that a person has developed antibodies as a result of a surviving Covid-19 disease does not mean that these antibodies were also decisive for the victory over the virus. Which in turn means that not all donors are equally good when it comes to helping sick people.
Nevertheless, says study leader Seifried, the antibody concentration does not play a role in the selection of donors for CAPSID. If only because the study should find out whether the number of antibodies is relevant for the success of the therapy. The scientists are still divided on this question. Researchers like the transfusion medicine specialist Rainer Blasczyk from the Hannover Medical School believe that one must “Identify donors who have many neutralizing antibodies“Study leader Seifried, however, gives cause for concern that currently no one can say how high the antibody concentration should actually be in order to be able to carry out an effective therapy. In theory, according to Seibert in conversation with MDR Wissen, only a few antibodies could be sufficient for treatment success Checking this possibility is also part of the study.
Fluctuations in the concentration of antibodies in plasma and restrictions on their extraction are two reasons why researchers use them different approaches are trying to artificially produce antibodies and develop appropriate drugs against Covid-19. One approach is to use the plasma from recovered Covid-19 patients as the basis for a so-called To use hyperimmunoglobulin. These are highly enriched antibodies. The advantage: With the help of an appropriate drug, the antibodies are administered here in a much more concentrated form than is the case with normal serum.
Several large projects around the world are working intensively on the development of such anti-SARS-CoV-2 hyperimmunoglobulins. To this end, pharmaceutical companies, biotech companies and researchers have entered into collaborations almost overnight. Because one thing is clear: the fight against Covid-19 is not only about the best medicines, but also about upcoming market shares. This also applies, especially now, when the development of common, brand-free drugs is in the foreground.
For example, the biopharma group CLS and the pharmaceutical company Takeda are developing. According to the magazine, both companies control “Chemical & Engineering News“Already about half of the market for plasma-based therapies. In order to get started with a medication as quickly as possible, CSL and Takeda are planning an accelerated procedure in which the usual tests on small groups and the review of the therapy concept (test levels I and II ) is skipped and level III (test in larger groups) is started, so that the first representative results should already be available in summer.
Since antibodies can also be obtained from mammals, some companies also try it this way. The multinational Emergent BioSolutions, for example, uses horses to develop its hyperimmune globulin. SAB Biotherapeutics from the USA, on the other hand, uses one proprietary herd of genetically modified cows. The animals have already been used for the development of other drugs and used in the fight against MERS and Ebola.
What all these approaches have in common: They work polyclonally, that is, they use several (poly) antibodies to produce their highly concentrated immunoglobulins in large numbers, that is, clone them. But monoclonal approaches also promise success in the fight against Covid-19. Only one antibody (mono) is used in these, but it acts in a highly specific and therefore very efficient manner against the SARS-CoV-2 virus. This effect occurs when the antibody binds to the virus spike protein.
Research groups around the world are currently looking for such “super antibodies”. Scientists at the TU Braunschweig are included. You have already found hundreds of antibodies that work well against the virus. These are currently being tested further in order to ultimately be limited to a single “super-antibody”. This could have been found by the end of May. A drug against Covid-19 can then be developed from it. What is special: The Braunschweig researchers led by Prof. Michael Hust work with purely human antibodies, which they generate using the so-called antibody phage display technology in a test tube. The advantage of this approach: The researchers receive the blueprint for the respective antibody and can produce it in any quantity and in consistently high quality.
However, the entire development process is time consuming. In an interview with MDR Wissen, Prof. Hust explained that the corresponding clinical studies will not start until early 2021. However, this is also clear: the simple immune serum therapy using donor plasma is a bridge technology, but a necessary one, because it fills the gap in the acute care of Covid 19 patients that could not be closed otherwise.
Prof. Tonn from the University Hospital Dresden agrees. At the same time, he points out that the highly concentrated antibody preparations “are still important for immunocompromised patients if vaccines or antiviral drugs are available.”
Since the antibody concentrates have already proven their effectiveness in other pathogens, it is now “only” a matter of testing their effectiveness also with Covid-19. However, since results or even a finished medication cannot be expected before the end of 2020, simple immune serum therapy remains the measure of all things in practice. In order to determine their actual effectiveness with a view to SARS CoV-2 and to scientifically confirm the use of the donor serum, studies like CAPSID are essential. However, not everyone who has Covid-19 can participate in the study.
Who is considered as a participant in the CAPSID study – and who is not?
The Study protocol stipulates that only patients with severe Covid 19 disease are treated with the serum. Above all, this includes patients who need ventilation or who need other intensive care support. Patients with severe previous illnesses (e.g. pulmonary edema, heart failure, etc.) and a life expectancy of less than twelve months are generally excluded from participation. People who are older than 75 years or patients who have been mechanically ventilated for more than 72 hours are also excluded from the study.
Those who belong to the treatment group of the CAPSID study receive a total of three infusions, namely on the first, third and fifth day of the treatment, which is initially scheduled for 21 days. Participants receive around 200 ml of serum per infusion – a large amount compared to the few milliliters that have to be given to highly concentrated hyper-immunoglobulins. However, because these are not yet ready for the market for Covid 19 patients, this is currently the only way.
Since only 106 patients participate in the study and only the 53 participants in the treatment group receive the serum, care is not a problem. However, the small number of participants also means that at the almost twenty locations only a very few sufferers can use serum therapy as part of CAPSID. This is one of the reasons why the university clinics in Dresden and Erlangen, as well as other participating institutes, decided to carry out their own tests in addition to the study and to attract donors in order to supply as many Covid 19 patients with immune serum as possible. Because, just like in Bavaria, many municipal hospitals in Saxony are also interested in applying immune serum therapy to their Covid 19 patients – and as soon as possible.
The only question is: who will pay for it? In Dresden, it is currently still unclear how the plasma production and serum use will be financed outside of the study. Prof. Tonn wants help from politics here. “It would actually be nice to be able to rely on funding from the state of Saxony. The costs are comparatively low. An amount of 150,000 euros would bring enormous relief to the implementation of the project and ensure patient care for the next few months. ”
In addition to the political decision-makers, the health insurance companies are also in demand, because the immune serum cannot currently be billed because the corresponding billing number is missing.
The possibilities of immune serum therapy: prophylaxis and treatment
In general, immune serum can be used both for prophylaxis and for treatment of people already suffering from Covid-19. In one article published in March US researchers explained that passive immunizations should generally be used better as a preventative measure, since their effectiveness would then be higher than with treatment. Since the administered antibodies remain in the blood for only a few months on average, the prophylactic approach offers only temporary protection. Nevertheless, it is recommended by the researchers. In their view, prophylaxis is particularly advisable for those people who are at risk due to previous illnesses in the event of an infection and therefore need to be protected from infection from the outset. Antibodies should also be prophylactically administered to people who are at high risk of infection due to their profession, such as doctors and nurses.
However, the reverse phenomenon is currently more evident in the USA: Since many doctors and nurses were infected with Covid-19 at an early age and are already healthy again, they are now donating immune serum themselves Treatments in their hospitals and University hospitals to enable. But the well-known dark side of the American health system also comes to the fore with serum therapy, because there are first indications that African Americans and people in less well-served areas have less chance of receiving appropriate emergency treatment. So far, around 100 life-threatening patients in the United States have been provided with immune serum. However, not all treatments were successful, some patients died, others are still in critical condition.
Worldwide over 20 studies on immune serum therapy
Nonetheless, not only in the USA, but also in Germany, immune serum therapy is a glimmer of hope for many people with severe Covid 19 disease – and CAPSID is also intended for them. It will be seen in the coming weeks and months whether the approach to immune serum therapy will be generally successful. According to research from MDR knowledge over twenty studies worldwide planned or already underway that deal with the production and use of immune serum in Covid-19 patients.
While CAPSID is based on severe Covid-19 cases, others are investigating the effects on mild courses of the disease. This is also important because researchers believe that a person infected with Covid-19 can in principle be given immune serum at any stage of the disease. However, data from previous epidemics suggest that it is best to start therapy as early as possible. Especially if the patient has not yet produced antibodies. This assessment is shared by Prof. Tonn. He believes that antibody therapy is particularly useful “if you can stabilize immunocompromised and elderly patients so that ventilation is not necessary.”
Other researchers also consider such early use to be necessary, especially since the virus multiplies particularly quickly in this phase. Just like in Dresden, therefore, the Hannover Medical School wants to use the immune serum as early as possible and – regardless of the CAPSID program – also test it on less seriously ill patients. According to Rainer Blasczyk, director of the institute for transfusion medicine there, this could provide clues as to which patients are particularly good at immune serum therapy. This in turn could be used to develop criteria for further studies and to find out whether there is something like an ideal time for the plasma injection within the various disease courses.
Immune serum therapy can help save human lives. CAPSID and numerous other studies in the coming weeks and months will show how effective it is in the case of Covid-19 disease. There is always reason to hope. Not only because the historical experiences and the first data from China and the US are cautiously optimistic, but also because the side effects are extremely low. Simply put, you have nothing to lose with serum therapy.
From a medical point of view, the treatment approach may only be a bridging technology on the way to vaccination and the highly effective antibody drugs of the future. But not everyone can wait that long. Many who have Covid-19 now need medical help. Serum therapy can support your treatment and turn the course for the better. For these people, the bridge leads from illness to recovery – and thus back to a life as it was before Corona.