Low binding affinity improves vaccine efficacy
Joint press release by BIH, Charité and Max Delbrück Center
Conventional vaccines usually contain antigens – components of the respective pathogens – that bind to receptors on the surface of their target cells in order to trigger the disease. Scientists at the Berlin Institute of Health at Charité (BIH) and the Max Delbrück Center have now discovered that antigen variants with low receptor binding can be advantageous for the development of vaccines. The research team has succeeded in producing a new vaccine against the SARS-CoV-2 coronavirus by identifying spike protein mutants that lack binding affinity. The scientists have now published their findings in the “European Journal of Immunology”.
Vaccines induce the production of specific neutralizing antibodies against the pathogen antigens administered into the body, such as the SARS-CoV-2 virus’s spike protein. If a subsequent infection occurs, these antibodies can be mobilized to fight against the pathogen. To achieve high vaccine efficacy, it is essential that sufficient amounts of pathogen components circulate in the blood after vaccination.
The crux of the matter
Once vaccine components have bound to suitable receptors on cell surfaces,” explains de la Rosa, “they are more or less protected from being attacked by the immune system.
The number of pathogen components floating around freely in the blood is, however, reduced because they have the property of binding to receptors. Often, pathogens – and therefore the components of the inoculated pathogens as well – find suitable receptors at many sites in the host organism to which they can dock. This is also the case with the SARS-CoV-2 virus. The central role here is played by the ACE2 receptor, which interacts with the virus’s spike protein. This receptor is not only present in the respiratory tract, but is also widely distributed throughout the body. The spike protein can occupy ACE2 receptors in both COVID-19 infection and vaccination.
But Kathrin de la Rosa believes this is likely to be disadvantageous, particularly when it comes to the immune response. The immunologist holds the Johanna Quandt Professorship for Translational Immune Mechanisms at the BIH and also leads a research group at the Max Delbrück Center. “Once vaccine components have bound to suitable receptors on cell surfaces,” explains de la Rosa, “they are more or less protected from being attacked by the immune system. They provide B cells, which are responsible for producing pathogen-specific antibodies, with less of a target, because the receptor binding effectively masks the identifying feature from these immune cells. As a result, vaccine efficacy is reduced.”
And there may be another disadvantage: It cannot be ruled out that vaccine-induced receptor binding could lead to cellular malfunctions and a disturbance of balance within the body.
A clever bit of selection
Structure of SARS-CoV-2 Spike protein with G502E BIBAX modification in red.
In de la Rosa’s view, a vaccine should ideally be both “body inert” (barely reactive in the body) and “B-cell activating.” Out of this combination came the name BIBAX, which is what the researchers call the innovative type of vaccine they have developed and successfully tested against SARS-CoV-2. The spike protein served “merely” as a model protein, because – as was clear from the outset – the new strategy could also be of interest for other vaccines.
Variants that possess a low tendency to bind to receptors – in this case ACE2 receptors – should be advantageous for the development of vaccines, according to the scientists’ vision. Their work involves using various lab-made variants of the spike protein that each have slightly different functional properties as a result of point mutations (minute genetic changes). Using an innovative computational approach, the researchers sifted through deep mutational scanning data for spike antigen mutants that lack binding affinity but have high immunogenicity. And they found one – called RBD-G502E – that was very close to the desired profile and selected it as the antigen variant for their vaccine.
A new vaccine prototype?
“Our studies in cell cultures and in animal models indicate the superiority of the novel SARS-CoV-2 vaccine, which we believe is suitable as a prototype,” explains de la Rosa, adding that she expects it to have a targeted, potent effect on B cells. “We demonstrated that the spike protein variant RDB-G502E hardly binds at all to the ACE2 receptor.” Receptor transport to the cell interior, as would be typical after binding of the antigen to its receptor, was not observed when RDB-G502E was used.
This antigen variant also fulfilled expectations with regard to its immunogenicity. In rabbit immunizations, the RDB-G502E-based vaccine resulted in 3.3-fold higher concentrations of neutralizing antibodies in the blood compared to a conventional vaccine. The chances of providing reliable vaccine protection against SARS-CoV-2 could be significantly improved by a targeted selection of immunogenic pathogen antigens that lack binding affinity. And de la Rosa’s group believes this new type of vaccine design also holds promise for fighting other pathogens. “Effective vaccines are available for SARS-CoV-2, but they are lacking for other pathogens despite intensive research,” stresses de la Rosa. We have preliminary evidence that the BIBAX strategy may be beneficial for vaccine protection against other coronaviruses and herpes viruses, against which adequate vaccine protection has not been achieved to date.” Kathrin de la Rosa’s team now plans to investigate these findings further.
Text: BIH
Further information
Literature
Christoph Ratswohl et al. (2023): „A design strategy to generate a SARS-CoV-2 RBD vaccine that abrogates ACE2 binding and improves neutralizing antibody responses“; in “European Journal of Immunology; DOI: 10.1002/eji.202350408
Downloads
Structure of SARS-CoV-2 Spike protein with modification in red. Credits: de la Rosa lab, Max Delbrück Center
Press contact
Dr. Stefanie Seltmann
Head of Communication
Berlin Institute of Health (BIH) at Charité
+49 (0) 30 450 543019
stefanie.seltmann@bih-charite.de
Pressestelle-bih@bih-charite.de
- About the Berlin Institute of Health at Charité (BIH)
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The mission of the Berlin Institute of Health at Charité (BIH) is medical translation: transferring biomedical research findings into novel approaches to personalized prediction, prevention, diagnostics and therapies and, conversely, using clinical observations to develop new research ideas. The aim is to deliver relevant medical benefits to patients and the population at large. As the translational research unit within Charité, the BIH is also committed to establishing a comprehensive translational ecosystem – one that places emphasis on a system-wide understanding of health and disease and that promotes change in the biomedical translational research culture. The BIH was founded in 2013 and is funded 90 percent by the Federal Ministry of Education and Research (BMBF) and 10 percent by the State of Berlin. The founding institutions, Charité – Universitätsmedizin Berlin and the Max Delbrück Center, were independent member entities within the BIH until 2020. Since 2021 the BIH has been integrated into Charité as its so-called third pillar. The Max Delbrück Center is now the Privileged Partner of the BIH.
- About Charité – Universitätsmedizin Berlin
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Charité – Universitätsmedizin Berlin is one of the largest university hospitals in Europe, boasting 3,099 beds and more than 100 departments and institutes spread across 4 separate campuses. At Charité, the areas of research, teaching and medical care are closely interlinked. With a total of around 21,600 members of staff employed across its group of companies (some 18,200 of which at Charité), the organization is one of the largest employers in Berlin. More than 5,000 of its employees work in the field of nursing, with a further 5,200 in research and medical care and another 1,300 in administration. Last year, Charité treated more than 126,000 in- and day case patients, in addition to around 736,900 outpatients. In 2022, Charité recorded a turnover of approximately €2.3 billion (including external funding and investment grants) and set a new record by securing some €284 million in external funding. Charité’s Medical Faculty is one of the largest in Germany, educating and training more than 9,500 students across the subjects of medicine, dentistry, health sciences and nursing. Charité also offers more than 800 training positions across 12 different health care professions and 8 further professions.
- Max Delbrück Center
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The Max Delbrück Center for Molecular Medicine in the Helmholtz Association (Max Delbrück Center) is one of the world’s leading biomedical research institutions. Max Delbrück, a Berlin native, was a Nobel laureate and one of the founders of molecular biology. At the locations in Berlin-Buch and Mitte, researchers from some 70 countries study human biology – investigating the foundations of life from its most elementary building blocks to systems-wide mechanisms. By understanding what regulates or disrupts the dynamic equilibrium of a cell, an organ, or the entire body, we can prevent diseases, diagnose them earlier, and stop their progression with tailored therapies. Patients should benefit as soon as possible from basic research discoveries. The Max Delbrück Center therefore supports spin-off creation and participates in collaborative networks. It works in close partnership with Charité – Universitätsmedizin Berlin in the jointly run Experimental and Clinical Research Center (ECRC), the Berlin Institute of Health (BIH) at Charité, and the German Center for Cardiovascular Research (DZHK). Founded in 1992, the Max Delbrück Center today employs 1,800 people and is funded 90 percent by the German federal government and 10 percent by the State of Berlin.
