Center for Molecular Medicine Cologne

Long lasting activation of innate immunity following COVID-19 mRNA vaccination - signaling pathway deciphered

04/07/2022

In a new study performed with vaccinated individuals, a research team led by Jan Rybniker at the University of Cologne / the Unviersity Hospital Cologne focus for the first time on the signaling pathways of these immune cells and their effect on the acquired immune response.

Apparently, vaccination also leads to a memory function in these short-lived cells. This important finding is novel for mRNA vaccines. The underlying mechanism could also contribute to the strong protective effect we obtain with booster vaccinations. PD Dr. Dr. Jan Rybniker and Dr. Sebastian Theobald (Image K. Schmidt/M. Wodak)

Infection with SARS-CoV-2 causes severe inflammation of the lungs and other vital organs in some patients. Vaccines provide excellent protection against these severe courses of disease. Numerous studies have investigated the role of the so-called acquired immune response after SARS-CoV-2 vaccination and have shown that specific antibodies can be measured in the blood and that these then decrease over a period of months. However, to trigger a potent and long-lasting immune response, vaccines first need to activate the innate immune system, which reacts non-specifically to foreign virus or bacteria derived proteins.

Until now, it was not known how exactly and for how long the novel mRNA vaccines stimulate cells of the innate immune system. In a new study performed with vaccinated individuals, researchers at the University of Cologne and the Unviersity Hospital of Cologne focus for the first time on the signaling pathways of these immune cells and their effect on the acquired immune response.

The results have now been published in the renowned scientific journal EMBO Molecular Medicine with following title "Spleen tyrosine kinase mediates innate and adaptive immune crosstalk in SARS-CoV-2 mRNA vaccination" - EMBO Mol Med (2022)e15888 https://doi.org/10.15252/emmm.202215888.

The rapid development of potent vaccines against SARS-CoV-2 has greatly contributed to the containment of the pandemic. Numerous studies have demonstrated protection against severe disease progression and a reduction in transmissions following vaccination. In particular, the potent mRNA vaccines that could be developed and produced very rapidly were an important milestone for this development. Since marketing and mass-distribution of these vaccines, it has been relatively well studied how long protective effects last via the activation of the acquired immune system.

However, for a protective effect to be as long-lasting and potent as possible, it is first of all important to activate the innate immune system, which triggers the interaction of various immune cells required for an anti-viral memory function. In most conventional vaccines, so-called adjuvants are used for this purpose. These are additives that are supposed to stimulate cells of the innate immune system, such as macrophages. In the case of mRNA vaccines, these classical additives are missing and the mechanism by which immune cells are stimulated shortly after vaccination is not known. This is where the research of Dr. Jan Rybniker’s group as entering the stage.

"We were able to show that mRNA vaccines stimulate blood derived macrophages by exploiting a highly specific signaling pathway. Once these pre-stimulated macrophages come into contact with the SARS-CoV-2 spike protein, pro-inflammatory messenger molecules are released, which are needed for the activation of immune cells of the acquired immune system" Dr. Rybniker, the senior author of the study, comments. Dr. Rybniker is leading the Infectious Diseases Research Laboratory at the Clinic I of Internal Medicine of University Hospital of Cologne and is since many years strongly affilitated with the Center for Molecular Medicine Cologne.

"This pre-activation of the blood cells seems to represent a protective mechanism, by which inflammation only occurs in the spike protein-producing tissue and not systemically in the whole body. The inflammatory reaction is then most likely to happen locally in the lymph node, where blood cells are known to migrate to, speculates Dr. Jan Rybniker.

The highly specific response to the spike protein observed in the study is quite unusual for cells of the innate immune system. The responsible mechanism depends on several spike protein-binding receptors on the surface of the macrophages which activate an important regulatory protein called SYK. SYK then starts a pro-inflammatory cascade in the cells. Interestingly, the observed effects were particularly pronounced after the second vaccination. However, also the third vaccination (booster) was able to re-activate macrophages even months after the first two shots had been given. Macrophages circulating in the blood have a very short life span of only a few days.

"Apparently, vaccination also leads to a memory function in these short-lived cells. This important finding is novel for mRNA vaccines. The underlying mechanism could also contribute to the strong protective effect we obtain with booster vaccinations," reports Dr. Sebastian Theobald, irst author of the study and postdoctoral fellow in the Rybniker´s research team located athe Center for Molecular Medicine Cologne.

The SYK signaling pathway and upstream receptor molecules described in the study have long been considered as putative and attractive mechanisms by which cells of the innate immune system could be stimulated in the context of vaccination. This theory can now be confirmed for mRNA vaccines, which have a very good safety profile. The results could be used to activate similar immunity-boosting mechanisms in a very targeted manner in future vaccinations, for example via appropriate adjuvants.

"mRNA-based therapies and vaccines are on the rise. Therefore, it is pivotal to gather as much information as possible on the immune responses triggered by these constructs in order to fully exploit their potential" says Dr. Rybniker.

Interestingly, the SYK pathway also appears to play a role in severe COVID-19 disease. In a previous study, the group was already able to demonstrate similar effects on blood cells of COVID-19 patients. Therefore, SYK is also considered a potential therapeutic target for immunomodulatory therapies in severe COVID-19 infection - clinical trials with corresponding drugs are already underway.

These multifaceted and in-depth investigations were only possible with the help of several collaborative partners. "Our thanks therefore go to all the research groups and researchers who contributed to the success of the study. In particular, we would like to thank the numerous vaccinated individuals who provided us with their blood for the laboratory experiments," sais Dr. Rybniker.

The study was funded by the German Research Foundation (DFG). In addition, the study was significantly supported by the Immunology Platform COVIM, a collaborative project for the determination and utilization of SARS-CoV-2 immunity. COVIM is part of the Network University Medicine (NUM). The network encompasses the entire German university medicine and promotes cooperative and structure-building projects in which as many university hospitals as possible should be involved. In addition, the study was supported by the Center for Molecular Medicine Cologne of the University of Cologne.

Publication

  • Title: Spleen tyrosine kinase mediates innate and adaptive immune crosstalk in SARS-CoV-2 mRNA vaccination.
  • Journal: EMBO Mol Med. 2022 Jul 4:e15888. doi: 10.15252/emmm.202215888. Online ahead of print. PMID: 35785445 Free article, https://pubmed.ncbi.nlm.nih.gov/35785445/.
  • Authors: Theobald SJ#1,2, Simonis A#1,2, Mudler JM#1,2, Göbel U3, Acton R3, Kohlhas V1,2,3, Albert MC3,4, Hellmann AM2,5, Malin JJ1,2, Winter S1,2, Hallek M1,2,3, Walczak H3,4,6, Nguyen PH1,2,3, Koch M2,4,7 Rybniker J1,2,8      #Contributed equally
  • Author Affilications
    1
    Clinic I of Internal Medicine, Faculty of Medicine, University of Cologne
    2Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine, University of Cologne
    3Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne
    4Center for Biochemistry, Faculty of Medicine, University Hospital of Cologne
    5Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Medical Faculty of Medicine, University Hospital of Cologne
    6Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London
    7Institute for Dental Research and Oral Musculoskeletal Biology,Medical Faculty, University of Cologne
    8German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne

Contact
PD Dr. nat. med. Dr. med. Jan Rybniker
Clinic I of Internal Medicine - University Hospitl Cologne
Head: Translational Research Unit - Infectious Diseases (TRU-ID) - Faculty of Medicine, University of Cologne
located in the Center for Molecular Medicine Cologne
E-Mail: jan.rybniker[at]uk-koeln.de