Certain immune cells that people have produced in the past against cold coronaviruses boost the immune response against SARS-CoV-2 – both during natural infection and after vaccination. This is shown by researchers from Charité – Universitätsmedizin Berlin, the Berlin Institute of Health at Charité (BIH) and the Max Planck Institute for Molecular Genetics (MPIMG) in a recent study in the journal Science*. This „cross-immunity“ decreases with increasing age. This could contribute to the fact that older people fall seriously ill with COVID-19 more often and that their vaccination protection is often weaker than that of younger people.
Scientists at the Charité and the MPIMG were the first to make a surprising observation last year: Some people who have never had contact with SARS-CoV-2 have memory immune cells that recognise the pathogen despite its newness. The team attributed the observation to the fact that these so-called T-helper cells had to deal with more harmless cold coronaviruses in the past and also attack the new coronavirus due to the similar structure, especially the spike protein on the virus surface. Such cross-reactivity has now been confirmed in a whole series of studies.
However, the question of how these immune cells influence the course of a subsequent SARS-CoV-2 infection remained unclear – and intensively discussed worldwide. „We assumed that cross-reacting T helper cells have a protective effect, that an earlier cold with endemic coronaviruses, i.e. those that have been circulating in the population for many years, thus attenuates the symptoms in COVID-19,“ says Dr Lucie Loyal, a scientist at Si-M (The Simulated Human), a joint research space of the Charité and the Technical University of Berlin, and at the BIH Center for Regenerative Therapies (BCRT). She is first author of the study at that time and also of the current one. „However, the opposite could also have been the case. With some viruses, a second infection with a similar virus strain leads to a misguided immune response, with negative effects on the course of the disease.“ Now the Berlin research team presents evidence that supports the assumption of a protective effect. According to the data, cross-immunity could be one of several reasons not only for the different severity of COVID-19 courses, but also for the different effectiveness of vaccinations in different age groups.
For the study, the researchers recruited almost 800 people from mid-2020 who had not yet come into contact with SARS-CoV-2 and checked at regular intervals whether they had become infected with the pathogen. This was the case with 17 people. The research group analysed their immune systems in detail both before and during the infection. The results showed that the body mobilised T-helper cells, which it had produced against endemic cold coronaviruses, also against SARS-CoV-2. In addition, the immune response against SARS-CoV-2 was qualitatively better the more of these cross-reacting cells were present before the infection. The cells recognised a specific area of the spike protein particularly frequently. The structure of the old and the new coronavirus is „conserved“ at this point, i.e. it has a particularly similar design. „In the case of colds with more harmless coronaviruses, the immune system thus builds up a kind of universal, protective coronavirus memory,“ explains Dr. Claudia Giesecke-Thiel, head of the Flow Cytometry Service Group at the MPIMG and lead author of the study. „When it now comes into contact with SARS-CoV-2, such memory cells are activated again and now also attack the new pathogen. This could contribute to a faster immune response against SARS-CoV-2, which opposes an unhindered spread of the virus in the body at the beginning of the infection and thus probably influences the course of the disease favourably.“ However, the scientist also emphasises: „This does not mean that one is protected against SARS-CoV-2 with certainty by past colds. Vaccination is important in any case. Our study provides one of several explanations for the observation made since the beginning of the pandemic that SARS-CoV-2 infection can proceed so differently in different people.“
The researchers also demonstrated an immune-boosting effect of the cross-reacting T cells when COVID-19 vaccination was administered with BioNTech’s vaccine. Similar to a natural infection, the vaccine causes the body to produce the spike protein of SARS-CoV-2 – including the conserved fragment – and present it to the immune system. An analysis of the immune response of 31 healthy individuals before and after vaccination showed: while normal T-helper cells were activated gradually over a period of two weeks, the cross-reacting T-helper cells responded very quickly to the vaccination within one week. This also had a positive effect on the formation of antibodies: The body was able to produce antibodies against the conserved site in the spike protein already after the initial vaccination with a speed that is otherwise only observed with booster vaccinations. „So even with vaccination, the body can at least partially fall back on an immune memory if it has already gone through colds with endemic coronaviruses,“ says Prof. Dr. Andreas Thiel, also lead author of the study, who is a Charité scientist at Si-M and BCRT. „This could explain the surprisingly fast and very high protective effect that we observe, at least in younger people, already after a COVID-19 first vaccination.“
In a second part of the study, the researchers were able to show that cross-immunity decreases with age by analysing the T-helper cells in almost 570 healthy people: Both the number of cross-reacting T cells and their binding strength were lower in older study participants than in younger ones. The authors attribute the decreasing cross-immunity to natural changes in an ageing immune system. „The advantage that a harmless coronavirus cold often gives younger people in fighting SARS-CoV-2 and also in building up vaccine protection is unfortunately less in older people,“ says Prof. Thiel. „A third booster vaccination could probably compensate for the weaker immune response in this more vulnerable population and provide sufficient vaccine protection.“
Four coronaviruses are known in medicine that have been circulating in humans for a long time and are called endemic human coronaviruses (HCoV). They usually cause cold symptoms and are called HCoV-OC43, HCoV-229E, HCoV-HKU1 and HCoV-NL63. It is estimated that they account for up to 30 per cent of colds.
T-helper cells are responsible for controlling and coordinating the immune response. When a pathogen enters the body, so-called phagocytes take it up and present fragments of it („antigens“) on their surface. T-helper cells control these fragments; if they have a more or less suitable receptor for these pathogen fragments, they are activated. Activated T-helper cells then ensure that other immune cells fight the pathogen directly and form precisely fitting antibodies. In most immune responses, so-called memory T-helper cells are then also produced, which can survive in the body for many years and are responsible for a faster and more efficient immune response in the event of renewed contact with the same pathogen. A characteristic feature of T-helper cells is that they can be activated not only by an exactly matching pathogen, but also by „sufficiently similar“ invaders.
About the study
The work is based on the study „Charité Corona Cross“, which was launched in 2020 under the leadership of the Charité in cooperation with the Technical University of Berlin and the MPIMG. Funded by the Federal Ministry of Health (BMG), it is investigating how the course of COVID-19 disease is altered by cross-reactive T helper cells. Parts of this work were done within the framework of the joint project „COVIM – Determination and Utilisation of SARS-CoV-2 Immunity“. The COVIM consortium is investigating who is immunologically protected from SARS-CoV-2 infection, by what means and for how long, and how immunological protection can be transferred from a few immune individuals to many non-immune individuals. The project is coordinated by the Charité and the University Hospital Cologne. COVIM is one of 13 collaborative projects within the Network University Medicine (NUM), which was initiated and coordinated by Charité and is funded by the Federal Ministry of Education and Research. The NUM unites the strengths of the 36 university hospitals in Germany.