Covid-19: Previous colds improve immune response

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.

Cross-immunity decreases with age

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).

Researchers at Charité and MPIMG were the first to make a surprising observation last year: Some people who have never had contact with SARS-CoV-2 possess memory immune cells that recognise the pathogen despite its novelty. The team attributed the observation to the fact that the 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. "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, 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) and first author of both studies. "However, the opposite could also have been the case. Indeed, with some viruses, a second infection with a similar viral strain leads to a misguided immune response, with negative effects on the course of the disease." According to the data of the Berlin research team, 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.

Body builds universal, protective coronavirus memory

For the study, nearly 800 people who had not yet been exposed to SARS-CoV-2 were recruited from mid-2020 onwards and tested at regular intervals to see if they had been 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 frequently recognised a specific area of the spike protein in particular. 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 be so different in different people."

BioNTech vaccine with similar effect

An immune-boosting effect of the cross-reacting T cells was also demonstrated in a COVID-19 vaccination 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 presents 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, an analysis of T helper cells in nearly 570 healthy individuals demonstrated that cross-immunity decreases with age: 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."

Loyal L et al., Pre-existing common cold coronavirus-cross-reactive CD4+ T cells enhance SARS-CoV-2 immune responses upon infection and vaccination. Science (2021)