What do we know about cross-reactivity and its effect on COVID-19 ?

By Fatéma Dodat

Image Source : Pixabay

As the race for vaccines against the novel coronavirus continues, the mechanisms relating to the existence of a pre-existing immunity to the virus begins to be unveiled. Indeed, many studies point to the existence of a cross-reactivity, which would result from infection by other types of coronavirus in the past. What is cross-reactivity and what does this phenomenon imply in the possible course of the pandemic?

Immune response in COVID-19

Various recently published scientific studies suggest that individuals who have never been exposed to the new coronavirus SARS-CoV-2 trigger an immune response to this virus and that this response is part of the memory of the immune system.

When the body is confronted with a pathogen that it has already fought, it activates immune defenses called upon during the first attack and which remain in "memory" in the body. These defenses are part of adaptive immunity and include T cells, white blood cells that have molecules on their surface that allow them to recognize different pathogens.

A study has shown that T cells react to different sequences of the new coronavirus SARS-CoV-2, in blood samples from patients collected in the United States between 2015 and 2018 - therefore before the appearance of this virus. It reveals that T cells react in 50% of cases to exposure to the virus, and that this immune response is mainly attributed to specific T cells called helpers. These act as intermediaries in the immune response and proliferate to activate other cell types that have a more direct action on the pathogen.

Another study carried out in the Netherlands on donated blood samples also detects activation of T helper cells against SARS-CoV-2 in patients who have not been exposed to the virus. However, the immune response appears to be different depending on the virus sequences that are presented.

Three other studies carried out in Germany, Singapore and England also showed an activation of T cells against SARS-CoV-2.

A hypothesis: cross-reactivity

T cells reactivity against the SARS-CoV-2 virus could have been explained by a previous exposure to this infectious agent, which is unlikely in the studies cited above. Nonetheless, individuals could have been infected by viruses whose sequences are - at least in part - similar to SARS-CoV-2, such as the coronaviruses that cause common colds called HCoVs.

This previous infection would allow T cells to adapt to fight these pathogens and to remain in memory. Thanks to homologous sequences of these virus with SARS-CoV-2, T cells could thus recognize this pathogen and trigger an immune response during infection.

This phenomenon is called cross-reactivity and is the hypothesis currently favoured to explain the activation of T cells against SARS-CoV-2 in previous studies.

Consequences for COVID-19

Various speculations have been made about the consequences of cross-immunity to the COVID-19 virus. One of these would be a fast and strong immune response against the virus and therefore a decrease in the severity of the disease in these individuals. In addition, people with a large amount of pre-existing memory T helper cells, involved in the development of neutralizing antibodies, may have facilitated production of antibodies against the virus.

At the same time, the presence of these lymphocytes could also influence the vaccination outcomes. A stronger and faster immune response could be observed, in particular through the development of antibodies against the virus. However, the presence of these T cells could also be a confounding factor in clinical trials as patients' immune responses to candidate vaccines could differ depending on their previous exposure to other viruses.

"If in a clinical trial there are many more people protected by TCDA [helper T lymphocytes] generated by cold coronaviruses, one could mistakenly think that a vaccine works when it does not" explains Dr. Sette, a biologist from California who published one of the first evidence for cross-immunity in May. [translation of the author]

This bias could still be limited by measuring pre-existing immunity in all the clinical trials that are starting.

Pre-existing immunity could also be harmful if the body limits its immune response due to recognition of the pathogen. In addition, the phenomenon of "antibody-dependent enhancement", which leads to a complex between the antibody and the virus and which leads to facilitated infection of the virus within the body, may also occur.

In the case of the H1N1 influenza in 2009, cross-reactivity was beneficial. Elderly patients showed a better immune response to the virus than young adults. This phenomenon was explained by the circulation of a similar strain of H1N1 decades earlier, contracted by older people and which would have provided them cross-reactivity.

Scientific research needed

In the case of the current pandemic, young people seem to be less affected than the elderly by COVID-19. The reasons for this phenomenon remain unknown.

Dr Sette points out that the cross-reactivity hypothesis raises many questions and that "the only way [to confirm that cross-reactivity is based on helper T lymphocytes] would be a prospective study evaluating the presence of these lymphocytes reacting to cold coronaviruses in patients who have never been infected with SARS-CoV-2. Then we would follow them and see their risk of being infected with SARS-CoV-2 and the severity of their illness.

However, such study would be complicated because of multiple confounding factors, notes La Presse.


In summary, it seems clear that a pre-existing immune response against SARS-CoV-2, to some degree, exists in part of the population. The preferred - but unproven so far – hypothesis, is that this immunity is due to cross-reactivity resulting from prior infection with coronaviruses causing the common cold. This cross-reactivity could have consequences for the severity of the disease, herd immunity and the development of a vaccine. Further scientific research is therefore needed to understand these mechanisms.

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