Cytokine storm could sabotage long-term immunity against SARS-CoV-2


In a recent paper from a team of researchers led by Shiv Pillai of the Ragon Institute of MGH, MIT and Harvard and Harvard Medical School (HMS; both MA, USA), it is demonstrated that COVID-19 patients who have high levels of cytokines from producing a cytokine storm in response to the infection could be less likely to develop long-term immunity to SARS-CoV-2.

“We’ve seen a lot of studies suggesting that immunity in COVID-19 may not be durable because the antibodies decline over time,” explained Pillai. “More telling for us was that in patients with both mild as well as severe disease, antibodies lacked a key structural feature that is a hallmark of the ‘highest quality’ antibodies in a normal immune response. By using our understanding of how two different types of immune cells normally collaborate to make the best antibodies, we were able to find a mechanism that could explain this lower-quality immune response in COVID-19 patients.”

Pillai’s team, in collaboration with Robert Padera, Associate Professor at HMS, found that the spleen and lymph nodes of deceased COVID-19 patients showed a distinct lack of germinal centers, which are integral in developing a long-standing immune response.

Germinal centers are activated upon infection or vaccination, where they encourage B cells responsible for producing antibodies, to mature into memory cells, which act against specific pathogens. Memory cells enable a timely immune response if the body encounters that same pathogen again, in essence, giving long-term immunity.

Germinal centers require helper T cells to develop. The paper, accepted for publication in Cell, showed that these specialist cells do not materialize in severely ill COVID-19 patients, meaning germinal centers cannot form.

Past research has found that formation of helper T cells, and therefore germinal centers, is prevented by high levels of cytokines such as TNF, released in cytokine storms. The patients in this study were shown to have large amounts of TNF accumulating in locations where germinal centers were likely to have formed.

This information also raises concerns over the likelihood of achieving herd immunity against SARS-CoV-2 infection.

“Without the formation of germinal centers, there is unlikely to be long-term memory to this virus developing from natural infections, meaning that while antibodies may protect people for a relatively short time, a single person who recovers from the disease could get infected again, perhaps six months later, or even multiple times with SARS-CoV-2. This suggests that developing herd immunity may be difficult,” concluded Pillai.

In the case of COVID-19, a vaccine continues to show the most promise for halting the spread of infection and providing long-term immunity against the virus as vaccines do not induce a cytokine storm. Upon vaccination, germinal centers would be able to form and B cells that produce the most effective antibodies could evolve into memory cells, providing the long-lasting protection we need.

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Sources: Kaneko N, Kuo H-H, Boucau J et al. Loss of Bcl-6-expressing T follicular helper cells and germinal centers in COVID-19. Cell, doi:org/10.1016/ j.cell.2020.08.025 (2020) (Epub ahead of print);


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