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Antibodies Mimicking SARS-CoV-2 Could Explain Long Covid And Some Rare Vaccine Side Effects

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New Delhi: Nearly 260 million Covid-19 cases have been reported worldwide as of November 25, with the pandemic claiming more than 5 million lives globally. Scientists are working to make effective vaccines, and are also trying to understand the long term effects of Covid-19. 

However, the effectiveness of vaccines is not fully understood. Vaccines also cause some rare side effects such as allergic reactions, heart inflammation (myocarditis) and blood-clotting (thrombosis). The side effects of the vaccine are believed to be caused by the patient’s immune response. 

Even after recovering from Covid-19, approximately one in four Covid-19 patients have lingering symptoms. This condition of persisting health problems in a recovered coronavirus patient, at four or more weeks after infection, even after testing negative, is known as “long Covid”. 

In an article published in The New England Journal of Medicine on Wednesday, two researchers presented an explanation to the diverse immune responses to SARS-CoV-2 and the vaccines. William Murphy, the Vice Chair of Research at University of California-Davis Health and Professor of Dermatology and Internal Medicine, and Dan Longo, Professor of Medicine at Harvard Medical School, are the authors of the study.

Antibodies Mimicking SARS-CoV-2

The authors suggest that Danish immunologist Niels Jerne’s work, titled ‘Network Hypothesis’, may offer insights into how the immune system produces antibodies and reacts to coronavirus.

Jerne, along with George’s Köhler and César Milstein, were awarded the Nobel Prize in Physiology or Medicine in 1984 for their research on classic immunological concepts.

Jerne’s hypothesis explains how the immune system regulates the production of antibodies. Antibody response is a cascade reaction which is launched by the immune system in response to an antigen (foreign body), such as a virus. The protective antibodies may trigger a new antibody response towards themselves, leading to their disappearance, the hypothesis states.

These secondary antibodies are called anti-idiotype antibodies, and can bind to and deplete the initial protective antibody responses. In other words, anti-idiotype antibodies mirror the original antigen itself, and result in adverse effects.

When SARS-CoV-2 enters the body, its spike protein binds with the ACE2 receptor, and this gives the virus entry to the cell. In response to the invading virus, the immune system produces protective antibodies, which block or neutralise the effects of the virus by binding to it. 

The protective antibodies can also cause immune responses with anti-idiotype antibodies, as a form of down-regulation (process of reducing or suppressing a response to a stimulus), the authors said in the article. The initial protective antibodies are cleared as a result of the anti-idiotype responses. This can result in limited efficacy of antibody-based therapies.

Murphy stated that a fascinating aspect of the newly formed anti-idiotype antibodies is that some of their structures can be a mirror image of the original antigen, and act like the antigen while binding to the same receptors the viral antigen binds, according to a statement by UC-Davis. The binding can potentially lead to unwanted actions and pathology, especially in the long term, he explained. 

The anti-idiotype antibodies can potentially target the same ACE2 receptors, the authors suggested. Various normal ACE2 functions can be affected due to the blocking or triggering of receptors.

Anti-Idiotype Antibodies May Cause Rare Vaccine Side Effects

Murphy said it would be important to determine if these regulatory immune responses are responsible for some of the off-target effects of vaccines, considering the fact that ACE2 receptors are widely distributed on numerous cells and perform critical functions. He added that anti-idiotype responses can also explain why long-term effects can occur long after the viral infection has passed. 

The SARS-CoV-2 spike protein is the primary antigen used in Covid-19 vaccines. Current research studies on antibody responses to these vaccines mainly focus on the initial protective responses and efficacy of neutralising the virus, according to Murphy and Longo.

Murphy said there is an immense need for more basic science research to understand complex immunological pathways. It is important to know what keeps the protective responses going, and to understand what leads to the potential unwanted side-effects of both the coronavirus infection, and the different SARS-CoV-2 vaccine types, he added. Since boosters are being administered, it is essential to know more about these responses. Murphy said the good news is that these questions can be partially addressed in the laboratory, and have been used with other viral models.

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