Anti-idiotype antibodies and symptoms after SARS-CoV-2 infection or vaccination

Anti-idiotype antibodies (Ab2 antibodies) are produced by the immune system as a means to tame to effect of the ‘original’ antibodies (Ab1 antibodies) induced to react to a specific antigen to prevent the immune response from getting out of hand. The SARS-CoV-2 spike protein antigen is one such primary Ab1 target.

A paper recently published in the The New England Journal of Medicine describes how Ab2 anti-idiotype antibodies can mimic the virus and cause subsequent adverse effects. The authors describe the scope of this concern as to regards individual responses to vaccines as well as the virus.

“The development of multiple efficacious vaccines has been critical in the control of the pandemic, but their efficacy has been limited by the appearance of viral variants, and the vaccines can be associated with rare off-target or toxic effects, including allergic reactions, myocarditis, and immune-mediated thrombosis and thrombocytopenia in some healthy adults. Many of these phenomena are likely to be immune-mediated. How can we understand this diversity in immune responses in different persons?”

Antibody responses to the original antigen-specific antibody

Primary antibody responses (Ab1) to an antigen such as a viral spike protein can induce a subsequent antibody response against the original antigen-specific antibody. While this is a way of ‘reining in’ the Ab1 activity to prevent it from becoming harmfully excessive, those Ab2 anti-idiotypic antibodies can cause problems including autoimmunity after viral infection and reactions to vaccines.

“The paratopes, or antigen-binding domains, of some of the resulting anti-idiotype (or “Ab2”) antibodies that are specific for Ab1 can structurally resemble that of the original antigens themselves. Thus, the Ab2 antigen-binding region can potentially represent an exact mirror image of the initial targeted antigen in the Ab1 response, and Ab2 antibodies have even been examined for potential use as a surrogate for the antigen in vaccine studies. However, as a result of this mimicry, Ab2 antibodies also have the potential to bind the same receptor that the original antigen was targeting.”

Anti-idiotype Antibodies and SARS-CoV-2

Binding of these Ab2 antibodies to normal cells has the potential to cause problems long into the future.

“Ab2 antibodies binding to the original receptor on normal cells therefore have the potential to mediate profound effects on the cell that could result in pathologic changes, particularly in the long term — long after the original antigen itself has disappeared.”

Anti-idiotype antibody responses to ACE2 receptors

ACE2 receptors are expressed on the surface of cells not only in the lungs, but also heart, kidney, intestinal, brain and nervous system, and vascular endothelial cells. Infection of the latter an result in systemic vasculitis, thromboembolism and disseminated intravascular coagulation, damaging circulation throughout the body, including the brain. Ab2 antibodies to ACE2 receptors can have similar effects.

“Given its critical role in regulating angiotensin responses, many physiological effects can be influenced by ACE2 engagement. The S protein itself has a direct effect on suppressing ACE2 signaling by a variety of mechanisms and can also directly trigger toll-like receptors and induce inflammatory cytokines. Anti-idiotype responses may affect ACE2 function, resulting in similar effects.”

This is a relevant consideration both for optimizing the response to vaccines and the clinical management of infections…

“…the reported occurrence of myocarditis after vaccine administration bears striking similarities to the myocarditis associated with Ab2 antibodies induced after some viral infections. Ab2 antibodies could also mediate neurologic effects of SARS-CoV-2 infection or vaccines, given the expression of ACE2 on neuronal tissues, the specific neuropathologic effects of SARS-CoV-2 infection, and the similarity of these effects to Ab2-mediated neurologic effects observed in other viral models.”

The authors conclude with an appeal for further research into the key role of anti-idiotype antibodies in infection, prevention, and treatment.

“It would therefore be prudent to fully characterize all antibody and T-cell responses to the virus and the vaccines, including Ab2 responses over time. Using huACE2 transgenic mice and crossing them with strains that are predisposed to autoimmunity or other human pathologic conditions can also provide important insights… However, much more basic science research is needed to determine the potential role idiotype-based immunoregulation of both humoral and cell-mediated responses may play both in antiviral efficacy and in unwanted side effects of both SARS-CoV-2 infection and the vaccines that protect us from it.”