Editor’s Note: These letters were published on February 2, 2022, at NEJM.org.


Anti-idiotype Antibodies in SARS-CoV-2 Infection and Vaccination

To the Editor

Murphy and Longo (published online on Nov. 24 at NEJM.org)1 elaborate on the possible role played by anti-idiotype antibodies in the pathogenesis of severe adverse reactions to SARS-CoV-2 infection and vaccination, mentioning only myocarditis and immune-mediated thrombosis and thrombocytopenia.

Neuropilin 1 is the second receptor for SARS-CoV-2; it is recognized by the spike protein of the virus and targeted by the virus early during replication.2,3 This protein has been so far been neglected with regard to vaccine adverse effects.

Over the past 3 months, I have cared for five patients who have had postvaccine serious adverse events involving the peripheral nerves. Four of the patients had severe peripheral neuropathy with sensory perception deficits and pain in the limbs; two patients had palsy, with partial recovery after 12 and 8 months. One patient had persistent tinnitus (approximately 50 decibels, 500 Hz) in both ears. All five cases occurred within 24 to 36 hours after the first dose of BNT162b2 (Pfizer–BioNTech) in patients without a history of vaccine reactions or of autoimmune or demyelinating disease. Other surveys4 and single-case reports5,6 have corroborated my personal observations.

The possibility that anti-idiotype antibodies or other immune-mediated mechanisms targeting neuropilin 1 may be involved in vaccine-related complications, including neurologic sequelae, should be considered during clinical evaluations and investigated to improve the current vaccines.

Andrea De Maria, M.D.
University of Genoa, Genoa, Italy

No potential conflict of interest relevant to this letter was reported.

This letter was published on February 2, 2022, at NEJM.org.

  1. 1. Murphy WJ, Longo DL. A possible role for anti-idiotype antibodies in SARS-CoV-2 infection and vaccination. N Engl J Med 2022;386:394-396.

  2. 2. Cantuti-Castelvetri L, Ojha R, Pedro LD, et al. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science 2020;370:856-860.

  3. 3. Daly JL, Simonetti B, Klein K, et al. Neuropilin-1 is a host factor for SARS-CoV-2 infection. Science 2020;370:861-865.

  4. 4. Patone M, Handunnetthi L, Saatci D, et al. Neurological complications after first dose of COVID-19 vaccines and SARS-CoV-2 infection. Nat Med 2021;27:2144-2153.

  5. 5. Luca A, Squillaci R, Terravecchia C, et al. Pure sensitive chronic inflammatory axonal polyneuropathy following Pfizer COVID-19 vaccine. Neurol Sci 2021 November 04 (Epub ahead of print).

  6. 6. Waheed W, Carey ME, Tandan SR, Tandan R. Post COVID-19 vaccine small fiber neuropathy. Muscle Nerve 2021;64(1):E1-E2.

To the Editor

We had previously1 developed and tested the hypothesis that Murphy and Longo propose in their article. The authors proposed that the Network Hypothesis of Niels Jerne2 could explain the formation of anti-idiotype immune responses. We wrote, “[It] is likely that these are anti-idiotypic antibodies …” and “… issues regarding the response to SARS-CoV-2 can potentially be explained using Jerne’s Network Theory of the Immune System ….” We showed that the measurable levels of angiotensin-converting–enzyme 2 (ACE2) antibodies that Murphy and Longo speculated may exist are present in 81% of patients who have recovered from Covid-19 and are not present in patients who have not been infected.1 Murphy and Longo proposed that anti-idiotype responses may affect ACE2 function, leading to the induction of inflammatory cytokines. We showed that patients with ACE2 antibodies have reduced ACE2 activity and wrote, “This provides a potential mechanism for alteration of the balance of angiotensin peptides leading to increased Ang II and activation of the immune system.” To our knowledge, we were the first to propose and test this hypothesis.

Terry O. Harville, M.D., Ph.D.
John M. Arthur, M.D., Ph.D.
University of Arkansas for Medical Sciences, Little Rock, AR

No potential conflict of interest relevant to this letter was reported.

This letter was published on February 2, 2022, at NEJM.org.

  1. 1. Arthur JM, Forrest JC, Boehme KW, et al. Development of ACE2 autoantibodies after SARS-CoV-2 infection. PLoS One 2021;16(9):e0257016-e0257016.

  2. 2. Jerne NK. Towards a network theory of the immune system. Ann Immunol (Paris) 1974;125C:373-389.


The authors reply: De Maria writes about potential anti-idiotype immune responses directed against other targets of the SARS-CoV-2 spike protein, such as neuropilin 1, which could also contribute to off-target effects. We agree that anything the spike protein can bind can therefore also be a target for mirror-image anti-idiotype antibodies and may affect cellular functions. The need for additional basic research on SARS-CoV-2 virus–host interactions is again highlighted. Given the complex and already diverse effects of ACE2 on multiple cell types and pathways, as well as the fact that anti-idiotype antibodies can also be diverse in their effects — in that they can be antagonistic and agonistic and can potentially cause immune-cell attack — further assessment of all potential target molecules is needed.

Harville and Arthur point out that their study, published in September 2021, showed the presence of anti-idiotype antibodies to ACE2 in patients after SARS-CoV-2 infection.1 Our article was submitted months before their study was published, and we were thus unaware of it. We are heartened by their data, since it supports the idea that anti-idiotype antibodies occur after SARS-CoV-2 infection and may have effects on ACE2 function. However, whether similar anti-idiotype responses and effects occur after SARS-CoV-2 vaccination still needs to be determined. Since the release of our commentary, we have received correspondence from both patients and clinicians describing evidence of potential autoantibodies to ACE2 in association with protracted adverse events after vaccination. Much more attention to these adverse effects of infection and vaccination, as well as an understanding of the immunologic mechanisms underlying them, is needed.

William J. Murphy, Ph.D.
University of California, Davis, Sacramento, CA

Dan L. Longo, M.D.

Since publication of their article, the authors report no further potential conflict of interest.

This letter was published on February 2, 2022, at NEJM.org.

  1. 1. Arthur JM, Forrest JC, Boehme KW, et al. Development of ACE2 autoantibodies after SARS-CoV-2 infection. PLoS One 2021;16(9):e0257016-e0257016.

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