Guillain-Barré syndrome: Honing treatment strategies

Recent insights into the pathophysiology of Guillain-Barré syndrome (GBS) – which affects 1 or 2 persons for every 100,000 people annually, usually post infection – indicate that classic subtypes represent varying manifestations of a shared disease process. This knowledge is yielding new treatment strategies aimed at halting the illness in its tracks. Promising therapies include inhibitors of complement and, perhaps one day, the calcium-activated protease calpain.

Meanwhile, an association between COVID-19 and GBS has been debunked, whereas a small risk of GBS following adenovirus-vectored COVID vaccination is now accepted and quantified. Regardless of cause, the potential severity of GBS and variability in its presentation demand constant vigilance.
 

Shutting down the disease process

When patients present to an emergency department with sensory symptoms and increasing muscle weakness, “most of the damage has been or is being done,” said Michael P. Lunn, MBBS, MRCP, PhD, professor of clinical neurology, consultant neurologist, and clinical lead in neuroimmunology at University College London Queen Square Institute of Neurology, who spoke at length about GBS with Neurology Reviews 2023 Rare Neurological Disease Special Report. “The crucial reason that GBS treatment has not advanced significantly – and why we’re still slightly stuck where we are in terms of helping people get better more quickly – is that we need something that absolutely turns the disease off as patients come through the door.”

GBS is probably the best-understood autoimmune-mediated neurological disease, in some respects surpassing myasthenia gravis, Dr. Lunn said. “We know very frequently the organisms and stimuli that set off Guillain-Barré syndrome. We understand, to an extent, the immunology and how you break tolerance of the immune system so that an invading organism can provoke an immune response that damages peripheral nerves.”

Compared to what was known about GBS in decades past, neurologists now better understand how and where antibodies attack the nerve; how complement then damages the nodes of Ranvier and paranodes; and how an external attack results in sometimes irreparable internal nerve damage. “We’ve got a string, beginning to end, of understanding the disease,” declared Dr. Lunn.

Understanding of differences in the spectrum of pathology of GBS has led to additional diagnostic categories, said Dr. Lunn. Acute inflammatory demyelinating polyradiculoneuropathy, or typical GBS, represents the most common form in affluent Western nations. A motor variant was recognized in the 1980s; in the mid-1990s, Ho and colleagues described a cohort of patients in China who had acute motor axonal neuropathy and acute motor sensory axonal neuropathy¹ – two forms that are particularly common throughout Asia and South America.
 

Shared mechanism

Based on the findings of electrophysiologic studies, Dr. Lunn said, experts traditionally believed that GBS attacked either axons themselves or their myelin sheaths. “That’s where the anti-ganglioside antibodies come in, providing targeting to nerve structures.” The dichotomous classification system, he added, was partially correct.

Then, through the 2010s and 2020s, neurophysiologist Antonio Uncini, MD, recognized, based partly on histologic studies by Ho and colleagues, that the myelin and axonal subtypes are both likely to stem from the same mechanism.² When antibodies and complement damage the node of Ranvier, Dr. Lunn said, “the myelin gets stripped off and the conduction becomes slow. But then the myelin can return, and patients get better.” But if damage is severe, it severs the axon, resulting in unrecoverable motor axonal neuropathy. “It’s basically all the same spectrum of disease,” Dr. Lunn said. “Anti-ganglioside antibodies may account for different GBS ‘flavors,’ but the immunological attack all occurs at the node of Ranvier in one way or another.”

The foregoing insight has focused development efforts on the shared seminal pathway of all GBS subtypes and given rise to the concept of nodo-paranodopathy, which incorporates damage at either the node of Ranvier or nearby paranodes.³

Simultaneously, Spanish and French researchers began elucidating new antibodies responsible for neuropathology at the node of Ranvier.⁴ Anti-ganglioside antibodies have long been loosely associated with acute motor axonal neuropathy and poor outcomes, although, Dr. Lunn said, they fail to tell the full story. Anti-GQ1b antibodies are associated with the Miller-Fisher syndrome subtype, well recognized for its medical features: double vision, loss of tendon reflexes, and arm and leg weakness.

However, Dr. Lunn said, most GBS cases lack anti-ganglioside antibodies. In some GBS cases, antibodies attack neurofascin, contactins, and gliomedin, which are mainly adhesion proteins at nodes of Ranvier.

“Therefore,” Dr. Lunn said, “there must be an antibody-mediated attack of the node of Ranvier or the paranode. That’s an important series of discoveries, primarily because it helps us understand the immunological attack at the node of Ranvier, which goes along with what Dr. Uncini was saying. But it also divides off a group of chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) that present acutely and look initially, for all purposes, like GBS.”

Recognizing acute CIDP (A-CIDP) is critically important for clinicians, Dr. Lunn stressed, because it requires treatment with rituximab (the most commonly used option), steroids, or plasma exchange.

Key clues that distinguish A-CIDP from GBS include:

• A high level of cerebrospinal fluid protein.

• Very slow nerve conduction.

• Early muscle wasting (rare in GBS).

Recognizing CIDP and A-CIDP is crucial, said Dr. Lunn, because it begins to bring all the pathology back together to make sense of GBS. Neurologists have known for decades that, if one damages a nerve with antibodies, then binds complement to those antibodies, the complement punches holes in the affected cells, resulting in death. “But it wasn’t quite clear how those cells might die,” Dr. Lunn said.

After complement-induced injury, calcium-activated calpain permanently damages the entire internal axonal structure.⁵ Perhaps more important, a 2022 mouse study showed that complement-mediated damage could be directed to myelin or axons using the genetically programmed presence or absence of gangliosides to understand subsequent calpain-induced destruction in either axons or myelin.⁶

Some of the engineered mouse cells included ganglioside; others did not. “So you can have anti-ganglioside antibodies directed at one cell type or the other, which would, or would not, have calpain within them,” Dr. Lunn said. Investigators also showed that a calpain inhibitor (AK295) or overproduction of an endogenous inhibitor, calpastatin, prevented damage to both cell types.⁶All existing calpain inhibitors are unsuitable for clinical use because they are highly toxic. “But if you could inhibit calpain and stop it from being activated by calcium,” Dr. Lunn explained, “you would have a mechanism for stopping cell degradation during GBS. That would be an important future target for pharmacotherapy. That whole story – from the beginning to the end of GBS – has opened up options for treatment.”

Because complement bound to antibodies, set up by infection, plays a pivotal role, complement inhibitors have become an exciting area of research over the past decade. The 36-patient Japanese Eculizumab Trial for GBS (JET-GBS) trial showed that, after 6 months, significantly more eculizumab-treated patients could run, compared with placebo-treated patients.⁷

“No other trials of complement inhibitors have yet been completed,” Dr. Lunn said. “But several different complement inhibitors work at different places, in a very complicated immune process. One of the complement inhibitors will become transformative in treating GBS – preventing disability and improving recovery – in the not-very-distant future.”

Additional investigational treatments that have demonstrated early promise in eliminating problem antibodies faster include imlifidase (Idefirix [Hansa Biopharma]), which destroys antibodies, and Fc receptor inhibitors such as efgartigimod alfa-fcab (Vyvgart [argenx]), which push antibodies into the natural catabolic pathway.

“We’ve been stuck with plasma exchange and intravenous immunoglobulin (IVIg) for three or four decades,” Dr. Lunn said. “We now have a series of strategies by which we can completely turn off complement and resulting nerve damage. If we can find a calpain inhibitor that turns off the end of that pathway, we will make dramatic improvements. Our understanding of the immunopathology has changed enormously and influences pharmacotherapy going forward.”
 

 

Recap of diagnosis and treatment

For decades, the diagnosis of GBS has relied on the presence of symptoms, including progressive weakness and loss of reflexes and sensations. Nerve-conduction studies and cerebrospinal fluid evaluation can help confirm the diagnosis.

IVIg shortens recovery, said Dr. Lunn, although nothing cures GBS. “And that’s a common problem: Clinicians think that they’re going to give somebody IVIg, and the patient’s going to get better immediately.” When that doesn’t happen, he said, physicians are tempted to give a second immunoglobulin dose.

However, a study published in 2021 shows that a second IVIg dose does not result in faster or better improvement – only in a significant risk of cardiovascular, cerebrovascular, and other thrombotic events 3 weeks later.⁸ Dr. Lunn noted that, although adverse-event data were “buried” in the supplemental materials of that study, the high cost of IVIg (approximately $12,500 per dose) means that the study has changed practice for the benefit of patients, providers, and health care systems.
 

COVID-19 and GBS triggers

Campylobacter jejuni infection still accounts for 30% to 40% of GBS cases, followed by other bacteria, including Mycoplasma pneumoniae and Haemophilus influenzae, and then by viruses, including cytomegalovirus and, rarely, human immunodeficiency virus. In recent years, severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection – COVID-19 – and vaccines against the viral infection have captured headlines for purportedly being a cause of GBS.

The Zika virus epidemic of 2015-2016 has been linked to GBS-like illness. The 2003 severe acute respiratory syndrome (SARS) pandemic and the Middle East respiratory syndrome coronavirus (MERS-CoV) epidemic were associated with GBS – although, taken together, SARS and MERS-CoV produced fewer than 10 cases of GBS, Dr. Lunn noted. Nevertheless, heightened awareness of these viruses fueled hypervigilance regarding the prospect that COVID-19 could cause GBS. Following reports of a single such case in Wuhan and hundreds in Italy, worry over pandemic GBS grew worldwide.

Dr. Lunn and colleagues addressed the COVID-19–GBS question in a 2023 publication.⁹ “Because GBS is largely treated only with IVIg, and IVIg costs a lot of money, and the U.K. government insists on every dose of IVIg being logged in a government database, we were able to identify virtually every case of GBS,” he said.

GBS diagnoses were reliable, he added, because each case was confirmed by physicians outside the emergency department. Analysis revealed that, in 2020, U.K. GBS cases actually declined by around one-third. “And even when there was a second wave of COVID-19 at the end of 2020, partly caused by better counting,” Dr. Lunn said, “there was no further increase in GBS cases. We concluded that there was no link between GBS and COVID-19, as the cases simply didn’t appear.”

The foregoing findings have since been corroborated by studies in Singapore, the United States, and South America, he pointed out. Earlier case series suggesting a link between COVID-19 and GBS were selective, Dr. Lunn added, with numbers too small to support robust conclusions.

The lack of a causal link between COVID-19 and GBS suggested to Dr. Lunn that there was no reason COVID-19 vaccination should cause GBS. All COVID-19 vaccines were designed to provoke an immune response either (1) by producing the SARS-CoV-2 spike protein on the surface of virus (through a replication-incompetent adenoviral vector) or (2) through DNA or mRNA transcription, he explained. “The spike protein is only a small part of COVID-19.”
 

 

GBS: ‘Adverse event of interest’

A link between modern vaccines and GBS first appeared in the 1970s with the hastily developed swine flu vaccine. “In late 1976,” Dr. Lunn explained, “it was identified that patients who were given that vaccine seemed to be developing illnesses consistent with GBS.” By 1980, Dr. Lunn said, the risk level was determined to be only five or six cases for every 1 million doses of vaccine administered. “But the vaccine program was aborted, and swine flu never really happened.” Every year since, “there has been a surveillance program looking at the occurrence of an association of GBS with influenza vaccine.”

Minor fluctuations aside, he said, the overall incidence of GBS with influenza vaccination – 1 GBS case for every 1 million vaccine doses given – has remained consistent over several decades. “Nevertheless, GBS became an adverse event of special interest for any vaccination campaign.”

COVID-19 vaccination. Dr. Lunn and colleagues used the United Kingdom National Health Service (NHS) National Immunoglobulin Database, and other databases, to pinpoint the risk of GBS presented by the first dose of the AstraZeneca ChAdOx1 nCoV-19 adenoviral vaccine.¹⁰ As with U.K. GBS cases, every COVID-19 vaccination is linked to an NHS number. “We identified all the cases of GBS, found their NHS numbers, and went back and found the exact dates they’d been vaccinated, and with which vaccine.” Only the adenoviral-vector vaccine carried an excess risk of GBS – 5.8 cases for every 1 million doses, associated only with the first dose and peaking at approximately 25 days post vaccination – compared with other vaccines used in the United Kingdom.

Researchers looked at data from the Vaccine Adverse Event Reporting System (VAERS), a program of the Centers for Disease Control and Prevention and the Food and Drug Administration, encompassing nearly 500 million COVID-19 vaccine doses given between December 2020 and January 2022. They found that patients who received the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) had a rate of GBS (within 21 and 41 days post vaccination) that was 9 and 12 times higher, respectively, than corresponding rates for the mRNA-1273 (Moderna) and BNT162b2 (Pfizer BioNTech) COVID-19 vaccines.¹¹ Risk was distributed relatively evenly by gender and age. Also at day 21 and day 41, observed event ratios with the adenoviral-vector vaccine (use of which has been suspended in the United States) were 3.79 and 2.34, respectively. Observed-event ratios with the other vaccines mirrored expected background rates.

The VAERS analysis confirms earlier data from the CDC’s Vaccine Safety Datalink, which showed that, among approximately 15 million U.S. vaccine doses given between mid-December 2020 and mid-November 2021, the unadjusted GBS incidence rate for every 100,000 person-years for the adenoviral vaccine, 21 days post exposure, was 32.4, compared with 1.3 for the mRNA vaccine. The adjusted relative risk with the adenoviral vaccine in the first 3 weeks post vaccination, compared to the 3- to 6-week interval post vaccination, was 6.03.¹² In addition, a head-to-head comparison of adenoviral versus mRNA vaccines at 21 days revealed an adjusted rate ratio of 20.56. Mechanistically, some experts theorize that antibodies induced by the Janssen vaccine might cross-react with glycoproteins on the myelin sheath of peripheral nerve axons to cause GBS, but this remains unproven.11

The AstraZeneca vaccine uses a chimpanzee adenovirus; the Janssen vaccine uses a human adenoviral carrier. “The only commonality between the Janssen/Johnson & Johnson and AstraZeneca vaccines, and the only thing that’s different from the other vaccines, is the adenoviral vector packaging,” Dr. Lunn emphasized. “I believe it’s what generates GBS after COVID-19 vaccination. It has nothing to do with the COVID-19 vaccination, the spike protein, the nucleic acid, the DNA, or anything else.”

The adenoviral vector probably also explains why GBS peaks during winter, said Dr. Lunn. “That’s when adenovirus is circulating.” When people contract the common cold, he explained, they don’t visit their family physician and request a swab to isolate the adenovirus. “By the time you get GBS, the adenovirus has been cleared. We’ve all got antibodies to adenovirus all over the place, anyway, because we get it so often.”

It would be difficult to prove conclusively that adenovirus belongs on the list of GBS causes, Dr. Lunn allowed. “But I have a strong suspicion that it does. COVID-19 and COVID-19 vaccination have given us some new avenues into identifying GBS causation potentially in the near future.” More research is needed in this area, he said.

Dr. Lunn has been a principal investigator for argenx (efgartigimod) and an adviser to AstraZeneca (ChAdOx1 nCoV-19). He has received travel grants from CSL Behring.
 

 

References

1. Ho TW et al. Guillain-Barré syndrome in northern China. Relationship to Campylobacter jejuni infection and anti-glycolipid antibodies. Brain. 1995;118(Pt 3):597-605. doi: 10.1093/brain/118.3.597.

2. Uncini A. A common mechanism and a new categorization for anti-ganglioside antibody-mediated neuropathies. Exp Neurol. 2012;235(2):513-6. doi: 10.1016/j.expneurol.2012.03.023.

3. Uncini A and Kuwabara S. The electrodiagnosis of Guillain-Barré syndrome subtypes: where do we stand? Clin Neurophysiol. 2018;129(12):2586-93. doi: 10.1016/j.clinph.2018.09.025.

4. Delmont E et al. Autoantibodies to nodal isoforms of neurofascin in chronic inflammatory demyelinating polyneuropathy. Brain. 2017;140(7):1851-8. doi: 10.1093/brain/awx124.

5. McGonigal R et al. Anti-GD1a antibodies activate complement and calpain to injure distal motor nodes of Ranvier in mice. Brain. 2010;133(Pt 7):1944-60. doi: 10.1093/brain/awq119.

6. Cunningham ME et al. Real time imaging of intra-axonal calcium flux in an explant mouse model of axonal Guillain-Barré syndrome. Exp Neurol. 2022 Sep;355:114127. doi: 10.1016/j.expneurol.2022.114127.

7. Misawa S et al; Japanese Eculizumab Trial for GBS (JET-GBS) Study Group. Safety and efficacy of eculizumab in Guillain-Barré syndrome: a multicentre, double-blind, randomised phase 2 trial. Lancet Neurol. 2018;17(6):519-29. doi: 10.1016/S1474-4422(18)30114-5.

8. Walgaard C et al; Dutch GBS Study Group. Second intravenous immunoglobulin dose in patients with Guillain-Barré syndrome with poor prognosis (SID-GBS): a double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2021;20(4):275-83. doi: 10.1016/S1474-4422(20)30494-4.

9. Keddie S et al. Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome. Brain. 2021;144(2):682-93. doi: 10.1093/brain/awaa433.

10. Keh RYS et al; BPNS/ABN COVID-19 Vaccine GBS Study Group. COVID-19 vaccination and Guillain-Barré syndrome: Analyses using the National Immunoglobulin Database. Brain. 2023;146(2):739-48. doi: 10.1093/brain/awac067.

11. Abara WE et al. Reports of Guillain-Barré syndrome after COVID-19 vaccination in the United States. JAMA Netw Open. 2023;6(2):e2253845. doi: 10.1001/jamanetworkopen.2022.53845.

12. Hanson KE et al. Incidence of Guillain-Barré syndrome after COVID-19 vaccination in the Vaccine Safety Datalink. JAMA Netw Open. 2022;5(4):e228879. doi: 10.1001/jamanetworkopen.2022.8879.
 

Recent insights into the pathophysiology of Guillain-Barré syndrome (GBS) – which affects 1 or 2 persons for every 100,000 people annually, usually post infection – indicate that classic subtypes represent varying manifestations of a shared disease process. This knowledge is yielding new treatment strategies aimed at halting the illness in its tracks. Promising therapies include inhibitors of complement and, perhaps one day, the calcium-activated protease calpain.

Meanwhile, an association between COVID-19 and GBS has been debunked, whereas a small risk of GBS following adenovirus-vectored COVID vaccination is now accepted and quantified. Regardless of cause, the potential severity of GBS and variability in its presentation demand constant vigilance.
 

Shutting down the disease process

When patients present to an emergency department with sensory symptoms and increasing muscle weakness, “most of the damage has been or is being done,” said Michael P. Lunn, MBBS, MRCP, PhD, professor of clinical neurology, consultant neurologist, and clinical lead in neuroimmunology at University College London Queen Square Institute of Neurology, who spoke at length about GBS with Neurology Reviews 2023 Rare Neurological Disease Special Report. “The crucial reason that GBS treatment has not advanced significantly – and why we’re still slightly stuck where we are in terms of helping people get better more quickly – is that we need something that absolutely turns the disease off as patients come through the door.”

GBS is probably the best-understood autoimmune-mediated neurological disease, in some respects surpassing myasthenia gravis, Dr. Lunn said. “We know very frequently the organisms and stimuli that set off Guillain-Barré syndrome. We understand, to an extent, the immunology and how you break tolerance of the immune system so that an invading organism can provoke an immune response that damages peripheral nerves.”

Compared to what was known about GBS in decades past, neurologists now better understand how and where antibodies attack the nerve; how complement then damages the nodes of Ranvier and paranodes; and how an external attack results in sometimes irreparable internal nerve damage. “We’ve got a string, beginning to end, of understanding the disease,” declared Dr. Lunn.

Understanding of differences in the spectrum of pathology of GBS has led to additional diagnostic categories, said Dr. Lunn. Acute inflammatory demyelinating polyradiculoneuropathy, or typical GBS, represents the most common form in affluent Western nations. A motor variant was recognized in the 1980s; in the mid-1990s, Ho and colleagues described a cohort of patients in China who had acute motor axonal neuropathy and acute motor sensory axonal neuropathy¹ – two forms that are particularly common throughout Asia and South America.
 

Shared mechanism

Based on the findings of electrophysiologic studies, Dr. Lunn said, experts traditionally believed that GBS attacked either axons themselves or their myelin sheaths. “That’s where the anti-ganglioside antibodies come in, providing targeting to nerve structures.” The dichotomous classification system, he added, was partially correct.

Then, through the 2010s and 2020s, neurophysiologist Antonio Uncini, MD, recognized, based partly on histologic studies by Ho and colleagues, that the myelin and axonal subtypes are both likely to stem from the same mechanism.² When antibodies and complement damage the node of Ranvier, Dr. Lunn said, “the myelin gets stripped off and the conduction becomes slow. But then the myelin can return, and patients get better.” But if damage is severe, it severs the axon, resulting in unrecoverable motor axonal neuropathy. “It’s basically all the same spectrum of disease,” Dr. Lunn said. “Anti-ganglioside antibodies may account for different GBS ‘flavors,’ but the immunological attack all occurs at the node of Ranvier in one way or another.”

The foregoing insight has focused development efforts on the shared seminal pathway of all GBS subtypes and given rise to the concept of nodo-paranodopathy, which incorporates damage at either the node of Ranvier or nearby paranodes.³

Simultaneously, Spanish and French researchers began elucidating new antibodies responsible for neuropathology at the node of Ranvier.⁴ Anti-ganglioside antibodies have long been loosely associated with acute motor axonal neuropathy and poor outcomes, although, Dr. Lunn said, they fail to tell the full story. Anti-GQ1b antibodies are associated with the Miller-Fisher syndrome subtype, well recognized for its medical features: double vision, loss of tendon reflexes, and arm and leg weakness.

However, Dr. Lunn said, most GBS cases lack anti-ganglioside antibodies. In some GBS cases, antibodies attack neurofascin, contactins, and gliomedin, which are mainly adhesion proteins at nodes of Ranvier.

“Therefore,” Dr. Lunn said, “there must be an antibody-mediated attack of the node of Ranvier or the paranode. That’s an important series of discoveries, primarily because it helps us understand the immunological attack at the node of Ranvier, which goes along with what Dr. Uncini was saying. But it also divides off a group of chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) that present acutely and look initially, for all purposes, like GBS.”

Recognizing acute CIDP (A-CIDP) is critically important for clinicians, Dr. Lunn stressed, because it requires treatment with rituximab (the most commonly used option), steroids, or plasma exchange.

Key clues that distinguish A-CIDP from GBS include:

• A high level of cerebrospinal fluid protein.

• Very slow nerve conduction.

• Early muscle wasting (rare in GBS).

Recognizing CIDP and A-CIDP is crucial, said Dr. Lunn, because it begins to bring all the pathology back together to make sense of GBS. Neurologists have known for decades that, if one damages a nerve with antibodies, then binds complement to those antibodies, the complement punches holes in the affected cells, resulting in death. “But it wasn’t quite clear how those cells might die,” Dr. Lunn said.

After complement-induced injury, calcium-activated calpain permanently damages the entire internal axonal structure.⁵ Perhaps more important, a 2022 mouse study showed that complement-mediated damage could be directed to myelin or axons using the genetically programmed presence or absence of gangliosides to understand subsequent calpain-induced destruction in either axons or myelin.⁶

Some of the engineered mouse cells included ganglioside; others did not. “So you can have anti-ganglioside antibodies directed at one cell type or the other, which would, or would not, have calpain within them,” Dr. Lunn said. Investigators also showed that a calpain inhibitor (AK295) or overproduction of an endogenous inhibitor, calpastatin, prevented damage to both cell types.⁶All existing calpain inhibitors are unsuitable for clinical use because they are highly toxic. “But if you could inhibit calpain and stop it from being activated by calcium,” Dr. Lunn explained, “you would have a mechanism for stopping cell degradation during GBS. That would be an important future target for pharmacotherapy. That whole story – from the beginning to the end of GBS – has opened up options for treatment.”

Because complement bound to antibodies, set up by infection, plays a pivotal role, complement inhibitors have become an exciting area of research over the past decade. The 36-patient Japanese Eculizumab Trial for GBS (JET-GBS) trial showed that, after 6 months, significantly more eculizumab-treated patients could run, compared with placebo-treated patients.⁷

“No other trials of complement inhibitors have yet been completed,” Dr. Lunn said. “But several different complement inhibitors work at different places, in a very complicated immune process. One of the complement inhibitors will become transformative in treating GBS – preventing disability and improving recovery – in the not-very-distant future.”

Additional investigational treatments that have demonstrated early promise in eliminating problem antibodies faster include imlifidase (Idefirix [Hansa Biopharma]), which destroys antibodies, and Fc receptor inhibitors such as efgartigimod alfa-fcab (Vyvgart [argenx]), which push antibodies into the natural catabolic pathway.

“We’ve been stuck with plasma exchange and intravenous immunoglobulin (IVIg) for three or four decades,” Dr. Lunn said. “We now have a series of strategies by which we can completely turn off complement and resulting nerve damage. If we can find a calpain inhibitor that turns off the end of that pathway, we will make dramatic improvements. Our understanding of the immunopathology has changed enormously and influences pharmacotherapy going forward.”
 

 

Recap of diagnosis and treatment

For decades, the diagnosis of GBS has relied on the presence of symptoms, including progressive weakness and loss of reflexes and sensations. Nerve-conduction studies and cerebrospinal fluid evaluation can help confirm the diagnosis.

IVIg shortens recovery, said Dr. Lunn, although nothing cures GBS. “And that’s a common problem: Clinicians think that they’re going to give somebody IVIg, and the patient’s going to get better immediately.” When that doesn’t happen, he said, physicians are tempted to give a second immunoglobulin dose.

However, a study published in 2021 shows that a second IVIg dose does not result in faster or better improvement – only in a significant risk of cardiovascular, cerebrovascular, and other thrombotic events 3 weeks later.⁸ Dr. Lunn noted that, although adverse-event data were “buried” in the supplemental materials of that study, the high cost of IVIg (approximately $12,500 per dose) means that the study has changed practice for the benefit of patients, providers, and health care systems.
 

COVID-19 and GBS triggers

Campylobacter jejuni infection still accounts for 30% to 40% of GBS cases, followed by other bacteria, including Mycoplasma pneumoniae and Haemophilus influenzae, and then by viruses, including cytomegalovirus and, rarely, human immunodeficiency virus. In recent years, severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection – COVID-19 – and vaccines against the viral infection have captured headlines for purportedly being a cause of GBS.

The Zika virus epidemic of 2015-2016 has been linked to GBS-like illness. The 2003 severe acute respiratory syndrome (SARS) pandemic and the Middle East respiratory syndrome coronavirus (MERS-CoV) epidemic were associated with GBS – although, taken together, SARS and MERS-CoV produced fewer than 10 cases of GBS, Dr. Lunn noted. Nevertheless, heightened awareness of these viruses fueled hypervigilance regarding the prospect that COVID-19 could cause GBS. Following reports of a single such case in Wuhan and hundreds in Italy, worry over pandemic GBS grew worldwide.

Dr. Lunn and colleagues addressed the COVID-19–GBS question in a 2023 publication.⁹ “Because GBS is largely treated only with IVIg, and IVIg costs a lot of money, and the U.K. government insists on every dose of IVIg being logged in a government database, we were able to identify virtually every case of GBS,” he said.

GBS diagnoses were reliable, he added, because each case was confirmed by physicians outside the emergency department. Analysis revealed that, in 2020, U.K. GBS cases actually declined by around one-third. “And even when there was a second wave of COVID-19 at the end of 2020, partly caused by better counting,” Dr. Lunn said, “there was no further increase in GBS cases. We concluded that there was no link between GBS and COVID-19, as the cases simply didn’t appear.”

The foregoing findings have since been corroborated by studies in Singapore, the United States, and South America, he pointed out. Earlier case series suggesting a link between COVID-19 and GBS were selective, Dr. Lunn added, with numbers too small to support robust conclusions.

The lack of a causal link between COVID-19 and GBS suggested to Dr. Lunn that there was no reason COVID-19 vaccination should cause GBS. All COVID-19 vaccines were designed to provoke an immune response either (1) by producing the SARS-CoV-2 spike protein on the surface of virus (through a replication-incompetent adenoviral vector) or (2) through DNA or mRNA transcription, he explained. “The spike protein is only a small part of COVID-19.”
 

 

GBS: ‘Adverse event of interest’

A link between modern vaccines and GBS first appeared in the 1970s with the hastily developed swine flu vaccine. “In late 1976,” Dr. Lunn explained, “it was identified that patients who were given that vaccine seemed to be developing illnesses consistent with GBS.” By 1980, Dr. Lunn said, the risk level was determined to be only five or six cases for every 1 million doses of vaccine administered. “But the vaccine program was aborted, and swine flu never really happened.” Every year since, “there has been a surveillance program looking at the occurrence of an association of GBS with influenza vaccine.”

Minor fluctuations aside, he said, the overall incidence of GBS with influenza vaccination – 1 GBS case for every 1 million vaccine doses given – has remained consistent over several decades. “Nevertheless, GBS became an adverse event of special interest for any vaccination campaign.”

COVID-19 vaccination. Dr. Lunn and colleagues used the United Kingdom National Health Service (NHS) National Immunoglobulin Database, and other databases, to pinpoint the risk of GBS presented by the first dose of the AstraZeneca ChAdOx1 nCoV-19 adenoviral vaccine.¹⁰ As with U.K. GBS cases, every COVID-19 vaccination is linked to an NHS number. “We identified all the cases of GBS, found their NHS numbers, and went back and found the exact dates they’d been vaccinated, and with which vaccine.” Only the adenoviral-vector vaccine carried an excess risk of GBS – 5.8 cases for every 1 million doses, associated only with the first dose and peaking at approximately 25 days post vaccination – compared with other vaccines used in the United Kingdom.

Researchers looked at data from the Vaccine Adverse Event Reporting System (VAERS), a program of the Centers for Disease Control and Prevention and the Food and Drug Administration, encompassing nearly 500 million COVID-19 vaccine doses given between December 2020 and January 2022. They found that patients who received the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) had a rate of GBS (within 21 and 41 days post vaccination) that was 9 and 12 times higher, respectively, than corresponding rates for the mRNA-1273 (Moderna) and BNT162b2 (Pfizer BioNTech) COVID-19 vaccines.¹¹ Risk was distributed relatively evenly by gender and age. Also at day 21 and day 41, observed event ratios with the adenoviral-vector vaccine (use of which has been suspended in the United States) were 3.79 and 2.34, respectively. Observed-event ratios with the other vaccines mirrored expected background rates.

The VAERS analysis confirms earlier data from the CDC’s Vaccine Safety Datalink, which showed that, among approximately 15 million U.S. vaccine doses given between mid-December 2020 and mid-November 2021, the unadjusted GBS incidence rate for every 100,000 person-years for the adenoviral vaccine, 21 days post exposure, was 32.4, compared with 1.3 for the mRNA vaccine. The adjusted relative risk with the adenoviral vaccine in the first 3 weeks post vaccination, compared to the 3- to 6-week interval post vaccination, was 6.03.¹² In addition, a head-to-head comparison of adenoviral versus mRNA vaccines at 21 days revealed an adjusted rate ratio of 20.56. Mechanistically, some experts theorize that antibodies induced by the Janssen vaccine might cross-react with glycoproteins on the myelin sheath of peripheral nerve axons to cause GBS, but this remains unproven.11

The AstraZeneca vaccine uses a chimpanzee adenovirus; the Janssen vaccine uses a human adenoviral carrier. “The only commonality between the Janssen/Johnson & Johnson and AstraZeneca vaccines, and the only thing that’s different from the other vaccines, is the adenoviral vector packaging,” Dr. Lunn emphasized. “I believe it’s what generates GBS after COVID-19 vaccination. It has nothing to do with the COVID-19 vaccination, the spike protein, the nucleic acid, the DNA, or anything else.”

The adenoviral vector probably also explains why GBS peaks during winter, said Dr. Lunn. “That’s when adenovirus is circulating.” When people contract the common cold, he explained, they don’t visit their family physician and request a swab to isolate the adenovirus. “By the time you get GBS, the adenovirus has been cleared. We’ve all got antibodies to adenovirus all over the place, anyway, because we get it so often.”

It would be difficult to prove conclusively that adenovirus belongs on the list of GBS causes, Dr. Lunn allowed. “But I have a strong suspicion that it does. COVID-19 and COVID-19 vaccination have given us some new avenues into identifying GBS causation potentially in the near future.” More research is needed in this area, he said.

Dr. Lunn has been a principal investigator for argenx (efgartigimod) and an adviser to AstraZeneca (ChAdOx1 nCoV-19). He has received travel grants from CSL Behring.
 

 

References

1. Ho TW et al. Guillain-Barré syndrome in northern China. Relationship to Campylobacter jejuni infection and anti-glycolipid antibodies. Brain. 1995;118(Pt 3):597-605. doi: 10.1093/brain/118.3.597.

2. Uncini A. A common mechanism and a new categorization for anti-ganglioside antibody-mediated neuropathies. Exp Neurol. 2012;235(2):513-6. doi: 10.1016/j.expneurol.2012.03.023.

3. Uncini A and Kuwabara S. The electrodiagnosis of Guillain-Barré syndrome subtypes: where do we stand? Clin Neurophysiol. 2018;129(12):2586-93. doi: 10.1016/j.clinph.2018.09.025.

4. Delmont E et al. Autoantibodies to nodal isoforms of neurofascin in chronic inflammatory demyelinating polyneuropathy. Brain. 2017;140(7):1851-8. doi: 10.1093/brain/awx124.

5. McGonigal R et al. Anti-GD1a antibodies activate complement and calpain to injure distal motor nodes of Ranvier in mice. Brain. 2010;133(Pt 7):1944-60. doi: 10.1093/brain/awq119.

6. Cunningham ME et al. Real time imaging of intra-axonal calcium flux in an explant mouse model of axonal Guillain-Barré syndrome. Exp Neurol. 2022 Sep;355:114127. doi: 10.1016/j.expneurol.2022.114127.

7. Misawa S et al; Japanese Eculizumab Trial for GBS (JET-GBS) Study Group. Safety and efficacy of eculizumab in Guillain-Barré syndrome: a multicentre, double-blind, randomised phase 2 trial. Lancet Neurol. 2018;17(6):519-29. doi: 10.1016/S1474-4422(18)30114-5.

8. Walgaard C et al; Dutch GBS Study Group. Second intravenous immunoglobulin dose in patients with Guillain-Barré syndrome with poor prognosis (SID-GBS): a double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2021;20(4):275-83. doi: 10.1016/S1474-4422(20)30494-4.

9. Keddie S et al. Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome. Brain. 2021;144(2):682-93. doi: 10.1093/brain/awaa433.

10. Keh RYS et al; BPNS/ABN COVID-19 Vaccine GBS Study Group. COVID-19 vaccination and Guillain-Barré syndrome: Analyses using the National Immunoglobulin Database. Brain. 2023;146(2):739-48. doi: 10.1093/brain/awac067.

11. Abara WE et al. Reports of Guillain-Barré syndrome after COVID-19 vaccination in the United States. JAMA Netw Open. 2023;6(2):e2253845. doi: 10.1001/jamanetworkopen.2022.53845.

12. Hanson KE et al. Incidence of Guillain-Barré syndrome after COVID-19 vaccination in the Vaccine Safety Datalink. JAMA Netw Open. 2022;5(4):e228879. doi: 10.1001/jamanetworkopen.2022.8879.
 

Recent insights into the pathophysiology of Guillain-Barré syndrome (GBS) – which affects 1 or 2 persons for every 100,000 people annually, usually post infection – indicate that classic subtypes represent varying manifestations of a shared disease process. This knowledge is yielding new treatment strategies aimed at halting the illness in its tracks. Promising therapies include inhibitors of complement and, perhaps one day, the calcium-activated protease calpain.

Meanwhile, an association between COVID-19 and GBS has been debunked, whereas a small risk of GBS following adenovirus-vectored COVID vaccination is now accepted and quantified. Regardless of cause, the potential severity of GBS and variability in its presentation demand constant vigilance.
 

Shutting down the disease process

When patients present to an emergency department with sensory symptoms and increasing muscle weakness, “most of the damage has been or is being done,” said Michael P. Lunn, MBBS, MRCP, PhD, professor of clinical neurology, consultant neurologist, and clinical lead in neuroimmunology at University College London Queen Square Institute of Neurology, who spoke at length about GBS with Neurology Reviews 2023 Rare Neurological Disease Special Report. “The crucial reason that GBS treatment has not advanced significantly – and why we’re still slightly stuck where we are in terms of helping people get better more quickly – is that we need something that absolutely turns the disease off as patients come through the door.”

GBS is probably the best-understood autoimmune-mediated neurological disease, in some respects surpassing myasthenia gravis, Dr. Lunn said. “We know very frequently the organisms and stimuli that set off Guillain-Barré syndrome. We understand, to an extent, the immunology and how you break tolerance of the immune system so that an invading organism can provoke an immune response that damages peripheral nerves.”

Compared to what was known about GBS in decades past, neurologists now better understand how and where antibodies attack the nerve; how complement then damages the nodes of Ranvier and paranodes; and how an external attack results in sometimes irreparable internal nerve damage. “We’ve got a string, beginning to end, of understanding the disease,” declared Dr. Lunn.

Understanding of differences in the spectrum of pathology of GBS has led to additional diagnostic categories, said Dr. Lunn. Acute inflammatory demyelinating polyradiculoneuropathy, or typical GBS, represents the most common form in affluent Western nations. A motor variant was recognized in the 1980s; in the mid-1990s, Ho and colleagues described a cohort of patients in China who had acute motor axonal neuropathy and acute motor sensory axonal neuropathy¹ – two forms that are particularly common throughout Asia and South America.
 

Shared mechanism

Based on the findings of electrophysiologic studies, Dr. Lunn said, experts traditionally believed that GBS attacked either axons themselves or their myelin sheaths. “That’s where the anti-ganglioside antibodies come in, providing targeting to nerve structures.” The dichotomous classification system, he added, was partially correct.

Then, through the 2010s and 2020s, neurophysiologist Antonio Uncini, MD, recognized, based partly on histologic studies by Ho and colleagues, that the myelin and axonal subtypes are both likely to stem from the same mechanism.² When antibodies and complement damage the node of Ranvier, Dr. Lunn said, “the myelin gets stripped off and the conduction becomes slow. But then the myelin can return, and patients get better.” But if damage is severe, it severs the axon, resulting in unrecoverable motor axonal neuropathy. “It’s basically all the same spectrum of disease,” Dr. Lunn said. “Anti-ganglioside antibodies may account for different GBS ‘flavors,’ but the immunological attack all occurs at the node of Ranvier in one way or another.”

The foregoing insight has focused development efforts on the shared seminal pathway of all GBS subtypes and given rise to the concept of nodo-paranodopathy, which incorporates damage at either the node of Ranvier or nearby paranodes.³

Simultaneously, Spanish and French researchers began elucidating new antibodies responsible for neuropathology at the node of Ranvier.⁴ Anti-ganglioside antibodies have long been loosely associated with acute motor axonal neuropathy and poor outcomes, although, Dr. Lunn said, they fail to tell the full story. Anti-GQ1b antibodies are associated with the Miller-Fisher syndrome subtype, well recognized for its medical features: double vision, loss of tendon reflexes, and arm and leg weakness.

However, Dr. Lunn said, most GBS cases lack anti-ganglioside antibodies. In some GBS cases, antibodies attack neurofascin, contactins, and gliomedin, which are mainly adhesion proteins at nodes of Ranvier.

“Therefore,” Dr. Lunn said, “there must be an antibody-mediated attack of the node of Ranvier or the paranode. That’s an important series of discoveries, primarily because it helps us understand the immunological attack at the node of Ranvier, which goes along with what Dr. Uncini was saying. But it also divides off a group of chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) that present acutely and look initially, for all purposes, like GBS.”

Recognizing acute CIDP (A-CIDP) is critically important for clinicians, Dr. Lunn stressed, because it requires treatment with rituximab (the most commonly used option), steroids, or plasma exchange.

Key clues that distinguish A-CIDP from GBS include:

• A high level of cerebrospinal fluid protein.

• Very slow nerve conduction.

• Early muscle wasting (rare in GBS).

Recognizing CIDP and A-CIDP is crucial, said Dr. Lunn, because it begins to bring all the pathology back together to make sense of GBS. Neurologists have known for decades that, if one damages a nerve with antibodies, then binds complement to those antibodies, the complement punches holes in the affected cells, resulting in death. “But it wasn’t quite clear how those cells might die,” Dr. Lunn said.

After complement-induced injury, calcium-activated calpain permanently damages the entire internal axonal structure.⁵ Perhaps more important, a 2022 mouse study showed that complement-mediated damage could be directed to myelin or axons using the genetically programmed presence or absence of gangliosides to understand subsequent calpain-induced destruction in either axons or myelin.⁶

Some of the engineered mouse cells included ganglioside; others did not. “So you can have anti-ganglioside antibodies directed at one cell type or the other, which would, or would not, have calpain within them,” Dr. Lunn said. Investigators also showed that a calpain inhibitor (AK295) or overproduction of an endogenous inhibitor, calpastatin, prevented damage to both cell types.⁶All existing calpain inhibitors are unsuitable for clinical use because they are highly toxic. “But if you could inhibit calpain and stop it from being activated by calcium,” Dr. Lunn explained, “you would have a mechanism for stopping cell degradation during GBS. That would be an important future target for pharmacotherapy. That whole story – from the beginning to the end of GBS – has opened up options for treatment.”

Because complement bound to antibodies, set up by infection, plays a pivotal role, complement inhibitors have become an exciting area of research over the past decade. The 36-patient Japanese Eculizumab Trial for GBS (JET-GBS) trial showed that, after 6 months, significantly more eculizumab-treated patients could run, compared with placebo-treated patients.⁷

“No other trials of complement inhibitors have yet been completed,” Dr. Lunn said. “But several different complement inhibitors work at different places, in a very complicated immune process. One of the complement inhibitors will become transformative in treating GBS – preventing disability and improving recovery – in the not-very-distant future.”

Additional investigational treatments that have demonstrated early promise in eliminating problem antibodies faster include imlifidase (Idefirix [Hansa Biopharma]), which destroys antibodies, and Fc receptor inhibitors such as efgartigimod alfa-fcab (Vyvgart [argenx]), which push antibodies into the natural catabolic pathway.

“We’ve been stuck with plasma exchange and intravenous immunoglobulin (IVIg) for three or four decades,” Dr. Lunn said. “We now have a series of strategies by which we can completely turn off complement and resulting nerve damage. If we can find a calpain inhibitor that turns off the end of that pathway, we will make dramatic improvements. Our understanding of the immunopathology has changed enormously and influences pharmacotherapy going forward.”
 

 

Recap of diagnosis and treatment

For decades, the diagnosis of GBS has relied on the presence of symptoms, including progressive weakness and loss of reflexes and sensations. Nerve-conduction studies and cerebrospinal fluid evaluation can help confirm the diagnosis.

IVIg shortens recovery, said Dr. Lunn, although nothing cures GBS. “And that’s a common problem: Clinicians think that they’re going to give somebody IVIg, and the patient’s going to get better immediately.” When that doesn’t happen, he said, physicians are tempted to give a second immunoglobulin dose.

However, a study published in 2021 shows that a second IVIg dose does not result in faster or better improvement – only in a significant risk of cardiovascular, cerebrovascular, and other thrombotic events 3 weeks later.⁸ Dr. Lunn noted that, although adverse-event data were “buried” in the supplemental materials of that study, the high cost of IVIg (approximately $12,500 per dose) means that the study has changed practice for the benefit of patients, providers, and health care systems.
 

COVID-19 and GBS triggers

Campylobacter jejuni infection still accounts for 30% to 40% of GBS cases, followed by other bacteria, including Mycoplasma pneumoniae and Haemophilus influenzae, and then by viruses, including cytomegalovirus and, rarely, human immunodeficiency virus. In recent years, severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection – COVID-19 – and vaccines against the viral infection have captured headlines for purportedly being a cause of GBS.

The Zika virus epidemic of 2015-2016 has been linked to GBS-like illness. The 2003 severe acute respiratory syndrome (SARS) pandemic and the Middle East respiratory syndrome coronavirus (MERS-CoV) epidemic were associated with GBS – although, taken together, SARS and MERS-CoV produced fewer than 10 cases of GBS, Dr. Lunn noted. Nevertheless, heightened awareness of these viruses fueled hypervigilance regarding the prospect that COVID-19 could cause GBS. Following reports of a single such case in Wuhan and hundreds in Italy, worry over pandemic GBS grew worldwide.

Dr. Lunn and colleagues addressed the COVID-19–GBS question in a 2023 publication.⁹ “Because GBS is largely treated only with IVIg, and IVIg costs a lot of money, and the U.K. government insists on every dose of IVIg being logged in a government database, we were able to identify virtually every case of GBS,” he said.

GBS diagnoses were reliable, he added, because each case was confirmed by physicians outside the emergency department. Analysis revealed that, in 2020, U.K. GBS cases actually declined by around one-third. “And even when there was a second wave of COVID-19 at the end of 2020, partly caused by better counting,” Dr. Lunn said, “there was no further increase in GBS cases. We concluded that there was no link between GBS and COVID-19, as the cases simply didn’t appear.”

The foregoing findings have since been corroborated by studies in Singapore, the United States, and South America, he pointed out. Earlier case series suggesting a link between COVID-19 and GBS were selective, Dr. Lunn added, with numbers too small to support robust conclusions.

The lack of a causal link between COVID-19 and GBS suggested to Dr. Lunn that there was no reason COVID-19 vaccination should cause GBS. All COVID-19 vaccines were designed to provoke an immune response either (1) by producing the SARS-CoV-2 spike protein on the surface of virus (through a replication-incompetent adenoviral vector) or (2) through DNA or mRNA transcription, he explained. “The spike protein is only a small part of COVID-19.”
 

 

GBS: ‘Adverse event of interest’

A link between modern vaccines and GBS first appeared in the 1970s with the hastily developed swine flu vaccine. “In late 1976,” Dr. Lunn explained, “it was identified that patients who were given that vaccine seemed to be developing illnesses consistent with GBS.” By 1980, Dr. Lunn said, the risk level was determined to be only five or six cases for every 1 million doses of vaccine administered. “But the vaccine program was aborted, and swine flu never really happened.” Every year since, “there has been a surveillance program looking at the occurrence of an association of GBS with influenza vaccine.”

Minor fluctuations aside, he said, the overall incidence of GBS with influenza vaccination – 1 GBS case for every 1 million vaccine doses given – has remained consistent over several decades. “Nevertheless, GBS became an adverse event of special interest for any vaccination campaign.”

COVID-19 vaccination. Dr. Lunn and colleagues used the United Kingdom National Health Service (NHS) National Immunoglobulin Database, and other databases, to pinpoint the risk of GBS presented by the first dose of the AstraZeneca ChAdOx1 nCoV-19 adenoviral vaccine.¹⁰ As with U.K. GBS cases, every COVID-19 vaccination is linked to an NHS number. “We identified all the cases of GBS, found their NHS numbers, and went back and found the exact dates they’d been vaccinated, and with which vaccine.” Only the adenoviral-vector vaccine carried an excess risk of GBS – 5.8 cases for every 1 million doses, associated only with the first dose and peaking at approximately 25 days post vaccination – compared with other vaccines used in the United Kingdom.

Researchers looked at data from the Vaccine Adverse Event Reporting System (VAERS), a program of the Centers for Disease Control and Prevention and the Food and Drug Administration, encompassing nearly 500 million COVID-19 vaccine doses given between December 2020 and January 2022. They found that patients who received the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) had a rate of GBS (within 21 and 41 days post vaccination) that was 9 and 12 times higher, respectively, than corresponding rates for the mRNA-1273 (Moderna) and BNT162b2 (Pfizer BioNTech) COVID-19 vaccines.¹¹ Risk was distributed relatively evenly by gender and age. Also at day 21 and day 41, observed event ratios with the adenoviral-vector vaccine (use of which has been suspended in the United States) were 3.79 and 2.34, respectively. Observed-event ratios with the other vaccines mirrored expected background rates.

The VAERS analysis confirms earlier data from the CDC’s Vaccine Safety Datalink, which showed that, among approximately 15 million U.S. vaccine doses given between mid-December 2020 and mid-November 2021, the unadjusted GBS incidence rate for every 100,000 person-years for the adenoviral vaccine, 21 days post exposure, was 32.4, compared with 1.3 for the mRNA vaccine. The adjusted relative risk with the adenoviral vaccine in the first 3 weeks post vaccination, compared to the 3- to 6-week interval post vaccination, was 6.03.¹² In addition, a head-to-head comparison of adenoviral versus mRNA vaccines at 21 days revealed an adjusted rate ratio of 20.56. Mechanistically, some experts theorize that antibodies induced by the Janssen vaccine might cross-react with glycoproteins on the myelin sheath of peripheral nerve axons to cause GBS, but this remains unproven.11

The AstraZeneca vaccine uses a chimpanzee adenovirus; the Janssen vaccine uses a human adenoviral carrier. “The only commonality between the Janssen/Johnson & Johnson and AstraZeneca vaccines, and the only thing that’s different from the other vaccines, is the adenoviral vector packaging,” Dr. Lunn emphasized. “I believe it’s what generates GBS after COVID-19 vaccination. It has nothing to do with the COVID-19 vaccination, the spike protein, the nucleic acid, the DNA, or anything else.”

The adenoviral vector probably also explains why GBS peaks during winter, said Dr. Lunn. “That’s when adenovirus is circulating.” When people contract the common cold, he explained, they don’t visit their family physician and request a swab to isolate the adenovirus. “By the time you get GBS, the adenovirus has been cleared. We’ve all got antibodies to adenovirus all over the place, anyway, because we get it so often.”

It would be difficult to prove conclusively that adenovirus belongs on the list of GBS causes, Dr. Lunn allowed. “But I have a strong suspicion that it does. COVID-19 and COVID-19 vaccination have given us some new avenues into identifying GBS causation potentially in the near future.” More research is needed in this area, he said.

Dr. Lunn has been a principal investigator for argenx (efgartigimod) and an adviser to AstraZeneca (ChAdOx1 nCoV-19). He has received travel grants from CSL Behring.
 

 

References

1. Ho TW et al. Guillain-Barré syndrome in northern China. Relationship to Campylobacter jejuni infection and anti-glycolipid antibodies. Brain. 1995;118(Pt 3):597-605. doi: 10.1093/brain/118.3.597.

2. Uncini A. A common mechanism and a new categorization for anti-ganglioside antibody-mediated neuropathies. Exp Neurol. 2012;235(2):513-6. doi: 10.1016/j.expneurol.2012.03.023.

3. Uncini A and Kuwabara S. The electrodiagnosis of Guillain-Barré syndrome subtypes: where do we stand? Clin Neurophysiol. 2018;129(12):2586-93. doi: 10.1016/j.clinph.2018.09.025.

4. Delmont E et al. Autoantibodies to nodal isoforms of neurofascin in chronic inflammatory demyelinating polyneuropathy. Brain. 2017;140(7):1851-8. doi: 10.1093/brain/awx124.

5. McGonigal R et al. Anti-GD1a antibodies activate complement and calpain to injure distal motor nodes of Ranvier in mice. Brain. 2010;133(Pt 7):1944-60. doi: 10.1093/brain/awq119.

6. Cunningham ME et al. Real time imaging of intra-axonal calcium flux in an explant mouse model of axonal Guillain-Barré syndrome. Exp Neurol. 2022 Sep;355:114127. doi: 10.1016/j.expneurol.2022.114127.

7. Misawa S et al; Japanese Eculizumab Trial for GBS (JET-GBS) Study Group. Safety and efficacy of eculizumab in Guillain-Barré syndrome: a multicentre, double-blind, randomised phase 2 trial. Lancet Neurol. 2018;17(6):519-29. doi: 10.1016/S1474-4422(18)30114-5.

8. Walgaard C et al; Dutch GBS Study Group. Second intravenous immunoglobulin dose in patients with Guillain-Barré syndrome with poor prognosis (SID-GBS): a double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2021;20(4):275-83. doi: 10.1016/S1474-4422(20)30494-4.

9. Keddie S et al. Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome. Brain. 2021;144(2):682-93. doi: 10.1093/brain/awaa433.

10. Keh RYS et al; BPNS/ABN COVID-19 Vaccine GBS Study Group. COVID-19 vaccination and Guillain-Barré syndrome: Analyses using the National Immunoglobulin Database. Brain. 2023;146(2):739-48. doi: 10.1093/brain/awac067.

11. Abara WE et al. Reports of Guillain-Barré syndrome after COVID-19 vaccination in the United States. JAMA Netw Open. 2023;6(2):e2253845. doi: 10.1001/jamanetworkopen.2022.53845.

12. Hanson KE et al. Incidence of Guillain-Barré syndrome after COVID-19 vaccination in the Vaccine Safety Datalink. JAMA Netw Open. 2022;5(4):e228879. doi: 10.1001/jamanetworkopen.2022.8879.