COVID-19 Postvaccination Guillain-Barré Syndrome: Introduction

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Dec 1, 2022

Animation of nerve damage in Guillain-Barré syndrome. *Credit: Doctor Jana. WikiMedia Commons. To support Dr. Jana visit his Patreon.*

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COVID-19 Post-vaccination Guillain-Barré Syndrome: Introduction

Definition and Relevance

Guillain-Barré syndrome (GBS) is the overarching term used to describe the spectrum of acute immune-mediated polyneuropathies. Those conditions are not very prevalent, however - they are clinically relevant since they are responsible for majority of episodes of sudden weakness (Ref). Its clinical relevance is increased by the fact that this syndrome maybe complicated by the life threatening conditions such as respiratory failure or autonomic dysfunction.

It is widely recognized that GBS may be triggered by variety of factors such as infections, exposure to various drugs and vaccines. One can argue that GBS notoriety in both lay press and professional literature is related to its robust historical association with vaccines. For those reason we will have a closer look at this clinically relevant but otherwise obscure syndrome - in the context of the ongoing, world-wide COVID-19 immunization campaign.

Notes on Nomenclature of COVID-19 Vaccines

The nomenclature of the COVID-19 vaccines may be confusing. Therefore we will summarize the terminology of the most widely discussed and/or currently authorized or approved (under EUA) in the USA COVID-19 vaccines. The difference between official FDA approval and authorization under EUA is crucial and it will be discussed in a separate article. In brief, with an EUA, the recipient is supposed to be informed that it is an experimental product, that receipt is voluntary and requires informed consent. Therefore , in addition to standard counseling around vaccine information - vaccine providers are required to inform potential recipients when a vaccine is available under emergency use authorization (EUA). It is not necessary, however, for recipients to sign informed consent documents (Ref).

mRNA vaccines. Two listed below mRNA vaccines are available for the use in the USA based upon FDA approval. Each mRNA vaccine has a monovalent formulation (antigenic target is based on the original SARS-CoV-2 strain) and a bivalent formulation (antigenic target is based on the original SARS-CoV-2 strain and the BA.4/BA.5 Omicron subvariants):
- BioNTech, Pfizer vaccine (BNT162b2), also known as: Comirnaty (Ref).On August 23, 2021, FDA announced the first approval of a COVID-19 vaccine. The vaccine has been known as the Pfizer-BioNTech COVID-19 Vaccine, and the approved vaccine is marketed as Comirnaty, for the prevention of COVID-19 in individuals 12 years of age and older. (Ref)
- Moderna, NIAID vaccine (mRNA-1273) also known as: Spikevax (Ref).On January 31, 2022, the FDA announced the second approval of a COVID-19 vaccine. The vaccine has been known as the Moderna COVID-19 Vaccine, and will now be marketed as Spikevax, for the prevention of COVID-19 in individuals 18 years of age and older. (Ref)

Adenovector Vaccines. Only one of the adenoviral vector vaccine, namely Janssen/Johnson & Johnson COVID-19 vaccine has been authorized in the USA:
- Jansen/Johnson & Johnson vaccine (Ad.26.COV2.S): a monovalent vaccine, available in the USA under EUA for individuals aged 18 years or older who cannot or elect not to use an mRNA vaccine (Ref).
- University of Oxford, AstraZeneca (ChAdOx1 nCoV-19/AZD1222) is NOT available in the USA, however it has been studied extensively abroad (Ref).
An adjuvanted recombinant protein vaccine (monovalent):
- Novavax COVID-19 vaccine (NVX-CoV2373): now available in the USA under EUA for individuals aged 12 years or older (Ref).

Other COVID-19 Vaccines: A list of vaccines that have been authorized in at least one country is maintained at the following Website as of 12/1/22:

covid19.trackvaccines.org/vaccines.

Historical association of GBS with vaccination

Historical association of GBS with vaccination is so strong that US Food and Drug Administration (FDA) and United States Centers for Disease Control and Prevention (CDC) strongly recommend that physicians should file the reports of possible cases of vaccination induced GBS - to the Vaccine Adverse Events Reporting System (VAERS).

Many instances of GBS which followed vaccinations have been documented. However the specific risks for the development of severe GBS due to various vaccinations are subject to the debate.

For instance, study by Lasky et. al demonstrated that subjects who received the 1992-1993 and 1993-1994 influenza vaccinations - when two those seasons were combined for statistical analysis had the adjusted relative risk of 1.7 for GBS (Lasky T, 1998). In a study that analyzed a large database of 253 general practices in the United Kingdom with a mean of 1.8 million registered patients from 1992 to 2000, there were 228 incident cases of GBS (Hughes RA, 2006). Onset of GBS within 42 days of any immunization occurred in seven patients (3.1 percent), with an adjusted relative risk of 1.03 (95% CI 0.48-2.18). Authors concluded that the risk of GBS associated with routine immunization practice in the United Kingdom was minimal but suggested that obtaining a precise estimate of any potential risk associated with an individual vaccine would require a study with more GBS cases.

However, a retrospective study that analyzed a northern California health care database from 1994 through 2006 found no increased risk of incident GBS following any vaccination and all vaccinations combined, whether using a 6-week or 10-week risk interval (Baxter R, 2013).

Based upon the sets of selected studies the officials at CDC have been concluding that there appears to be little or no risk of GBS associated with routine immunization schedules (CDC, 2022). It has been further argued that:

the risk of GBS after vaccination appears substantially lower than the risk of GBS triggered by acute infection (Greene SK, 2013) (Kwong JC, 2013).
preventing acute illness through vaccination can reduce infection-triggered GBS. Vaccination has not been associated with GBS recurrence (Baxter R, 2012), (Kuitwaard K, 2009).

Koike et al. have argued that while GBS is associates with vaccinations - such risk shall not be considered a legitimate reason to limit the administration of currently available vaccines, since only a trivial association or no association with GBS has been demonstrated (Koike, 2021).

Influenza vaccination and GBS

In the United States, an increased risk of GBS was associated with the swine influenza vaccine in 1976, although the severity of the risk has been controversial (Ref). Subsequent meta-analyses and cohort studies have found that influenza vaccination is associated with low or negligible risks of GBS and has supported the safety of vaccinations. As examples, a meta-analysis of data from six adverse event monitoring systems, the 2009 H1N1 influenza A vaccine used in the United States was associated with a small increased risk of GBS (relative risk [RR] 2.35, 95% CI 1.42-4.01) (Ref). The number of excess GBS cases was estimated to be 1.6 per 1 million people vaccinated. In a population-based cohort study from Quebec evaluating the H1N1 vaccination during the fall of 2009, a small but significantly increased risk of GBS was reported for the eight-week postvaccination period (adjusted RR 1.80, 95% CI 1.12-2.87) and during the four-week postvaccination period (RR 2.75, 95% CI 1.63-4.62) (Ref). The number of excess GBS cases attributable to the vaccine was approximately 2 per 1 million doses (Ref).

Other studies have failed to identify a risk of GBS associated with influenza vaccination (Ref). In a multinational self-controlled case series in Europe, there was an elevated risk of GBS following influenza infection but not following influenza vaccination (Ref) Moreover, when adjusted for confounding by influenza-like illnesses, there was no association of GBS with the pandemic H1N1 vaccine (Ref).

A history of GBS should not be considered a strict contraindication for influenza vaccination, except for patients who had GBS over the preceding three months or had vaccination-related GBS (Ref).

The risk of GBS associated with influenza vaccination, approximately one to two excess cases of GBS per million people vaccinated, is substantially less than the overall health risk posed by naturally occurring influenza (Ref).

Meningococcal vaccination and GBS

Cases of GBS have been reported following administration of the quadrivalent meningococcal conjugate vaccine MCV4 (Menactra). However, two large studies were conducted to investigate whether GBS was caused by the vaccine or was coincidental with vaccination. These studies included a combined total of over 2 million vaccinated adolescents. The results of these studies showed that there was no link between Menactra and GBS:

A 2012 study used health records of over 9.6 million preteens and teens to evaluate a possible link between Menactra and GBS. The study found that youth who received Menactra were not at increased risk of developing GBS.
Another large 2012 study combined the above study with data from the Vaccine Safety Datalink to search for diagnoses of GBS in 11.2 million preteens and teens who received Menactra. This study also found no link between GBS and Menactra and observed 0 confirmed GBS cases.

Recombinant zoster vaccination and GBS

Cases of GBS have been observed in a postmarketing observational study during the 42 days following vaccination (Ref).These cases represent an increased risk of 3 cases per 1 million doses of vaccine administered to adults age 65 and older.

In a postmarketing observational study, an increased risk of GBS was observed during the 42 days following vaccination with Shingrix. FDA evaluated data from a postmarketing observational study that assessed the risk of GBS following vaccination with Shingrix. Based on this evaluation, FDA has determined that the results of this observational study show an association of GBS with Shingrix, but that available evidence is insufficient to establish a causal relationship (Ref).

GBS and COVID-19 Vaccines

A safety signal - a potential association between the adenovector vaccines: Johnson & Johnson COVID-19 vaccine and AstraZeneca COVID-19 vaccine and Guillain-Barre syndrome has been reported and it is being investigated as described below.

It is important to note that to date: a similar strong signal has not been observed with the mRNA COVID-19 vaccines. For those reasons the US Food and Drug Administration (FDA) and Centers for Disease Control and Prevention (CDC) and European regulators affirm that the benefits of these vaccines outweigh their risks. The surveillance however is ongoing.

Adenovirus vector COVID-19 vaccines

Cases of GBS have been observed and well documented with the adenovector vaccines: that is Janssen/Johnson & Johnson COVID-19 vaccine and AstraZeneca COVID-19 vaccines in the United States and Europe (Ref), (Ref),(Ref).

In the United States, 123 cases occurring within six weeks of immunization were reported among 13.2 million administered doses (Ref). It is notable that:

cases of GBS, including recurrent cases, have also been reported in the setting of SARS-CoV-2 infection (Ref), (Ref), AND
observational data suggest the risk of GBS after infection exceeds the risk after vaccination (Ref).

Nevertheless - pending further research - for individuals with a documented history of GBS, it was suggested using COVID-19 vaccines other than adenovirus vector vaccines (Ref).

Under the conditions in which ONLY an adenovirus vector vaccine is available - its administration shall be individualized based on the person’s SPECIFIC INDIVIDUAL risk for severe COVID-19 and GBS history (Ref).

In the United States, as of July 24, 2021, there had been 132 preliminary reports of GBS among Janssen COVID-19 Vaccine recipients after approximately 13.2 million doses (Ref). The estimated rate was 9.8 cases per million doses, a rate that is approximately four times the background rate. The median age was 56 years (interquartile range 45 to 62 years), the median time to onset was 13 days following vaccination, 35 percent had a life-threatening case, and 1 patient died. In an earlier report of 100 cases, a quarter of the patients reported bilateral facial weakness (Ref). Another analysis suggested an incidence of 32 cases per 100,000 person-years within the three weeks following Ad26.COV2.S receipt; the estimate for mRNA vaccines was 1.3 per 100,000 person-years (Ref).

In the European Union, a total of 227 cases of GBS in Oxford–AstraZeneca COVID‑19 vaccine (ChAdOx1 nCoV-19/AZD1222) recipients had been reported to regulators as of June 27, 2021, at which point approximately 51 million doses had been administered (Ref). Other scattered reports have also described GBS, including variant GBS with bilateral facial weakness, following Oxford–AstraZeneca COVID‑19 vaccine vaccination (Ref), (Ref). However, in a cohort study including over 4 million individuals who received Oxford–AstraZeneca COVID‑19 vaccine, the rate of GBS following the vaccine dose was not higher than the expected pre-pandemic background rate (Ref).

mRNA COVID-19 Vaccines and GBS

As mentioned above, the strong signal has not been observed with the mRNA COVID-19 vaccines at least in the following detailed study (Ref):

From December 13, 2020, through November 13, 2021, 15 120 073 doses of COVID-19 vaccines were administered to 7 894 989 individuals (mean [SE] age, 46.5 [0.02] years; 8 138 318 doses received [53.8%] by female individuals; 3 671 199 doses received [24.3%] by Hispanic or Latino individuals, 2 215 064 doses received [14.7%] by Asian individuals, 6 266 424 doses received [41.4%] by White individuals), including 483 053 Jansen/Johnson & Johnson vaccine (Ad.26.COV2.S) doses, 8 806 595 BioNTech, Pfizer vaccine (BNT162b2) doses, and 5 830 425 Moderna, NIAID vaccine (mRNA-1273) doses.
Eleven cases of GBS after Ad.26.COV2.S were confirmed. The unadjusted incidence rate of GBS per 100 000 person-years in the 1 to 21 days after Ad.26.COV2.S was 32.4 (95% CI, 14.8-61.5), significantly higher than the background rate, and the adjusted RR in the 1 to 21 vs 22 to 42 days following Ad.26.COV2.S was 6.03 (95% CI, 0.79-147.79).
Thirty-six cases of GBS after mRNA vaccines were confirmed. The unadjusted incidence rate per 100 000 person-years in the 1 to 21 days after mRNA vaccines was 1.3 (95% CI, 0.7-2.4) and the adjusted RR in the 1 to 21 vs 22 to 42 days following mRNA vaccines was 0.56 (95% CI, 0.21-1.48). In a head-to-head comparison of Ad.26.COV2.S vs mRNA vaccines, the adjusted RR was 20.56 (95% CI, 6.94-64.66).

Authors concluded that:

in this cohort study of COVID-19 vaccines, the incidence of GBS was significantly and markedly elevated after receiving the Ad.26.COV2.S vaccine
BUT only minimally elevated after mRNA vaccines.

The surveillance is ongoing.

General Epidemiology of GBS

GBS occurs worldwide with an overall incidence of 1 to 2 cases per 100,000 per year (Ref). While all age groups are affected, the incidence increases by approximately 20 percent with every 10-year increase in age beyond the first decade of life. In addition, the incidence is slightly higher in males than in females.

There is regional variation among the variant forms of GBS with axonal forms being more common in Asia than North America or Europe, where demyelinating forms predominate.

Pathogenesis of GBS

The acute polyneuropathy of GBS is often triggered when an immune response to an antecedent infection or other event cross-reacts with shared epitopes on peripheral nerve (molecular mimicry) (Ref). All myelinated nerves (motor, sensory, cranial, sympathetic) can be affected.

Pathology

The range and extent of pathologic changes depend on the clinical forms of GBS. Patients with the common acute inflammatory demyelinating polyneuropathy (AIDP) form have prominent demyelination on electrodiagnostic studies and lymphocytic infiltration on sural nerve biopsies, while those with other forms such as acute motor axonal neuropathy (AMAN) form have prominent axonal loss without lymphocytic infiltration or complement activation and few degenerating nerve fibers (Ref).

Demyelination

In AIDP and the Miller Fisher syndrome (MFS) variant form, a focal inflammatory response develops against myelin-producing Schwann cells or peripheral myelin (Ref). Demyelination is thought to start at the level of the nerve roots where the blood-nerve barrier is deficient. The breakdown of the blood-nerve barrier at the dural attachment allows transudation of plasma proteins into the cerebrospinal fluid. Infiltration of the epineurial and endoneurial small vessels (mostly veins) by activated T cells is followed by macrophage-mediated demyelination with evidence of complement and immunoglobulin deposition on myelin and Schwann cells (Ref).

Demyelination blocks electrical saltatory conduction along the nerve. This causes conduction slowing and leads to muscle weakness. More widespread but patchy peripheral nerve demyelination follows, with added electrical conduction block causing further weakness and electrophysiologic evidence of nonuniform conduction slowing within and across different nerves. Axonal degeneration occurs as a secondary bystander response; the extent relates to the intensity of the inflammatory response.

Peripheral nerve remyelination occurs in recovery over several weeks to months. However, in a small percentage of patients, there is superimposed severe axonal degeneration with markedly delayed and incomplete recovery.

Axonal loss

Immune reactions against epitopes in the axonal membrane cause the acute axonal forms of GBS: AMAN and acute motor and sensory axonal neuropathy (AMSAN) (Ref). These forms are relatively uncommon in the United States but have more frequent presentations of GBS in Asia.

In the axonal variants of GBS, antibody and complement-mediated humoral immune response leads to direct axolemma injury (Ref). There is a paucity of inflammatory infiltration. The primary immune process is directed at the nodes of Ranvier (short intervals between successive segments of the myelin sheath along a nerve), leading to axonal involvement with conduction block caused by paranodal myelin detachment, node lengthening, sodium channel dysfunction, and altered ion and water homeostasis (Ref). This process can rapidly reverse in some cases but may progress to axonal degeneration in others. The motor nerves are involved at the ventral roots, peripheral nerve, and the preterminal intramuscular motor twigs (Ref). In the motor-sensory variant, sensory nerves also are affected.

Autoantibodies and molecular mimicry

GBS is triggered by a cross-reaction of an immune response to an antecedent infection or other event with shared epitopes on peripheral nerve (molecular mimicry). Autoantibodies that react with epitopes on peripheral nerve appear to be the immune trigger after an acute infection in many cases of GBS (Ref).

A case report from Japan in 1990 linking AMAN to a preceding infection with Campylobacter jejuni and antibodies to the GM1 monosialoganglioside prompted interest in the role of Campylobacter and antiganglioside antibodies in GBS (Ref). Subsequent reports on C. jejuni have provided further insight into the mechanistic role of autoantibodies in the development of GBS through molecular mimicry (Ref).

Infection with C. jejuni is the most common antecedent in GBS and a leading cause of acute gastroenteritis (Ref).

C. jejuni can generate antibodies to specific gangliosides, including GM1, GD1a, GalNac-GD1a, and GD1b, which are strongly associated with AMAN and AMSAN (Ref). A strain of C. jejuni isolated from an AMAN patient carrying immunoglobulin (Ig)G anti-GM1 antibody expressed an oligosaccharide structure identical to that of the terminal tetrasaccharide of the GM1 ganglioside (Ref). Autopsy studies show that, in AMAN, IgG is deposited on the axolemma of the spinal anterior root, indicating that IgG is an important factor in the development of AMAN (Ref).

Similarly, C. jejuni infection can generate antibodies to the GQ1b ganglioside, a component of oculomotor nerve myelin. GQ1b antibodies are frequently found in variants characterized by ophthalmoplegia, such as MFS and Bickerstaff brainstem encephalitis (BBE) (Ref). Antibodies to GT1a, which cross-react with GQ1b, have also been associated with bulbar forms of GBS (Ref).

Patients with C. jejuni enteritis not complicated by GBS do not produce the specific antiganglioside antibodies. Genetic polymorphisms in liposaccharide biosynthesis genes in C. jejuni that modify ganglioside expression as well as immunogenetic factors in the host are thought to play a role in the development of GBS.

There is also an association between GBS and infection with Haemophilus influenzae, Mycoplasma pneumoniae, and cytomegalovirus. Cytomegalovirus infections were associated with antibodies to the ganglioside GM2 and with severe motor and sensory deficits. Other infections were not related to specific antiganglioside antibodies and neurologic patterns in GBS, but these relationships are not well documented.

These antiganglioside antibodies are considered to be the pathogenic components that trigger GBS because of their association with the acute illness in GBS and because immune-mediated therapies such as plasma exchange are effective treatments for GBS.

Conclusions

Guillain-Barré syndrome (GBS) is the uncommon but clinically relevant due to its morbidity and mortality neurological syndrome - which encompasses the wide spectrum of acute immune-mediated polyneuropathies.

GBS etiology is multifactorial and the pathological processes leading to development of this syndrome may be triggered by numerous factors. However, historically GBS has been linked to side effects of variety of vaccines. In the view of the ongoing world-wide COVID-19 immunization campaign an interest in the GBS as a potential side effects of vaccines has been rekindled.

A potential association between the GBS and adenovector vaccines: Johnson & Johnson COVID-19 vaccine and AstraZeneca COVID-19 vaccine has been reported and it is being investigated. To date, a similar strong safety signal has not been observed with the mRNA COVID-19 vaccines. However, the surveillance is ongoing.

To read about Diagnosis and Management of COVID-19 Postvaccination GBS click [here -COMING SOON]

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