Is there a causal nexus between COVID-19 infection, COVID-19 vaccination, and Guillain-Barré syndrome?

Guillain-Barré syndrome (GBS) is an acute inflammatory peripheral radiculopathy and neuropathy characterized by progressive limb weakness, sensory deficits, cranial nerve involvement, tendon areflexia, and cerebrospinal fluid (CSF) albuminocytological dissociation with a reported global incidence of approximately 100,000 new cases annually [1]. It is reported that up to 70% of patients developed preceding infections in the upper respiratory and digestive tracts within 2 weeks before the onset of neurological signs and symptoms. Campylobacter jejuni (C. jejuni) is the most common pathogens causing the antecedent infection of GBS, which is thought to be induced through molecular mimicry between the lipopolysaccharides (LPSs) of C. jejuni and the gangliosides of the nerve system [2]. In other words, C. jejuni LPSs result in the production of antibodies response to nerve gangliosides by molecular mimicry. According to the pathology, clinical manifestations, and neurophysiological characteristics, GBS is mainly divided into several variants, which mainly includes acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), and acute motor and sensory axonal neuropathy (AMSAN) [3]. Multidisciplinary medical care and immunotherapy, such as intravenous immunoglobulin (IVIG) and plasma exchange (PE), are optimal treatments in GBS [2]. Most GBS patients get a full recovery, while some patients developed chronic disabilities and 3–10% of cases die during the acute phase [4]. The novel outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, named as coronavirus disease 2019 (COVID-19), usually manifests with respiratory symptoms, and neurological harm, such as GBS. With the global wide vaccination of COVID-19 vaccine, GBS cases after vaccination have gradually increased. Although extensive attention has been attracted to COVID-19 and its vaccine-associated GBS, there was still lack of the pathogenic mechanism between GBS and SARS-CoV-2 infection or COVID-19 vaccination. In this review, we summarized the clinical characteristics of GBS after SARS-CoV-2 infections and COVID-19 vaccination and discussed the updated knowledge about the possible relationship between GBS and SARS-CoV-2 infection or COVID-19 vaccination, as well as the behind pathogenic mechanisms, aiming to further deepen the understanding of COVID-19-associated GBS and provide potential precise treatment worldwide.

GBS is a common cause of acute flaccid paralysis with a crude incidence of 0.16 to 3.0 cases per 100,000 person-years worldwide. The annual global incidence of GBS, based on North American and European studies, mainly fluctuates from 0.81 to 1.91 cases per 100,000 person-years in adults and about 0.6 per 100,000 person-years in children [1]. The variation in incidence may be partly associated with the geographical area because of differences in genetic susceptibility or exposure to pathogenic bacteria among different populations [5].

GBS can occur at any age. Many epidemiological studies of GBS revealed that incidence of GBS increased with age after 50 years, increasing by 20% for each additional decade of age [1].

In Italy, the monthly incidence during March–April period of 2017–2019 years was 0.12 new cases/100,000 inhabitants per month, and the increase of GBS cases in 2020 is 5.41-fold [6]. Another study in northern Italy also suggested an increased incidence of GBS from March to April 2020 compared with that in the same months in 2019 (rate per year estimated to be 2.43/ 1,000,000 and 0.93/1,000,000 in 2020 and 2019, respectively) [7]. Fragiel and his colleagues identified 11 cases of GBS among 71,904 COVID patients who were treated in the Spanish emergency departments (EDs) during the 2-month pandemic peak. The relative frequency of GBS in COVID and non-COVID was 0.15 versus 0.02 among EDs patients, as was the standardized incidence (9.44cases/100,000 inhabitant-years versus 0.69 cases/100,000) [8]. As mentioned above, the overall number of GBS admissions has been reduced during the COVID outbreak. In addition to wash hands frequently, pay attention to hygiene and use preventive measures to minimize the risk of infection, potential reasons include the mildest cases did not seek medical attention but remained at home, due to the fear of contracting the coronavirus.

SARS-CoV-2 is a member of the betacoronavirus genus, which are enveloped viruses with a positive-sense ribonucleic acid (RNA)-strand genome [9]. The COVID-19 caused by SARS-CoV-2 has led to a global pandemic outbreak in the twenty-first century. Except for severe respiratory symptoms, COVID-19 could trigger neurological harm, such as myositis, myasthenia gravis, stroke, encephalitis, acute meningitis, and also GBS [10, 11]. Over 200 cases of GBS following COVID-19 infection have been reported from Europe, America, India, Brazil, Iran, China, and the Middle East. So far, at least 23 countries reported GBS associated with COVID-19: 80 cases in Italy [6, 7, 12], 41 cases in the United Kingdom (UK) [13‐15], 25 cases in Spain [8, 14, 16, 17], 30 cases in the United States (USA) [15, 16, 18], 16 cases in Iran [16], 12 cases in India [14‐16], 6 cases in France, 4 cases in Belgium, Germany, and Switzerland, respectively, 2 cases in China, and Guinea, Austria, Brazil, Canada, Columbia, Japan, Morocco, Netherlands, Sudan, Tanzania, Turkey, and Saudi Arabia reported one case, respectively [16].

A meta-analysis in 2021 revealed that the overall prevalence of GBS among the COVID-19 patients were 15/100,000 population-years [14]. In January 2020, the first case of GBS after COVID-19 infection was reported in China, mainly with acute weakness in both legs, distal hypoesthesia, like typical demyelinating characteristics, and albumin-cytologic dissociation of CSF, which alerted clinicians to the potential link between COVID-19 and GBS [19]. Considering the onset of GBS symptoms in this patient overlapped with the period of COVID-19 infection, it suggested that COVID-19-GBS associated with COVID-19 might follow parainfective mechanism. Currently, the correlation between COVID-19 infection and GBS remains controversial.

GBS is featured by rapidly progressive flaccid paralysis of the limb with areflexia or hyporeflexia. The onset of GBS is acute or subacute, and the disease reaches its nadir within 2–4 weeks [20]. In typical GBS, sensory disturbance, including pain and numbness, and muscle weakness in limbs are usually the first symptoms. Rapidly progressive weakness, the most common clinical characteristic of GBS, mainly affects the distal or proximal muscles of limbs, accompanied by distal paresthesia or sensory deficits. More than 50% of GBS patients have cranial nerve deficits, mainly involving bilateral facial nerves, oculomotor nerves, glossopharyngeal nerves, and vagus nerves, which resulted in bilateral facial weakness, bulbar palsy, and ophthalmoplegia, respectively [21]. Currently available 204 cases of GBS following COVID-19 infection are summarized in Table 1 with a comparison of clinical characteristics between different countries (Table 1). The median age of patients was 57 years, and males are at higher risk than women, with a male-to-female ratio of 2.4 to 1. Most patients developed neurological symptoms within 2 weeks after COVID-19 infection, while patients in India tend to present with neurological symptoms about 1 week after COVID-19 infection. The clinical manifestations, electrophysiological findings, and therapies of COVID-19-related GBS resembled those of International Guillain-Barre´ syndrome Outcome Study (IGOS), with limb weakness as the most typical symptom, AIDP as the most common subtype, and IVIG as the main treatment. However, the frequency of autonomic dysfunction among patients with GBS after COVID-19 infection varies considerably between regions, with a higher proportion in America (48%) and a lower incidence in Spain (7%). Several rare variants, including Miller Fisher syndrome (MFS), pure sensory GBS, pharyngeal-cervical-brachial (PCB) variant, acute panautonomic neuropathy, pharyngeal-cervical-brachial weakness, and paraparetic GBS, have been reported in GBS following COVID-19 infection [6, 7, 22‐24]. Besides, axonal GBS (AMAN/AMSAN) are more frequent in Iran and India, and their proportion is comparable to that of AIDP in their regions. Compared with the results of IGOS, more than 30% of patients required mechanical ventilation. In addition to respiratory muscle weakness caused by GBS, the high proportion of ventilator dependency may also be attributed to acute lung injury caused by COVID-19. Besides, the prognosis of COVID-19-triggered GBS is worse than that of non-COVID-19 GBS, which may be related to systemic damage caused by COVID-19. It is important to interpret the results with caution due to additional studies with a larger sample size are needed to verify these results [25].

At this time, the available COVID-19 vaccines include messenger RNA (mRNA)-based vaccines, recombinant adenoviral vector vaccines, and inactivated whole-virus vaccines. To date, the Food and Drug Administration (FDA) of U.S.A. has granted emergency use authorization for four COVID-19 vaccines: two mRNA vaccines, that are BNT162b2 (Cominarty; Pfizer BioNTech) and mRNA-1273 (Spikevax; Moderna), and one replication-deficient adenovirus-based vaccine, that is, Ad26.COV2.S (Johnson & Johnson). An additional vaccine based on a radically innovative approach, that is, recombinant protein nanoparticles, NVX-CoV2373 (Novavax), adjuvanted contains the SARS-CoV-2 spike protein and Matrix-M adjuvant, is authorized for emergency use as a two-dose primary series to prevent COVID-19. Two other adenovirus-based vaccines, ChAdOx1 nCoV-19 vaccine (AstraZeneca/Oxford or Vaxzevria), and COVID-Vac/Sputnik V (Gamaleya Institute) have been approved conditional marketing authorization in Europe. For other vaccine multiple candidates, some of which already are available for use in different countries. Among them, BBIBP-CorV vaccine (Sinopharm, Beijing Bio-Institute of Biological Products Co. Ltd.), an inactivated SARS-CoV-2 isolate, has been listed for emergency use by the World Health Organization (WHO), potentially expediting its global roll out [42].

The mRNA vaccines introduce mRNA into cells, usually via a lipid nanoparticle (LNP). Inside the human body, mRNA enters the human cell and instructs the cells to identify the spike protein on the surface of SARS-COV-2, the virus that causes COVID-19. Our bodies then recognize the spike protein as an invader and produce antibodies against it. Later, if these antibodies encounter the actual virus, they are ready to recognize and kill the virus before it can cause diseases. In some patients, this immune response can trigger autoimmune processes that lead to the production of self-antibodies against the myelin, causing GBS via this pathway [43]. The adenovirus-based vaccine, which induces antibodies against SARS‐CoV‐2 spike glycoprotein, can mimic an actual infection and theoretically produce GBS. Simian adenovirus, the vector used in the adenovirus-based vaccine, may also be a trigger for GBS [44]. Probably, the mechanism for GBS development is a less specific immune cascade triggered by the adenovirus vector to generate host antibodies and cross-reactions with proteins on nerves [45].

The association between GBS and vaccination has been long debated since initial reports of increased incidence of GBS after the swine influenza vaccine during the USA/New Jersey 1976 vaccination campaign. The occurrence of GBS has been reported after the use of vaccines for other conditions, including polio, tetanus, rabies, hepatitis B, and meningococcal disease. Following the start of the worldwide mass vaccination campaign, real‐world case reports of GBS after COVID‐19 vaccine have emerged.

As of July 24, 2021, 130 reports of presumptive GBS were identified in Vaccine Adverse Event Reporting System (VAERS) following Ad26.COV2.S vaccination (median age: 56 years; interquartile range [IQR]: 45–62 years; 77 men [59.7%]). The median time to onset of GBS following vaccination was 13 days (IQR, 10–18 days), 105 cases (81.4%) beginning within 21 days and 123 (95.3%) within 42 days. The clinical symptoms in 121 reports (93.1%) were serious, including 1 death. The US Centers for Disease Control and Prevention reported that the overall estimated observed-to-expected rate ratio was 4.18, meaning an absolute increase of 6.36 cases per 100 000 person-years for the Ad26.COV2.S vaccine [46].

Data derived from the English National Immunoglobulin Database from January to October 2021, found a 2.04‐fold increased risk for GBS (95% confidence interval [CI]: 1.60–2.60) within 28 days after the AstraZeneca vaccine administration, but not after the Pfizer vaccine [47].

A study analyzing all cases of GBS reported to the Mexican Ministry of Health by recipients receiving the BNT162b2 mRNA COVID-19 vaccine between December 24, 2020, and March 19, 2021. Seven cases of GBS were detected among first-dose recipients, and no cases were reported after second-dose administration. Data showed that GBS was infrequent among recipients receiving the BNT162b2 [48].

A retrospective study of a nationwide registry of GBS among recipients receiving SARS-CoV-2 vaccines in Mexico also found the unadjusted GBS incidence for mRNA-based vaccines is similar to a previous report, including mRNA-1273 and BNT162b2 among Ad26.COV2.S recipients, when compared with other vaccines. In this cohort, patients with axonal variants, known to develop a more severe disease course with worse functional outcomes, accounted for 60.5% [49].

In a head-to-head comparison of Ad.26.COV2.S vs mRNA vaccines, the incidence rate of confirmed GBS in the 1 to 21 days after receiving the Ad.26.COV2.S (Janssen) vaccine was 32.4 per 100 000 person-years, which was significantly higher than the background rate of GBS, while the incidence rate of confirmed GBS in the 1 to 21 days after mRNA vaccines was 1.3 per 100 000 person-years, which did not differ from the background rate. These findings suggest an increased risk of GBS after Ad.26.COV2.S vaccination [50].

Klugar and others found that viral vector vaccines were the predominant vaccine type administered in early-onset post-COVID-19-vaccination GBS and GBS occurring after the 1st vaccination dose [51].

As of 30 May 2022, China had reported more than 3.38 billion doses of COVID-19 vaccines with238215 cumulative post-vaccination adverse events, and an overall reported incidence of adverse events was 70.45 per 1 million. A total of 290 cases of GBS were among the reported adverse events. Generally, the reporting rate of adverse reactions to China's new crown vaccines is lower than the report level of other routine vaccinations in the country in 2020.

A cohort study conducted from January 1, 2021 to June 30, 2021 at the Birmingham University Hospital, UK found a 2.6‐fold increase in number of admissions for GBS during the study period, compared to the same period in the previous 3 years. Patients presenting with GBS after AstraZeneca vaccine had more frequent facial and bulbar involvement than the historical cases, and more commonly they had the GBS variant with bifacial weakness and distal paresthesia [52].

As of April 22, 2021, around 1.5 million individuals in India had been vaccinated with COVID-19 vaccines. Over 80% of these individuals (1.2 million) received the ChAdOx1-S/nCoV-19 vaccine. In this population, there were seven cases of GBS that occurred within 2 weeks of the first dose of vaccination. All seven patients developed severe GBS. The frequency of GBS was 1.4- to tenfold higher than that expected in this period. In addition, a higher rate than expected rate of bilateral facial weakness was observed [53]. In a large multi‐institutional study in Taiwan involving 18,269 healthcare workers who received AstraZeneca vaccine, one single case of GBS variant (bilateral facial palsy with paresthesia) after the first vaccine dose was identified [54]. Pegat and others found a higher frequency of GBS occurring after adenovirus-vectored vaccines [55].

Patients with post-COVID-19 vaccination GBS, admitted to the six hospitals that cover the whole Liguria Region, Northwestern Italy, from February 1 to October 30, 2021, were included. The findings confirmed that most post-COVID-19 vaccination GBSs belong to the AIDP subtype, mainly characterized by sensory involvement, and occurred after the first vaccine dose, and that bilateral seventh cranial nerve involvement was not an uncommon manifestation [56].

Compared with classical GBS, patients with GBS related to COVID-19 vaccination showed unique clinical features, which include a more severe manifestation of the syndrome and more frequent bifacial diplegia. Hence, it is important for clinicians to have a high index of awareness to identify potential cases of bifacial weakness with paresthesias variant GBS following vaccination for SARS-CoV-2.

Considering the growing number of individuals vaccinated for COVID-19 worldwide, such reports of GBS will increase in the near future. Even so, the causal relationship between COVID-19 vaccines and GBS development should be considered with caution. Because of the heterogeneity of the sources of information, associations between COVID-19 vaccine and GBS must be confirmed in clinical epidemiological studies. In any case, the risk of GBS is not considered a legitimate reason to limit administration of currently available COVID-19 vaccines considering the efficacy of these vaccines in preventing COVID-19.

From the data that can be looked up, the incidence of GBS following SARS-CoV-2 infection fluctuated from 0.12 per 100,000 person-years to 9.44 per 100,000 person-years [6, 8], while after receiving the Ad.26.COV2.S (Janssen) vaccine was 32.4 per 100 000 person-years [50]. It seemed that people were more susceptible to be GBS when vaccinated, actually, the data about GBS related to vaccinations are incomplete [57]. Therefore, it is hard to compare the rate of GBS after SARS-COV-2 infection and after COVID-19 vaccination reasonably.

In this review, we summarized recent developments in the understanding of the possible molecular mechanisms in SARS-CoV-2 infection causing GBS. At present, worldwide efforts for prevention of COVID-19 have focus on developing effective vaccines. Yet despite extensive efforts to develop vaccines against COVID-19, some vaccinated individuals still got infected even after the wide introduction of vaccine for COVID-19. Thus, there is a major need to understand better the molecular basis of SARS-CoV-2 infection in order to develop effective therapeutic strategies.