The coronavirus disease-2019 (COVID-19), induced by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has been challenging all over the world since December, 2019 (1). As of December 29, 2021, the total number of confirmed cases is over 281 million worldwide, including more than five million deaths (2). SARS-CoV-2 infection is commonly characterized by fever, cough, shortness of breath, headache fatigue, pneumonia and congestion (3, 4). In severe cases, especially among individuals over 60 years old and those with underlying chronic comorbidities, the infection leads to acute respiratory distress syndrome (ARDS), renal failure, meningoencephalitis, cerebrovascular accidents, sepsis and even death (5). Compared with its predecessors (i.e., SARS-CoV and MERS-CoV), SARS-CoV-2 transmits much more efficiently from person to person (6).

Currently, mass vaccine immunization is believed essential to control the pandemic (7). The SARS-CoV-2 vaccine has been expedited through preclinical and clinical investigations (8). As of December 29, 2021, a total of 8,687,201,202 vaccine doses have been administered worldwide (2). Efforts have been made to promote mass vaccination programs against SARS-CoV-2. The unprecedented campaign of mass immunization will pose many challenges to the assessment of vaccine safety. Potential adverse events following immunization (AEFI), induced by vaccination of SARS-CoV-2, will foreseeably raise potential concerns under the pandemic. The public needs frequent reassurance of vaccine safety when adverse events occur in temporally coincident association with SARS-CoV-2 vaccination, even when the events are not caused by the vaccines. Awareness of possible adverse events is essential for the assessment of vaccine safety and may help to separate AEFI from events that are temporally associated with but might not be attributed to vaccination (9).

Viral vaccines were considered to be related to AEFIs including vomiting, diarrhea, nausea or abdominal pain, acute otitis media, vaccine-related paralytic poliomyelitis (VAPP), Guillain-Barré syndrome (GBS), anaphylactic shock, epilepsy and meningitis (10), among which GBS is considered one of the most severe conditions (11). GBS is featured by immune mediators damaging to peripheral nerves and associated with muscle weakness or paralysis (12). The initial symptoms of GBS are severe nerve pain in the neck, shoulder and waist, followed by acute progressive acute paralysis of limbs and subjective sensory disturbance (13). Reported incidence rates of GBS for all ages combined range from 0.2 to 3.0 per 100,000 person-years (14).

An 11- to 18-fold increase of incidence rate of GBS within three weeks after influenza vaccination and a 4- to 9-fold increase within six weeks have been released previously (12). Consideration about GBS that was in the wake of post-vaccination appeared for the first time in the influenza vaccine season from 1976 to 1977 (15). Mass human papillomavirus (HPV) immunization has also been suggested to be related to GBS (16). At present, HPV vaccines are recommended by World Health Organization (WHO) for girls between 9 and 13 years old (17, 18).

Recently, an 82-year-old female developed GBS two weeks after receipt of the first dose of Pfizer COVID-19 vaccine (19). Thereby, rational interpretation of GBS occurrence temporally associated with vaccination is needed to the public. A valid interpretation of the coincidental adverse events may prevent from misunderstanding such reports, and contribute to the acceptance of vaccination campaigns.

In order to identify the incidence rate of GBS in populations that received viral vaccines during mass immunization campaigns, we conducted this systematic review and meta-analysis. We expected to provide the reference for the public to assess post-vaccination GBS validly, and engage in averting potential spurious association between the vaccine and coincidental adverse events during the mass vaccination against SARS-CoV-2.

This study was conducted by reference to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline (20), which is provided in Table S1 .

To the best of our knowledge, this study is the first to comprehensively summarize the incidence rates of GBS following mass immunizations of viral vaccines. Our meta-analyses, involving 58 original studies and 2,110,441,600 participants, identified a pooled rate 5.29 per million (95% CI:3.66 to 6.93 per million) among people received viral vaccines, and a pooled rate 3.09 per million (95% CI:2.67 to 3.51 per million) in 6 weeks of vaccination, equally 2.47 per 100,000 person-year (95%CI: 2.14 to 2.81 per 100,000 person-year). There was no significant increase in GBS incidence among population received viral vaccines compared to general population without prior vaccination. Subgroup analyses released the pooled rates of 2.77 per million (95%CI: 2.47 to 3.07 per million) for individuals received influenza vaccine and 2.44 per million (95%CI: 0.97 to 3.91 per million) for HPV vaccinees, respectively.

GBS is a demyelinating transient neurological disorder characterized by lack of paralysis and sensory impairment. GBS is an immune-related disorder, in which the immune response generates antibodies that cross-react with gangliosides (i.e., GM1, GD1a, GT1b and GQ1b) at nerve membranes (75). This autoimmune response results in nerve damage or functional blockade of nerve conduction (76). Aberrant active immunization induced by artificial vaccines, hypothetically, is able to stimulate the immune system to produce specific antibodies, which contribute to cross reaction with epitopes on myelin or axons, leading to nerve damage (77). Vaccines might, as understood, damage the peripheral nerves directly (78). However, the causal associations between vaccines and GBS have not been substantially proved, i.e., the association might not be causally established.

The mass immunization against COVID-19 has started unprecedentedly on a global scale. Recently, coincident GBS case was observed after administrated with COVID-19 vaccine (19). New considerations about vaccine safety will undoubtedly arise. Toward the public, it is critical to distinguish events that are temporally associated with vaccination from those directly caused by vaccines. Misinterpretation of GBS incidence that is only temporally coincident with but not caused by vaccination will not only obstruct the success of mass vaccination, but also hinder the development of newer vaccines (9).

During the 1976-77 A/H1N1 influenza immunization campaign, an increase of GBS was reported after vaccine administration (15), which suspended the immunization program temporarily, and initiated vaccine safety concerns. In the 1993-1994 influenza seasons, public concern of vaccine-related GBS arose again due to the increment of GBS (79). The 2009 H1N1 influenza pandemic motivated H1N1 vaccine campaigns in North America and Europe, where post-vaccination GBS concern was raised consequently (29). However, in 2009-2010, a surveillance of H1N1 influenza vaccine in 45 million persons showed a lower excess risk for GBS during the immunization campaign compared to earlier vaccination (73). In France, a study did not support the causation between GBS and H1N1 vaccination (80). Our pooled results show that the temporal coincidence of GBS in influenza vaccinees is not higher than that among general populations unvaccinated.

With regard to HPV, the debate on vaccine safety still exists, which remains one of the barriers to achievement of intensive global vaccination coverage. The Vaccine Adverse Event Reporting System (VAERS) in the United States reported a GBS rate of 0.2 per 100,000 dosages coincided with HPV vaccination from 2006 to 2008 (24). In a school-based HPV study in Canada, the overall background rate was 0.73/100,000 person-year for adolescents aged 7-17 years (81). Similarly, our study did not observe an increase in background rate of GBS after HPV vaccine administration.

The adjuvants of vaccines could affect the magnitude and quality of immune response. The AS03 adjuvant contains α-tocopherol, which might promote immune system activation in the nonregional lymph nodes (82), whereas MF59 might modulate cellular immune response at the injection site or regional lymph nodes (83). Moreover, an in vitro study demonstrated that α-tocopherol can raise the expression of hypocretin, leading to antigen presentation via human leukocyte antigens (84), which results in an autoimmune response, and damages hypocretin-producing neurons. In this current study, both vaccines adjuvanted with AS03 and those with MF59 have lower background rates of GBS than that of general populations, even though the background rate among individuals received vaccines with AS03 adjuvant is higher than that with MF59 adjuvant.

Our study has potential limitations that usually exist in observational studies and systematic reviews. Firstly, we aimed to summary data from studies that reported background rate of GBS in mass immunizations, which reflected the temporally coincidence of GBS in “real world”. In accordance with the predefined protocol, we did not include clinical trials that evaluate the safety of vaccines. Secondly, there was heterogeneity across original studies, which might limit the consolidation of the findings. Thirdly, most of original studies involved Caucasian participants, limiting the representability of our findings for other ethnic groups. Fourthly, as all the original studies are based on vaccine surveillance data, the methodological quality was not able to be evaluated. Fifthly, the increase in GBS reported in vaccination campaigns might result from the higher detection rate among vaccinees and increased reporting levels of GBS cases following receipt of vaccines.

In conclusion, our findings evidenced a mild increase in coincidental GBS during virus vaccination. We presented a reference for evaluation of the coincidental occurrence of GBS in mass vaccination campaigns, including SARS-CoV-2 vaccine.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

HH, YXW, and WW designed this study. FW, DW, YJW, and CL contributed to literature search, review, data extraction. YLZ, ZG, PL, and YCZ conducted statistical analyses. FW, DW, YJW, and CL wrote the manuscript. HH, YXW, and WW contributed to manuscript revision. All authors have reviewed and approved the final version of this manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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