Following a 1976 swine flu vaccination campaign in New Jersey, increased reports of Guillain-Barre syndrome (GBS) raised concern throughout the United States. As a result, the influenza vaccination program was suspended and the nationwide surveillance of the potential link between GBS and influenza vaccination began.1
The rare neurologic disorder, GBS, occurs when the body attacks its nerves due to immune reactions triggered by certain bacterial or viral infections. It typically occurs in 0.4 to 4.0 cases per 100,000 individuals, with higher rates seen in men aged 75 years and older.2
Recent research on vaccines and GBS has yielded mixed findings, with some studies supporting an association, while others suggest vaccination may offer protection against GBS.
A Proposed Mechanism
When a virus triggers an immune reaction, the frontline immune cells of the body will activate T cell differentiation, which triggers macrophages and B cells. Macrophages secrete matrix metalloproteinases (MMPs) and nitric oxide; B cells produce immunoglobulin G (IgG) to eradicate the virus, but when these proteins and immunoglobulins leak through the blood-nerve barrier, this mechanism can damage the peripheral nervous system. IgG can also trigger the complement system which can result in further nerve cell damage.
The most common triggering infections are Campylobacter jejuni and cytomegalovirus (CMV). Evidence for links between GBS and varicella, measles, and influenza has also been studied. However, regarding vaccine-associated GBS, the mechanism could potentially involve similar immune patterns during vaccine-induced autoimmunity.3
First Incidence of Vaccine-Associated GBS
In the first incidence of vaccine-associated GBS, surveillance found that 532 of 1,098 patients with a new onset of GBS had recently received an influenza vaccination. Higher attack rates were also observed among vaccinated individuals. The overall incidence was observed to be 7.1 cases per a million individuals, higher than the average incidence for GBS in the general population. Further analysis found that GBS risk varied with age and gender; individuals from ages 25-64 and men had a higher risk. The period of highest risk was found to be within the first 6 weeks of vaccine administration.1
These findings helped to substantiate a small but significant association between GBS and vaccination and lead to an increased sensitivity to vaccine adverse events and monitoring tactics. As vaccine safety became increasingly monitored, GBS association with vaccines other than influenza began to be studied.
Vaccine Adverse Event Reporting
Numerous programs in the US, including Centers for Disease Control and Prevention’s (CDC) National Vaccine Adverse Reporting System (VAERS)4 and the CDC’s Vaccine Safety Datalink (VSD)5 monitor vaccine adverse events.
In 2005, research from VAERS spanning from 1990 to 2005 revealed the influenza vaccine was associated with the highest proportion of GBS cases, following the hepatitis B, tetanus, diphtheria, pertussis (Tdap), measles mumps and rubella (MMR), and pneumococcal vaccines; but, rates of severe outcomes were comparable with the general GBS population.6
Compared with previous seasons, in the 2018-2019 influenza season, a VSD analysis7 found no statistically significant increase in GBS risk with the high-dose influenza vaccine.
GBS Severity and Clinical Features
GBS severity can vary drastically from patient to patient with Campylobacter jejuni infection associated with more severe and disabling clinical features. Although postvaccination GBS can have similar severity at nadir, compared with typical postinfectious GBS, a 2017 retrospective review in Korea8 classified most cases as Brighton criteria levels 1-3 (level 1, highest level of certainty vs 4, the lowest certainty of diagnosis), indicating moderate to high certainty of GBS diagnosis associated with influenza vaccination.
Influenza Vaccination May Protect Against GBS
Although some evidence suggests an association between influenza vaccination and GBS incidence, most research indicates that active influenza infection poses a higher risk for GBS, and vaccination may provide protection against it.9
In a 2013 Canadian study, researchers utilized universal health care system data from 1993 and 2011 for a self-controlled risk interval trial. Of the 2,831 incidence admissions for GBS, the researchers found that 330 individuals received an influenza vaccine and 109 cases were preceded by influenza infection. Although the attributable risk for GBS hospital admissions was reported to be 1.03 per million vaccinations, the attributable risk was 17.2 GBS admissions per million influenza infections.10
In a 2015 simulation study, the researchers aimed to evaluate the impact of seasonal influenza vaccination on the absolute risk of GBS. Probabilistic decision tree simulation models demonstrated that vaccination is more likely to reduce overall GBS risk in individuals. For a hypothetical 45-year-old woman and a 75-year-old man, the calculated excess GBS risk after vaccination was reported to be −0.36/1 million vaccinations and −0.42/1 million vaccinations, respectively. However, in rare instances of low influenza incidence and poor vaccine effectiveness, the models predicted a slight increase in GBS risk, although the overall excess risk is estimated to be approximately 1 in 1 million individuals.11
“[N]atural incidence rates of GBS are similar to postvaccination rates of GBS; vaccines also play a major role in preventing various infections that may put an individual at higher risk for naturally acquiring GBS.
In a 2022 cross-sectional study conducted in Taiwan, the researchers specifically studied GBS risk among adults aged 65 and older who received the influenza vaccine. The incidence rate ratio for GBS during days 1 to 7, 1 to 15, and 1 to 42 days after vaccination were 0.95, 0.87, and 0.92, respectively; no statistical significance was found. Subgroup analyses also reported consistent findings and support the notion that influenza vaccine benefits outweigh GBS concerns.12
GBS Recurrence After Vaccination
Outside of direct vaccine and GBS association, another potential concern is that vaccination may trigger a relapse of GBS.
In 2012, the researchers retrospectively identified cases of GBS from Kaiser Permanente databases from 1995-2006 to examine whether or not vaccination impacts GBS recurrence rates. Of the 550 cases of GBS identified, 989 vaccines were given to 279 of these individuals, of which 405 were trivalent inactivated influenza vaccines given to 107 individuals before GBS diagnosis. After chart review and neurologist evaluation, only 6 individuals were confirmed as having recurrent GBS. The calculated recurrence rate for GBS was 1.5 per 1,000 person-years; among the 6 individuals, only 1 had vaccine exposure prior to their recurrent GBS.13
Other Vaccinations and GBS Risk
The incidence of GBS has been closely monitored as a potential adverse event following influenza vaccination, leading to investigations into its occurrence with other vaccines, including recombinant zoster virus (RZV), MMR, human papillomavirus (HPV), and meningococcal vaccines.
In a 2021 observational case series cohort study utilizing Medicare claims data, RZV vaccinations were associated with an increase of 3 GBS cases per 1 million vaccinations during the 42 days following vaccinations, with a significant risk ratio (RR) of 2.84 (P =.001). Despite this increased risk, the researchers highlighted the importance of considering the benefits of reducing herpes zoster and its complications with the RZV vaccine, as the risk-benefit balance remains favorable.14
Case reports have documented a possible association between the MMR vaccination and GBS; however, several of the studies investigating this link remain controversial due to design limitations. In a study conducted in South America, the researchers compared the baseline incidence of GBS from 1990 to 1994 to 1-month periods of widespread measles vaccination campaigns from 1992 to 1993 in several South American countries. Among 73 million immunized children, GBS incidence rates were 0.67 per 100,000 individuals per year: a rate that is within the typical baseline frequency of GBS.15
HPV vaccination and GBS risk results have been historically conflicting; however recently, a large self-controlled case-series analysis was conducted in the United Kingdom, where a relative incidence of 1.10 of GBS was calculated for a 12-month risk period after the HPV vaccine.15
The quadrivalent meningococcal vaccine (MCV4) was studied in a retrospective trial with 9.5 million subjects where 15% had received the MCV4 vaccine. No confirmed GBS cases were diagnosed within 42 days of vaccine receipt; after 42 days, the incidence rate was calculated to be 0.45 cases per 100,000 person-year.15
COVID-19 Vaccination and GBS
The COVID-19 pandemic revived vaccine controversies, leading to extensive scrutiny of COVID-19 vaccines for safety and efficacy due to the antivaccine movement. As mandates spread globally, the link between COVID-19 vaccination and GBS has also been assessed,
The association between COVID-19 vaccination and GBS was first brought to light after 5 patients were reported to have GBS after COVID-19 onset in Italy.16
In a meta-analysis from January 2020 and November 2021, a total of 88 COVID-19 vaccine-associated GBS cases were studied; with 59.1% attributed to the AstraZeneca vaccine and 22.7% to Pfizer; 63% of patients had favorable outcomes despite varying severity and latency between vaccination and onset. In this group, 2 patients had a history of GBS and 5 patients had also received the influenza vaccine.17
In a recent retrospective cohort study, the researchers analyzed US Vaccine Adverse Reporting System (VAERS) data to compare COVID-19 vaccination methods with GBS case reports. Of the 487,651,785 COVID-19 vaccine doses, 295 individuals reported GBS diagnosis following vaccination; the researchers found that specifically, Ad25.COV2.5 COVID-19 vaccination had the highest risk for GBS with minimal risk associated with mRNA COVID-19 vaccines.18
What’s the Scientific Consensus?
The scientific consensus for vaccine usage overwhelmingly supports the safety and efficacy of vaccines. Regarding GBS in particular, natural incidence rates of GBS are similar to postvaccination rates of GBS; vaccines also play a major role in preventing various infections that may put an individual at higher risk for naturally acquiring GBS. However, given unique patient risk factors and history, it is important to individualize therapy based on the clinical evidence and risk/benefit analyses.