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No Relationship Reported Between Seasonal Influenza Vaccine and Increased Incidence of Guillain-Barré Syndrome

Article In Brief

New findings show that the influenza vaccine does not increase the risk of Guillain-Barré syndrome within 42 days receive the vaccine. The use of different study designs and failure to account for potential confounding factors may have led to conflicting results in the scientific literature, the study authors suggest.

There has long been a concern that influenza vaccinations could pose a risk for Guillain-Barré syndrome (GBS). Now, findings of a new study dispel that belief.

Published online first on April 28 in Neurology, the retrospective review of medical files of more than 3,000 people enrolled in the government-sponsored French National Health Insurance did not find an increased rate of GBS in the 43-days post-vaccine.

Not surprising, the scientists did report a fourfold increase in GBS in people who had suffered from an acute respiratory infection or gastrointestinal infection. It is known that viral infections can trigger an autoimmune response and lead to a paralysis that begins in the feet and moves north of the body. GBS is an acute inflammatory response of the peripheral nerves and can ultimately affect breathing.

This study comes on the heels of a worldwide push to create a vaccine against SARS-CoV-2, which causes COVID-19. It was a collaborative effort between scientists at the health insurance agency and colleagues at INSERM, the Institut Pasteur, and the Conservatoire National des Arts et Métiers in Paris.

“Although controversial in the scientific literature, our study provides strong arguments in favor of not significantly increasing the risk of GBS within 42 days of seasonal influenza vaccination,” Clémence Grave, MD, and his colleagues wrote in the discussion section of the paper. “One of the hypotheses to explain the conflicting results of the scientific literature could be the use of different designs less suitable for vaccine safety studies, or the failure to consider potential confounding factors.”

Study Design, Findings

To study the association, the scientists collected data on every person diagnosed with GBS in metropolitan France from September 2010 through March 2014 and reviewed the database that tracks claims and hospitalizations. They identified every case of GBS that occurred within 42 days of the vaccination. (A national campaign to promote influenza vacation during those years of the study led to five million vaccinations a year. The vaccines included the H1N1, H3N2, and B strains.) People with a prior diagnosis of GBS before this study period were excluded from the analysis.

The database included information on the timing for patient reimbursements for the vaccinations. It was assumed that they received their vaccinations during the next office visit with their health care provider. The date of the GBS diagnosis was considered the first day of admission to the hospital. The number of GBS patients hospitalized in the first 42 days of the vaccination was then compared to a control group of GBS patients who were admitted to the hospital after 43 days. Many earlier GBS-vaccine studies suggested a window of risk within the first month.

The team also collected clinical diagnoses of acute respiratory and gastrointestinal infections based on the prescriptions ordered and paid for by the French government. (When applicable, they also used hospital records to confirm the discharge diagnosis.) Statisticians adjusted for seasonality and acute infections identified.

They conducted separate analyses for people younger and older than 65-years-old. They also did separate analyses of children younger than 5 and patients older than 90, and they also separated the analysis based on the type of vaccine—a split-viron or a subunit influenza vaccine. They only included patients whom they knew had been vaccinated within four days of receiving the vial from their pharmacy.

The research team limited their analysis to those treated with immunoglobulins and/or plasma exchange and those who had been admitted to the intensive care unit or who needed mechanical ventilation. After they arrived at the first level of data, they went back and conducted a sensitivity analysis that went from 28 days to 56 days after the vaccination.

They identified 3,523 patients who developed GBS and met criteria for entry into the analysis. Fifteen percent of them—527 patients—had received the influenza vaccine. The average age at the time of the GBS diagnosis was 51-years-old, and women appeared at much greater risk (58.4 percent versus 41.6 percent of men). Almost 30 percent—1,055 patients—were admitted to an ICU and 13.8 percent (485 patients) were put on mechanical ventilation. Seventy-two percent (2,735 patients) had been treated with immunoglobulins and 3.5 percent (122 patients) had plasma exchange.

The risk of developing GBS during the first 42 days (26.6 percent of the 527 patients) was no higher than it was in the control group of people who developed GBS after 43 days. (The mean duration of the control period was 107 days.)

Neither type of vaccine led to an increased risk, even in those over 65, the scientists said. In a secondary sensitivity analysis, they said there was a hint of an association between GBS and the influenza vaccine when they reduced the number of post-vaccination days, from 42 to 28. They also reported a “weak association” for the 2012-2013 vaccine campaign, although the numbers may have been too small to give the finding statistical power. That year, they added, three influenza viruses—type A H1N1, H3N2, and type B Victoria—that were circulating around France. Victoria was not in the vaccine.

They found a fourfold risk of GBS on the heels of an acute respiratory or gastrointestinal infection, also during the same seasons included in the analysis. The risk of GBS was during the first 42 days following an acute infection, they said. Other studies have also reported an association between GBS and acute viral infections.


“The question still comes up and people are hesitant to say that influenza vaccines do not increase this risk, even though a number of studies, including this one, says that there is no increased risk of GBS that is related to the vaccine itself.”—DR. AVINDRA NATH

The scientists said they decided not to use data from the pre-vaccination period, as other studies have done, as it would have skewed the study results. Presumably, anyone who developed GBS would have been advised to put off vaccination. And it could have “led to a bias in the estimation of the baseline risk (during the control period) and thus artificially increased the risk of GBS after vaccination, compared to this period,” they wrote in the study.

Expert Commentary

“GBS is certainly one of those acute conditions that anti-vaccine people are worried about,” said Avindra Nath, MD, FAAN, senior investigator of the section of infections of the nervous system, and clinical director of the National Institute of Neurological Disorders and Stroke. “The question still comes up and people are hesitant to say that influenza vaccines do not increase this risk, even though a number of studies, including this one, says that there is no increased risk of GBS that is related to the vaccine itself.”

Dr. Nath added: “The researchers have taken advantage of an incredible database that includes the entire metropolis of France over a period of four and a half years. They were able to identify every case of GBS over that period of time. However, there are a few caveats. The date of hospitalization was considered to be the date of onset of the disease, however, symptoms may predate the date of hospitalization for a variable period of time so it might not be accurate.

“The population also received several different types of influenza vaccines depending on the circulating viruses at the time. And not all viruses were included in the vaccines. These factors could have influenced the accuracy of the data. It would have been useful to know what criteria were used to diagnose GBS and if there were any differences in the risk for demyelinating and axonal forms of GBS. Despite these caveats, this is a critically important study that attests to the safety of the influenza vaccines in terms of the risk for GBS and the significantly higher risk of getting GBS from the respiratory infections.


“It is a very tricky issue. There are a number of studies that show that GBS can be triggered by a viral infection. Some studies have also suggested that vaccines could increase a risk but it is often impossible to tell whether the person also had a viral infection.”—DR. STANLEY H. APPEL

Previous studies have documented an increase in GBS after viral epidemics, including a 2016 study published in the New England Journal of Medicine study showing an increase of GBS following Zika infections in Columbia.

“This self-control control case study design is relatively new and generally used to study vaccine-related events,” said James J. Sejvar, MD, a neuro-epidemiologist in the division of high-consequence pathogens and pathology in the National Center for Emerging and Zoonotic Infectious Diseases at the Centers for Disease Control and Prevention. “You use exposure periods versus the control period where you don't think the vaccine would have had a clinical impact regarding a side effect.”

“This is a conformational study,” he added. “Others have shown this, too. But this large sample size gives us more confidence in the results. The public health message is this: People are more likely to develop side effects from the influenza virus itself rather than the vaccine.”

“There has been evidence that following the Swine flu there were increased cases of GBS,” added Stanley H. Appel, MD, FAAN, the Peggy and Gary Edwards distinguished endowed chair for the treatment and research of ALS at Houston Methodist Neurological Institute. In 1980, the US District Court convened a panel of medical experts, including Dr. Appel, to address the issue. There were a number of lawsuits filed in federal court by people who alleged that the Swine flu vaccine, delivered during the National Swine Flu Immunization Program of 1976, led to the development of GBS.

“It is a very tricky issue,” said Dr. Appel. “There are a number of studies that show that GBS can be triggered by a viral infection. Some studies have also suggested that vaccines could increase a risk but it is often impossible to tell whether the person also had a viral infection. This latest study looked at a large number of GBS patients and determined that there was no increased risk. They also found a fourfold increased risk in patients who had had an acute respiratory or gastrointestinal infection. We have known about this risk for a long time.”

“Although the vaccination did not appear to influence the number of GBS cases when the observation time was 42 days post-vaccination in this study,” he added, “there was an association when the time period following vaccination was shortened to 28 days. Other studies may be warranted.”


Drs. Nath, Sejvar, and Appel had no relevant disclosures.

Link Up for More Information

• Grave C, Boucheron P, Rudant J, et al. Seasonal influenza vaccine and Guillain-Barré syndrome: A self-controlled case series study Neurology 2020; Epub 2020 Feb 25.
    • Toscano G, Palmerini F, Ravaglia S, et al. Guillain-Barré syndrome associated with SARS-CoV-2 N Engl J Med 2020; Epub 2020 Apr 17.
      • Delannoy A, Rudant J, Chaignot C, et al. Guillain-Barré syndrome in France: A nationwide epidemiological analysis based on hospital discharge data (2008-2013) J Peripher Nerv Syst 2017;22(1):51–58.