COVID-19 Vaccine and Guillain-Barré Syndrome: Let's Not Leap to Associations

Michael P. Lunn; David R. Cornblath; Bart C. Jacobs; Luis Querol; Peter A. van Doorn; Richard A. Hughes; Hugh J. Willison

Disclosures

Brain. 2021;144(2):357-360. 

In This Article

Abstract and Introduction

Introduction

A worldwide mass vaccination campaign to control the COVID-19 pandemic is imminent. Understanding the epidemiology of rare diseases whose onset will inevitably occur by coincidence following SARS-CoV-2 vaccination, but which have little to no evidence of being caused by them in any significant number of cases, is critical. Failure to appreciate these issues will result in misattribution of adverse events to the vaccination programme. This could lead to poor uptake of vaccines, delay or even withdrawal of vaccines, or vaccine programmes resulting in unnecessary morbidity and mortality.

Global cases of the COVID-19 respiratory illness caused by the virus SARS-CoV-2 have surpassed 50 million, with a pandemic resulting in medical and economic devastation worldwide. As of late November 2020, four vaccines involving over 100 000 participants have displayed favourable efficacy without significant reported side effects in phase 3 trials. At least 57 COVID-19 vaccines are in phase 1–3 trials: six already have limited approval, and 87 are under active animal study investigation (https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html accessed 18 November 2020).

Guillain-Barré syndrome (GBS) is an acute inflammatory peripheral nerve disorder resulting in severe and sometimes lasting paralysis; about one-third of patients develop respiratory failure requiring intensive care unit (ICU) admission and ventilation (Leonhard et al., 2019). GBS is fatal in 3–5% of patients, and about two-thirds have residual disability. The lifetime individual risk of acquiring GBS is about 1:1000, and the annual incidence of GBS is ~1.7 persons per 100 000 population (Sejvar et al., 2011; Keddie et al., 2021). Some 1500 cases of GBS are recorded in the UK each year, or by extrapolation, about 100 000 worldwide. It is thus an alarming illness for the public and healthcare providers.

Around half of those affected by GBS have a preceding history of an identified infection and two-thirds preceding infectious symptoms. The remainder have no overt trigger for their illness. The commonest triggering infection worldwide is gastroenteritis caused by Campylobacter jejuni (Doets et al., 2018). Many other infections can also trigger GBS including cytomegalovirus, influenza, Mycoplasma pneumoniae, the flaviviruses Zika and dengue, and the alphavirus, chikungunya (Brito Ferreira et al., 2020). Notably, during the recent Zika virus epidemic in Latin America, many countries reported a sharp rise in cases of GBS confirmed by strict epidemiological analysis, a relationship widely considered to be causal (Brito Ferreira et al., 2020).

The possibility of SARS-CoV-2 also driving a global spike in GBS has unsurprisingly been eagerly monitored with many cases and small series already published asserting a causal link. However, a surge in GBS cases after the SARS-CoV-2 pandemic has not been detected as it happened in the Zika virus pandemic. In a recent epidemiological study conducted across the UK, there was no increased incidence in GBS during the first wave of COVID-19, and thus no causal link of COVID-19 to GBS could be made in this population (Keddie et al., 2021). A small increase in GBS incidence might be disguised behind a much larger decrease in GBS cases from other causes. Filosto et al. (2020) published a series of 34 GBS patients from a Northern Italian population of 8.4 million people. They reported a 2.6-fold increase in incidence of GBS, a 3.3-fold decrease in non-COVID-19-associated GBS and calculated a rate of 47.9 cases of GBS per 100 000 COVID-19 infections. However, with such small numbers, the confidence intervals (CIs) of the GBS incidences overlap. Furthermore, using a published Italian Statistical Institute (ISTAT) seroprevalence of COVID-19 for the same period makes the COVID-19-associated rate a maximum of 4.7 cases per 100 000 COVID-19 infections; a small increase may represent a chance finding (Filosto et al., 2020). Thus, whilst one cannot exclude the possibility of a COVID-19–GBS association without case-control studies, there is currently no definitive evidence that there is an appreciable increase in GBS cases with COVID-19.

Why does GBS rear its head in the context of the SARS-Cov-2 pandemic and vaccination programmes? To understand this, we need to revisit the 1976/77 USA/New Jersey/76 vaccination programme that brought GBS to world-wide attention. Following dire warnings from experts of pandemic 'swine flu', President Ford instituted a rapid vaccine development program in the USA to prevent this (Neustadt and Fineberg, 1978). Unfortunately, the vaccine was found to be associated with a spike in cases of GBS with an initial calculation of a relative risk of 7.6 (95% CI 6.7–8.6) in the 6 weeks following vaccination, amounting to an attributable risk of just under one case of GBS per 100 000 vaccinations (Neustadt and Fineberg, 1978; Schonberger et al., 1979). As soon as this was known, the program was halted, but not before implanting the idea of a lasting association between GBS and vaccination (Langmuir, 1979; Langmuir et al., 1984). We must not allow hasty and misattributed associations to result from the occurrence of GBS shortly after COVID vaccination without very careful statistical thought and analysis.

Following the 'swine flu' programme, numerous national surveillance studies to identify vaccine-related GBS have been carried out, notably in the 2008/09 H1N1 influenza seasons, because the H1N1 influenza strain was also of swine origin. Any vaccine-related increase in GBS following modern influenza vaccines has been tiny, with the consensus of many robust studies being about one additional case per million vaccinations (10-fold less than in 1976) (Perez-Vilar et al., 2020; Salmon et al., 2020). In one UK GP database study, influenza vaccination was significantly protective, as it is in modelling studies of influenza vaccine where influeza prevalence is >5% and vaccine effectiveness >60% (Hawken et al., 2015). The risk of hospitalization after influenza infection is far greater than these at about 17 per million (Vellozzi et al., 2014), Around 22 000 deaths were attributed to influenza infection in the USA in 2019/20.

Multiple other vaccines including hepatitis B, polio, tetanus, meningococcus, rabies, and importantly, an orally administered adenovirus vaccine, have also previously been alleged to be associated with the occurrence of GBS (McNeil et al., 2019; Chen et al., 2020). No causative links have been conclusively proven despite these individual reports being widely quoted. In a defensive posture, but one that further heightens worries about GBS and vaccines, GBS is recorded as a warning in every vaccination summary of medical product characteristics (SmPC) in the EU or Package Insert (PI) insert in the USA.

All this leads to the relevance of GBS to the current proposed vaccination programme for COVID-19. The world is about to vaccinate at least 1 billion people, and possibly many more if production and logistics allow. The vaccination effort will likely begin in December 2020 and continue for several years. It will be the largest mass vaccination campaign ever undertaken in history. Most COVID-19 vaccinations are based on the Sars-CoV-2 spike protein. Sars-CoV-2 has not so far been shown to result in a significant increase in GBS. The vaccines developed to this point are delivered by different routes to natural infection and present the S-protein in unconventional ways. However, they contain no additional immunogenic material known or proven to drive GBS. Thus, although an association of any vaccination to GBS cannot be ruled out and we must remain vigilant to its potential occurrence, it is not to be presumptively expected.

Herein lie the statistics: within a population of 1 billion people, one would expect about 17 000 cases of GBS to occur sporadically per annum, of which 1962 would occur in any 6-week period. When considering a more optimistic 4-billion-person immunization programme conducted over 1 year, 68 000 cases of GBS would be expected to occur naturally within this time period, irrespective of any vaccination programme. Of these GBS cases, 13 076 would occur in the 10-week window following double-dose vaccination with injections separated by 4 weeks. It is therefore inevitable that many thousands of sporadic cases of GBS caused by other factors will appear temporally associated with COVID-19 vaccination. But, as any statistician can confirm, this cannot be considered causal.

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