COVID-19 infection presents greater risk of causing very rare neurological events than vaccines

Key facts

• Study compared the risks of developing neurological complications before and after vaccination with either the ChAdOx1 nCov-19 (Oxford-AstraZeneca) or BNT162b2 mRNA (Pfizer-BioNTech) vaccination or a positive COVID-19 PCR test.
• People who received the Oxford-AstraZeneca vaccine had an increased risk of developing two types of complications – Bell’s palsy and Guillain-Barre syndrome – in the 28 days following first dose vaccination, while those receiving the Pfizer-BioNTech vaccine had an increased risk of haemorrhagic stroke.
• Infection with COVID-19 carried a much higher risk of developing neurological complications than either vaccine.
• Confirmatory analysis undertaken in Scotland’s national COVID-19 dataset (EAVE II).
• Study authors included a UK-wide team, all of whom were fully independent from Oxford vaccine developers.

Researchers from across the UK, led by the University of Oxford, have today reported on the risks of developing neurological complications following a positive COVID-19 PCR test, or a first dose of either the Oxford-AstraZeneca or Pfizer-BioNTech COVID-19 vaccinations. Two cases of such complications led to pauses in Oxford-AstraZeneca trials for investigation, and in some countries to limit use of the Oxford-AstraZeneca vaccine to people considered at low risk of severe outcomes from COVID-19 infection (i.e., to young people).

Writing in Nature Medicine, the researchers detail the findings from an analysis of anonymised healthcare records of over 32 million people across England. They assessed the risk of developing neurological complications within 28 days of a first dose of either the ChAdOx1 nCov-19 or BNT162b2 mRNA vaccines, or within 28 days of a positive COVID-19 PCR test. They found that both vaccines result in an increase of certain types of neurological ‘adverse’ events for a short time after administration, but that infection with COVID-19 led to a greater risk than receiving either vaccine.

Martina Patone, Medical Statistician at the Nuffield Department of Primary Care Health Sciences, University of Oxford, and co-lead author said:
“We found different risks for different types of neurological condition depending on which vaccine people received. However, these were substantially lower than the risks occurring in association with a positive COVID-19 PCR test. For example, we estimate 145 excess cases of Guillain-Barre syndrome per 10 million people in the 28 days after a positive SARS-CoV-2 test, compared to 38 per 10 million for those who received the ChAdOx1nCoV-19 vaccine.”

Dr Lahiru Handunnetthi, Clinical Lecturer at the Nuffield Department of Clinical Neurosciences, University of Oxford, and co-lead author of the paper, said:
“In our study of over 32 million people, we found that several neurological complications such as Guillain-Barre syndrome were linked to both COVID19 infection and first dose vaccination. These neurological complications were very rare, but awareness of these will be important for patient care during mass vaccination programmes across the world.”

The researchers also carried out an additional analysis limited to people who had a positive COVID-19 test before vaccination. This did not change their results, showing a greater risk of all neurological complications following SARS-CoV-2 infection before vaccination. However, the number of people infected after vaccination was too small for a separate analysis.

Initial vaccine clinical trials were not large enough to be able to detect very rare adverse neurological events – those that happen in less than 1 person out of 10,000. This study was able to achieve this by looking at the real-world data from over 32 million healthcare records in England.

The study used what is known as a ‘self-controlled case series (SCCS)’ design. An SCSS compares how often ‘adverse events’ – in this case neurological complications – happen in different set windows of time within the same person; before, in a short period after, and in a later period after an exposure. In this case, the ‘exposure’ was either of the two common COVID vaccines in the UK or a positive test for COVID-19.

In an SCCS a separate control group is not needed as each patient is used as their own control, since the trail compares the rates of adverse events before the exposure (i.e., the control time) to after exposure. Combining and analysing the data for millions of individuals then allows the rates of adverse events before and after a vaccine or positive COVID-19 test to be determined and compared.

This has the advantage that ‘confounding factors’ that do not vary over time, such as genetics, where people live, their socio-economic status, occupation, education levels and so on, are implicitly controlled for.

Julia Hippisley-Cox, Professor of Clinical Epidemiology and General Practice at the University of Oxford, and co-author said:
“We know the COVID-19 vaccines are very effective at reducing risks of severe outcomes from COVID-19 infection. Whilst there are some increased risks of very rare neurological complications associated with the Oxford-AstraZeneca vaccine, these are much smaller than the risks associated with COVID infection itself. However, these very rare conditions are very important to spot to ensure that clinicians know what to look for, aid earlier diagnosis, and inform clinical decision making and resource management.”

The authors noted that there were several limitations to the study, including:

• Only risks associated with the first vaccine dose were examined, as data on outcomes following second doses was limited at the time of this study since the vaccination program in the UK is still underway.
• They could not distinguish between different types of Guillain-Barre syndrome due to the way healthcare records were coded.
• Only hospital admissions and mortality were included, so patients with milder neurological disease may not have been included and the overall burden of neurological adverse events from vaccination and infection could be underestimated.
• The data set came only from England, though a confirmatory analysis was undertaken using a Scottish dataset, but different populations may experience different rates of very rare complications.

Aziz Sheikh, Professor of Primary Care Research & Development and Director of the Usher Institute at The University of Edinburgh and a co-author of the paper, said:
‘A key strength of this study was that we were able to replicate the analysis in Scotland’s national COVID-19 dataset. Overall, this provided strong support to the findings observed in the English dataset, namely that COVID-19 poses a greater risk of neurological adverse events than seen with wither the Oxford-AstraZeneca or Pfizer-BioNTech vaccines.

‘This study demonstrates the very considerable power of UK data to investigate very rare safety concerns at pace and at scale. As far as we’re aware, no other country has this capability to do this and independently replicate findings.’