Type I interferons as the potential mechanism linking mRNA COVID-19 vaccines to Bell's palsy.

Abbreviations

coronavirus disease 2019

messenger RNA

Safe and effective coronavirus disease 2019 (COVID-19) vaccines are well recognized as a first-line tool for curtailing the ongoing pandemic. As the first vaccines are being approved in several countries, their safety is a topic of major interest. Based on adverse events from phase 3 clinical trials [1], [2], Bell's palsy appears as an atypical and rare adverse reaction of messenger RNA (mRNA) COVID-19 vaccines, leading to its mention in their summary of product characteristics. Although the frequency of Bell's palsy in the vaccine group was considered consistent with the expected rate in the general population, its imbalance between groups is puzzling. Out of the 8 cases of Bell's palsy, 7 occurred in the vaccine group, whereas only 1 occurred in the placebo group (Table 1 ). One case in a participant who received the vaccine was considered as serious. All cases occurred shortly after injection (i.e. from 3 to 48 days after the second dose). Bell's palsy was resolved in 2 cases, and was continuing or being resolved in 6 cases at data cutoff.

Table 1

Description of the 8 cases of Bell's palsy in clinical trials of mRNA vaccines against COVID-19 [1], [2]. The participant did not receive the second dose.

Sponsor	Seriousness	Group	Sex	Age, years	Time of onset of Bell's palsy, days (after dose #n)	Duration of Bell's palsy, days	Outcome of Bell's palsy at data cutoff
Pfizer-BioNTech	Non-serious	Vaccine	Not available	Not available	3 (2)	3	Resolved with sequelae
Pfizer-BioNTech	Non-serious	Vaccine	Not available	Not available	9 (2)	> 10	Continuing or resolving
Pfizer-BioNTech	Non-serious	Vaccine	Not available	Not available	37 (1)*	> 15	Continuing or resolving
Pfizer-BioNTech	Non-serious	Vaccine	Not available	Not available	48 (2)	> 21	Continuing or resolving
Moderna	Non-serious	Vaccine	Female	72	22 (2)	Not available	Continuing
Moderna	Non-serious	Vaccine	Female	30	28 (2)	Not available	Resolved
Moderna	Serious	Vaccine	Female	67	32 (2)	Not available	Resolving
Moderna	Non-serious	Placebo	Male	52	17 (not available)	Not available	Resolving

One explanation for this imbalance may be a link between mRNA COVID-19 vaccines and Bell's palsy. Early transversal pharmacological analysis enabled to propose type I interferons as the potential mechanism. In addition to the temporal association already suggesting a contribution of the vaccine, the following three biological arguments further strengthen this hypothesis.

First, mRNA vaccines are known to elicit a profound response of type I interferons [3], which regulate lymphocyte recirculation and cause transient lymphopenia [4]. On the one hand, transient lymphopenia was precisely the most commonly hematology changes observed in phase 1 clinical trials of mRNA COVID-19 vaccines (i.e. < 0.8 × lower limit of normal from 1 to 3 days after the first dose). On the other hand, previous studies also described a decrease in CD3 and CD4 cells during the acute stage of Bell's palsy [5].

Second, Bell's palsy is a rare adverse reaction also reported with interferon-α (i.e. a type I interferon) therapy in hepatitis C virus infection. Some authors postulated that interferon-α therapy can cause a breakdown of tolerance to myelin sheath antigens and lead to neuropathy [6]. It is worth noting that autoimmunity against the myelin sheath is suggested to play a role in the pathogenesis of Bell's palsy [5].

Third, in a phase 1 clinical trial of an mRNA rabies vaccine in 101 participants, a case of transient grade 2 Bell's palsy was reported 7 days after the second dose [7]. The strong similarities in terms of time of onset and outcome suggest that Bell's palsy may be a class effect of mRNA vaccines.

To conclude, considering the converging evidence of temporal association and biological plausibility, the contribution of mRNA COVID-19 vaccines to Bell's palsy cannot be excluded, and constitute a signal of pharmacovigilance [8]. Beside idiopathic causes and viral infections including COVID-19 itself [9], mRNA COVID-19 vaccine should therefore be considered as an additional possible cause in the etiology of Bell's palsy.

Disclosure of interest

The authors declare that they have no competing interest.