Potential association of cluster headache with certain COVID-19 vaccines: An assessment from the pharmacovigilance databases

Objectives/background: The main objective of our study was to assess the potential association between coronavirus disease 2019 (COVID-19) vaccination and cluster headache (CH) using a pharmacovigilance approach. A secondary objective was to determine whether COVID-19 vaccines predominantly triggered onset or worsening of the disease. Recent pharmacovigilance studies and case reports have suggested an association between COVID-19 vaccines and cluster headache. In order to evaluate whether COVID-19 vaccines could possibly elicit the onset of cluster headache or be responsible for worsening of the disease, we conducted a retrospective case-non-case pharmacovigilance study using the international VigiBase pharmacovigilance database and analyzed the reported cases of cluster headache in the Base Nationale de Pharmacovigilance, French National Pharmacovigilance Database (BNPV).

Methods: VigiBase was queried up to February 23, 2025, for all reports related to cluster headache and COVID-19 vaccines. To evaluate the potential association, we performed a disproportionality analysis. This analysis relied on the calculation of the information component, for which a 95% confidence interval lower-bound positivity was required for signal detection. The narratives of the reported cases of cluster headache in the BNPV were analyzed to determine whether COVID-19 vaccination was responsible for the onset or worsening of the disease.

Results: When focusing on the different COVID-19 vaccines, Vaxzevria was found to be the strongest signal (IC₀₂₅: 3.05). Lower signals were observed for the other COVID-19 vaccines, including Comirnaty (IC025: 1.62), Spikevax (IC₀₂₅: 1.24), and Jcovden (IC₀₂₅: 0.05). The analysis of the 55 CH cases reported in the BNPV revealed a slight predominance of onset (24/55 cases classified as CH) over worsening of the disease (17/55 cases classified as CH).

Conclusions: Our study supports the possibility of a potential association between COVID-19 vaccines and cluster headache through an updated pharmacovigilance analysis. The signal appears to be more pronounced with the Vaxzevria vaccine.