COVID-19 Vaccination Modifies COVID-19-Related Headache Phenotype: Evidence from Case–Control Study on 309 Participants

<b>Background:</b> Headache is a common symptom during acute viral infections, and its pathophysiology has been linked with the immune response to the virus. Headache is one of the most frequent symptoms of coronavirus disease 2019 (COVID-19), and it has been associated with a more efficient immune response and a better prognosis. The aim of this article is to evaluate whether vaccination could modify the clinical phenotype and the probability of developing persistent headache after acute COVID-19. <b>Methods:</b> A case-control study comparing the duration of the headache and the clinical phenotype between fully vaccinated individuals and non-vaccinated controls was conducted. Each case was matched with two controls that were paired by age, sex, and prior history of headache. Patients were evaluated by a physician that administered a structured questionnaire and were followed up for at least three months. <b>Results:</b> The sample included 103 cases and 206 controls, with a median age of 42 (inter-quartile range (IQR) 33-51); 68% were female; and 26% had a prior history of headache. Headache had a shorter duration for vaccinated patients (4 (IQR 2-8) vs. 8 (IQR 4-16.5) days, <i>p</i> < 0.001). Vaccinated patients had a higher frequency of holocranial topography, pressing quality, phonophobia, and cranial autonomic symptoms. <b>Conclusions:</b> Our results suggest that full vaccination modifies the clinical phenotype of COVID-19 onset-associated headache and might lead to a shorter duration. These findings could represent an additional benefit of COVID-19 vaccines, which could extend to the post-COVID-19 phase and decrease the probability of a persistent disabling symptom such as headache.