After the emergence of the COVID-19 pandemic, vaccination has become the most promising and effective weapon against the infection. Since then, vaccines against COVID-19 have played a major role in preventing the spread of the virus and reducing the disease-related mortality worldwide and still maintain their importance where there is a lack of certain effective medication or treatment [1]. As a result, the development of new vaccines specific to SARS-CoV-2 has accelerated globally [1]. Since early December 2020, several different vaccines have been approved by the European Medicines Agency (EMA). These include BNT162b2 (Comirnaty by Pfizer-BioNTech), an mRNA vaccine, followed by mRNA-1273 (Moderna), Oxford-AstraZeneca vaccine AZD1222 (ChAdOx1), JNJ-78436735 (Ad26.COV2.S by Janssen), along with 178 vaccines currently in the clinical development stage [2]. These vaccines have various adverse effects, with headache being one of the most frequently reported among the spectrum of neurological side effects [3,4,5]. The frequency, clinical characteristics, phenotypes, and pathophysiological basis of headaches following COVID-19 vaccination have become a new area of investigation with numerous unanswered questions [6]. These include the condition of patients with pre-existing headaches or a history of COVID-19, the long-term course of these headaches, patients in need of prophylactic medication against headaches before vaccination, and patients who require further diagnostic investigations.

Currently, there are a considerable number of papers focused on the acute presentations of COVID-19 vaccine-related headaches, revealing that headaches are a frequent and disabling problem in up to half of the vaccine recipients, with the majority of them experiencing symptoms consistent with tension-type headache [6,7,8]. Classically, headache occurs within the first 72 h after vaccination and is frequently accompanied by systemic symptoms such as fever, myalgia, diarrhea, arthralgia, and fatigue [7]. Although post-vaccination headache in the acute setting is now well-recognized, little is known about the long-term course of these headaches. Whether these headaches subside over time or persist as part of long-COVID symptoms are some of the unclear points that require clarification [9]. Currently, only a few papers have reported on the long-term course of COVID-19 vaccination-related headaches, with a focus on headache characteristics. However, the effects of a prior primary headache disorder on the course of vaccination-related headaches are still not fully understood [4].

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In this multinational, multicenter, and prospective study, our aim was to identify different phenotypes of COVID-19 vaccination-related prolonged/worsened headaches and document the changes in these phenotypes over the long-term course. For this aim, we used a standardized questionnaire administered by headache experts during the first visit and two follow-up visits (in the 3rd and 6th months after vaccination). As a secondary aim, the questionnaire included detailed questions about patients’ pre-vaccination and post-vaccination headache conditions, as well as accompanying long COVID symptoms.

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