Recent studies have reported on the occurrence of headache after inoculation with COVID-19 vaccines; however, the present study is the first to evaluate this event in individuals who have been vaccinated after initial infection by and recovery from COVID-19 and who experienced post-vaccination headaches. It should be noted that, post-vaccination, there were no signs of re-infection among participants.
The predominant finding of the present study has been that about one-third of the vaccinated individuals in the study group reported various types of post-vaccination headache. A review of the literature (Table 5) showed that the incidence of post-vaccination headache ranged from 19.5% to 49.4% regardless of the type of vaccine used or the target population (general population or healthcare workers). In a meta-analysis of these studies, we found an overall prevalence of 31.2% (95% CI: 25.3% to 37.9%) for headache, with a prevalence of 34.6% (95% CI: 27.4% to 42.5%) among healthcare workers, but with considerable heterogeneity across the studies (I2 = 99.037 (Figure 2) and 98.343 (Figure 3), respectively; p < 0.001) [13-33]. These divergent results could relate to the different brands of vaccine used as well as differences in the study populations. It could concluded that about one-third of individuals who have been vaccinated against COVID-19 experienced various degrees of headache, with a slightly higher incidence rate among healthcare personnel.
More interestingly, most headaches occurred within the first 24 h after vaccination (83.2%) with the mean time between vaccination and headache onset to be 26.78±6.93 h. As indicated by Göbel et al. [34], the latency between vaccination against COVID-19 and the occurrence of headache was on average 18.0 ± 27.0 h. More than half of their participants perceived the headache in less than 10 h and 80% within 24 h after vaccination, which is similar to our findings. Koji Sekiguchi et al. [35] also reported that the median onset of headache after the first and second vaccine doses were 10 and 12 h, respectively, and mean duration of headache was 4.5 and 8.0 h, respectively. In that study, the mean time to onset of headache after vaccination was 4.22±1.26 h. In 50% of their participants, the headache duration was less than 6 h and in 80% was less than 22 h. Göbel et al. [34] reported a mean headache duration of 14.2+ 21.4 h.
About one-third of participants reported generalized headache. Göbel et al. [34] reported bilateral headache in 73.1% of their subjects, with the most prominent zones being the forehead (38.0%) followed by the temple (32.2%). Sekiguchi et al. [35] reported the rate of bilateral headache in healthy controls having no history of headache, and history of migraine and non-migraine headaches as being 78.8%, 62.5% and 75.9%, respectively. The participants in the present study primarily reported compression-type headaches. Göbel et al. [34] reported compression headache and dull pain in 49.2% and 40.7% of participants, respectively. Ekizoglu et al. [36] reported throbbing headaches in 40.1% of participants and compression headache in 30.4%.
Another important finding was the occurrence of post-vaccination headache as being potentially influenced by the factors of the female gender and severity of the initial COVID-19 infection. Research released by the CDC on the safety of COVID-19 vaccinations indicated post-vaccination side-effects occurred among 79.1% of women but only in 61.2% of men [37]. As migraine and tension headaches are more prevalent in women than in men (38, 39), such a difference may affect the likelihood of post-vaccination headache among women compared to men.
The current study found a significant difference in the prevalence of headache according to vaccine brand used among different countries. As shown, the highest rate of headache was after AstraZeneca vaccination, followed by Sputnik V; however, the literature reviewed (Table 5) did not differentiate between vaccines in relation to post-vaccination headache. For example, the rate of post-vaccination headache following vaccination by Pfizer-BioNTech ranged from 6.0% to 48.7%. Additionally, information about the incidence of side-effects of brands such as Sinopharm and Sputnik V vaccines has been limited.
There is no documented and comprehensive explanation of the pathomechanisms of headache following vaccination against COVID-19. Some believe that such a headache may originate from the spike protein of the virus used to produce the vaccine [40]. Others have speculated that the immune response triggered by such proteins plays a significant role [41]. This means that flaring pro-inflammatory cascades and secretion of cytokines and prostaglandins may be responsible for vaccination-related headache and other concurrent symptoms [42, 43]. It should be noted that the technologies and materials used for creating the vaccines could play a role in post-vaccination headache. This should be evaluated in further studies.
One limitation of the study was that some of the most commonly used brands globally, such as Pfizer, were not widely available in Iran; thus was not possible to evaluate the post-vaccination headache for these brands. Additionally, the pattern of headache among the healthcare workers as participants was not evaluated during the first exposure to COVID-19.