The present study is the first to evaluate the occurrence of headache in individuals who have been vaccinated after recovering from an initial infection by COVID-19. In these participants, there were no signs of reinfection following vaccination. However, the predominant finding in the present study was that about one-third of vaccinated individuals showed evidence of different types of headache following vaccination. A review of the literature (Table 5) shows that the post-vaccination headache ranged from 19.5–49.4% regardless of the type of vaccine or the target population (general population or healthcare employees).
Table 5
Review of studies on post-vaccination headache
Author, Country
|
Study type
|
Population size
|
Targeted population
|
Type of vaccine
|
Headache prevalence
|
Serwaa, Ghana [13]
|
cross-sectional
|
654
|
personnel
|
AstraZeneca
|
27.3% 178
|
García-Azorín,
Norway [14]
|
cross-sectional
|
77
|
general
|
Non-replicant adenovirus vector-based vaccine
|
49.4% 38
|
Ekizoglu, Turkey [15]
|
cross-sectional
|
1819
|
personnel
|
Pfizer
|
30.6% 556
|
Göbel, Germany [16]
|
cohort
|
12000
|
general
|
AstraZeneca
|
19.5% 2340
|
Sekiguchi, Japan [17]
|
cross-sectional
|
171
|
personnel
|
Pfizer
|
39.7% 68
|
Hatmal, Jordan [18]
|
cross-sectional
|
2213
|
general
|
Sinopharm, AstraZeneca, Pfizer-BioNTech
|
46.9% 1038
|
Solomon, Ethiopia [18]
|
cross-sectional
|
672
|
personnel
|
AstraZeneca
|
50.2% 337
|
Adam,
Saudi Arabia [19]
|
cross-sectional
|
330
|
general
|
Pfizer, AstraZeneca
|
24.2% 86
|
Pokharel, Nepal, [20]
|
cross-sectional
|
220
|
personnel
|
Covishield
|
19.5% 43
|
Klugar,
Czech Republic [21]
|
cross-sectional
|
599
|
personnel
|
Pfizer, AstraZeneca
|
53.6% 321
|
Saeed, UAE [22]
|
cross-sectional
|
1102
|
general
|
Sinopharm
|
10.0% 110
|
Almufty, Iraq [23]
|
cross-sectional
|
1012
|
general
|
Pfizer, AstraZeneca, Sinopharm
|
34.0% 344
|
Quiroga, Spain [24]
|
cross-sectional
|
708
|
general
|
Pfizer
|
34.0% 240
|
Cuschieri, Malta [25]
|
cross-sectional
|
1480
|
personnel
|
Pfizer
|
44.2% 655
|
Kaya, Turkey [26]
|
cohort
|
329
|
personnel
|
Pfizer
|
16.8%, 56
|
Raid,
Czech Republic [27]
|
cross-sectional
|
92
|
personnel
|
AstraZeneca
|
29.3%, 27
|
Abu-Hammad,
Jordan [28]
|
cross-sectional
|
409
|
personnel
|
Pfizer, AstraZeneca, Sinopharm
|
42.0% 172
|
Lee, Korea [29]
|
cross-sectional
|
265
|
personnel
|
Pfizer
|
48.7% 129
|
Zhang, China [30]
|
cross-sectional
|
1526
|
personnel
|
Pfizer
|
6.0% 92
|
El-Shitany,
Saudi Arabia [31]
|
cross-sectional
|
124
|
general
|
Pfizer
|
22.5% 28
|
Kadali, USA [32]
|
cross-sectional
|
1245
|
personnel
|
Pfizer
|
45.4% 565
|
Kim, Korea [33]
|
cross-sectional
|
1403
|
personnel
|
Pfizer, AstraZeneca
|
47.4% 665
|
Our study, Iran
|
cross-sectional
|
334
|
personnel
|
AstraZeneca, Sinopharm, Sputnik V, Bharat Covaxin, COVIran Barekat
|
39.2% 131
|
Meta-analysis of the relevant studies indicates an overall prevalence of 31.2% (95% CI; 25.3–37.9%) for headache in all populations and a specific prevalence of 34.6% (95% CI; 27.4–42.5%) among healthcare employees. There was considerable heterogeneity across the studies (I2 values of 99.037 and 98.343, respectively; p < 0.001; see Figs. 2 and 3) [13–33]. These divergent results might be due to the type of vaccine used as well as differences among the populations enrolled in the studies. It could be concluded that about one-third of individuals that had been vaccinated against COVID-19 experienced various intensities of headache, with a slightly higher incidence rate among healthcare employees.
Interestingly, in the present study, 83.2% of participants reported headache within the first 24 h after vaccination and a mean time between vaccination and headache onset was 26.78 ± 6.93 h. Göbel et al. [16] reported that the latency between vaccination and the onset of a headache was, on average, 18.0 ± 27.0 h. More than half of the participants experienced a headache in less than 10 h and 80% within 24 h after vaccination, which is similar to the findings of the present study. Similarly, Sekiguchi et al. [17] reported that the median onset of headache after the first and second inoculations were 10 and 12 h, respectively, and the mean durations of headache were 4.5 and 8.0 h, respectively. In the present study, the mean duration to onset of headache after vaccination was 4.22 ± 1.26 h. In 50% of the participants, the headache duration was less than 6 h and, in 80%, it was less than 22 h. Göbel et al. [16] reported a mean headache duration of 14.2 + 21.4 h.
The current study recorded generalized headache in about one-third of participants. Göbel et al.[16] reported that the headache appeared bilaterally in 73.1% of their subjects and that the most prominent zones were the forehead (38.0%), followed by the temple region (32.2%). Sekiguchi et al. [17] reported a rate of bilateral headache in the control group without headache to be 78.8%, for the migraine group to be 62.%, and for the non-migraine headache group to be 75.9%. The participants in the present study primarily experienced pressure type headaches. Göbel et al. [16] reported pressure and dull pain in 49.2% and 40.7% of subjects, respectively. Ekizoglu et al. [15] reported throbbing headache in 40.1% and pressure type headache in 30.4%.
Another important finding was that the occurrence of a post-vaccination headache also was potentially influenced by the factors of female gender and severity of initial COVID-19 illness. Overall, it appears that because migraine and tension headache are more prevalent in females than males [34, 35], this could have affected the greater likelihood of post-vaccination headache in females.
In the current study, there was a significant difference in the prevalence of headache by vaccine type among the different communities. As shown, the highest rate of headache was recorded after vaccination with AstraZeneca, followed by Sputnik V. The literature review (Table 5) did not differentiate between vaccines with regard to incidence of headache. For example, the rate of post-vaccination headache following the use of Pfizer ranged broadly from 6.0–48.7%. However, independent information about the incidence of brands such as Sinopharm and Sputnik V is limited.
There is no documented, 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[36]. Others propose that the resulting immune response triggered by such proteins plays a significant role[37]. In other words, it could be that flaring pro-inflammatory cascades and secretion of related cytokines and prostaglandins may be responsible for the onset of vaccination-related headache and other concurrent symptoms[38, 39]. It also is possible that the technologies and the materials used for creating vaccines may have a role in the onset of post-vaccination headaches. This should be evaluated in future studies.
A limitation of this study was that some of the most commonly used brands globally, such as Pfizer, were not available in Iran, making it impossible to evaluate their post-vaccination headache statistics. Additionally, the pattern of headache among healthcare employees was not evaluated after their exposure to COVID-19.