Headache After Vaccination: An Update on Recent Clinical Trials and Real-World Reporting

Abstract

Purpose of Review

The aim of this review is to characterize headache as a vaccine adverse event (VAE) in clinical trials.

Recent Findings

Of the recent phase III vaccine RCTs (non-COVID-19), 53 studies reported on headache (13 infectious agents). The median rate (interquartile range) of headache was 15.6% (IQR: 9.6–37.6%). Of these, 24.5% of the RCTs reported headache greater in the vaccine group compared to the placebo/control group. In the herpes zoster vaccination trials, headache was more common in all active groups: median rate 33.9% (IQR: 29.7–40.5%) as compared to placebo: median rate 17.7% (IQR: 15.4–23.8%). Influenza and HPV vaccination trials were the 2nd and 3rd most common to have headache as a VAE. Of the 6 widely distributed COVID-19 vaccinations, median rate of post-vaccination headache was 39% (IQR: 28–50%).

Summary

Headache is a common VAE in vaccine trials. Standardized grading methods, predictors of persistence, and treatment regimens are warranted.

Introduction

Vaccine programs are one of the most effective public health measures to control the threat of communicable diseases. Phase III clinical trials are performed to study the effectiveness and safety of novel vaccines, with comparison to the gold standard, an established vaccine, or placebo. Vaccine adverse events (VAEs) are important to evaluate. In one meta-analysis, vaccine safety was among the top reasons for COVID-19 vaccination hesitancy in healthcare workers [1]. In post-licensure surveillance, headache is one of the most reported VAEs, which is especially relevant given the high burden of headache disorders in the general population [2].

The aim is to characterize headache as a VAE and summarize the quality of reporting in randomized controlled trials (RCTs). There is focus on COVID-19 vaccinations, due to the novelty of mRNA-based technologies and nanovaccines. As post-vaccination headache is not defined in the International Classification of Headache Disorders (ICHD-3), we also characterize a case presentation, possible mechanisms, and clinical relevance.

Methods

We conducted a search of RCTs involving vaccines from November 30, 2018 through November 30, 2021 which resulted in 1501 articles (PubMed). From these, 1058 were randomized controlled trials (RCTs), of which 211 were phase III RCTs. Of these 211 phase III RCTs, articles were excluded if they pertained to experimental tumor vaccines or mentioned vaccines but did not test safety and immunogenicity. According to these criteria, 185 studies were obtained. We included COVID-19 RCTs but limited our evaluation to those with FDA approval within the USA. Medians, 25th, and 75th percentiles describing rate of vaccination headache and rate of headache due to placebo were calculated.

We reviewed 11 RCTs published within the last 2 years of six widely distributed COVID-19 vaccinations.

Headache as an Adverse Event in Vaccination Trials

In the majority of the 148 RCTs (non-COVID-19) reviewed, data on headache as a VAE was either not reported or nonspecific. Ten (6.8%) of the studies reported only the most and least common VAE without mention of all VAEs that occurred.

Of the 148 reviewed studies, headache as a VAE was measured in 56. These 56 studies included testing of vaccines against 13 different infectious agents in total. Fifty-three of the studies reported the headache data (Table 1), while three did not report. Of the 53 which reported headache data, 34 RCTs had active comparison groups while the remaining 19 were placebo controlled.

Table 1.

Headache as an adverse event following vaccinations in clinical trials

	Vaccine type	Headache reported in vaccine group	Headache reported in placebo group	Headache grading/severity	Overall headache results/key findings
1. Ward et al. [3]	Influenza vaccine	• 18–64 years Quadrivalent virus-like particle vaccine: 1020/5064 (20.1%) • 65 plus years Quadrivalent virus-like particle vaccine: 624/6352 (9.8%) • 65 plus years Quadrivalent inactivated vaccine: 656/6366 (10.3%)) 967/5072 (19.1%)	• 967/5072 (19.1%)	• No grading system reported	• Headache was greater in the quadrivalent virus-like particle vaccine group than in the placebo group but headache was greater in the placebo group than in the quadrivalent virus-like particle vaccine and quadrivalent inactivated vaccine At least one life threatening or vaccine associated headache: • Quadrivalent virus-like particle vaccine: 17 (0.3%) • Quadrivalent virus-like particle vaccine: 10/6352 (0.2%) • Quadrivalent inactivated vaccine: 11/6366 (0.2%) • Placebo: 23/5072 (0.5%)
2. Chang et al. [4]	Influenza vaccine	IIV4-HD influenza vaccine group reported higher headache than IV3-HD influenza vaccine	• No placebo reported	• Fewer than 1% subjects reported grade 3	• Headaches began within 3 days of vaccination • Headaches resolved within 3 days onset
3. Vesikari et al. [5]	Influenza vaccine	• QIV vaccine group: 24.0% • TIV vaccine group: 20.9%	• No placebo reported	• No grading system reported	• Local/systemic reactions were analyzed within 7 days post-vaccination • There were no significant differences in reporting of local and systemic adverse reactions between the two vaccine arms • Headache was one of the most common systemic reactions along with fatigue/tiredness and irritability/fussiness
4. Endo et al. [6]	Influenza vaccine	MA group: 132/369 (35.8%) CI [30.9–40.9]	• No placebo group reported	• Grade 3 severity headache: 10.3% Incidence CI [0.0–1.5] • Drug related grade 3 headache: 1 (0.3%) CI [0.0–1.5]	• Headache solicited adverse drug reactions: 131 (35.5%) CI [36.6–40.6] • Headache was the second highest solicited systemic adverse events along with myalgia (30% and 40%)
5. Chu et al. [7]	Influenza vaccine	• IIV4: 8/1160 (0.69%) • IIV3-BV: 4/580 (0.69%) • IIV3-BY: 1/580 (0.17%)	• No placebo group reported	• No grading system reported	• There was no statistical significance of headache among the three vaccine groups with a P-value: 0.4085 • The most common local reaction was pain while fever was the most common systemic reaction
6. Lan et al. [8]	Influenza vaccine	• 121/740 (16.4%) CI [13.76–19.22]	• 29/148 (19.6%) CI [13.53–26.91]	• No grading system reported	• There was no significant differences between vaccine receiving and placebo receiving groups with a P-value of 0.3369 • Headache in the placebo group was greater than headache in the vaccine group
7. Loebermann et al. [9]	Influenza vaccine	Younger age group: 17% Older age group: 10%	• No placebo group reported	• No grading system reported	Headache was the most common solicited systemic adverse event in both the younger and older group
8. Sarkar et al. [10]*	Influenza vaccine	Cohort 1 and 2: less than 5 VAEs among reported solicited VAEs	• No placebo group reported	• No grading system reported	Headache was combined with pain, redness, swelling, fever, loss of appetite, fatigue, muscle ache, joint pain, and shivering to make up the solicited adverse events category of adverse events
9. Ward et al. [11]*	Influenza vaccine	At least one subgroup: over 20% Headache within adverse events: 11/281 (3.9%) Overall participants: 356/1200 (29.7%)	• No placebo group reported	• No grading system reported	• Headache was one of the most reported solicited systemic reactions along with muscle aches and fatigue • Incidence rates of TEVAEs were similar across all influenza lot groups
10. Song et al. [12]	Influenza vaccine	GC3110A vaccine: 91/647 (14.1%)	• Control 1 TIV: 46/325 (14.2%) • Control 2 TIV: 40/326 (12.3%)	• No grading system reported	Headache was greater in the vaccine group than the control 2 TIV group but was less than headache in the control 1 TIV group • There was no significant difference in headache across all groups with a P-value: 0.65
11. Beran et al. [13]*	Influenza vaccine	Systemic solicited VAEs influenza vaccine group: 128/665 (19.2%)	• Systemic solicited VAEs non-influenza comparator group: 109/667 (`6.3%)	• 1 severe headache was reported	• Incidence of headache among solicited VAEs vaccine group: 10.8% • Incidence of headache among solicited VAEs non-comparator vaccine group: 8.3% • Headache was combined with arthralgia, chills, diarrhea, fatigue, fever, loss of appetite, myalgia, nausea, and vomiting to make up the solicited systemic adverse events category • Headache was greater in the vaccine group than placebo group
12. Yamazaki et al. [14]*	Pneumococcal conjugate vaccine	• Systemic events 6 to 17 year olds: 31/51 (60.8%) • Systemic events 18 to 64 year olds: 85/145 (58.6%)	• No placebo group reported	• 1 severe headache was reported	• Most common systemic events were fatigue, muscle pain, and headache • Headache in 6 to 17 year old group made up 35% of all systemic events • Headache in 18 to 64 year olds made up 34% of all systemic events
13. Klein et al. [15]*	Pneumococcal conjugate vaccine	• 20-valent pneumococcal conjugate vaccine: Approx. 38% of systemic events • 13-valent pneumococcal conjugate vaccine: Approx. 40% of systemic events	• No placebo group reported	• No grading system reported	Headache was combined with fatigue, muscle pain, joint pain, and fever to make up the systemic events category • VAEs reported were similar between both vaccine groups • Infections were the most common VAE reported post-vaccination
14. Song et al. [16]*	Pneumococcal conjugate vaccine	• V114 vaccine: 14.1% and 12.1% • PCV13 vaccine: 12.7% and 12.6%	• No placebo group reported	• Headaches were defined as mild, moderate, or severe	Headaches were combined with muscle pain, myalgia, joint pain, arthralgia, and fatigue to make up the systemic adverse events category • Participants who experienced at least 1 VAE were comparable in both vaccine groups
15. Bastidas et al. [17]	Herpes zoster	302/901 (33.5%) CI [30.4–36.7]	• 166/892 (18.6%) [16.1–21.3]	• Grade 3 vaccine: 26/901 (2.9%) [1.9–4.2] • Grade 3 placebo: 10/892 (1.1%) [0.5–2.0]	• Headache in the vaccine group is greater than headache in the placebo group • Headache VAEs were higher after second vaccine dose
16. Dagnew et al. [18]*	Herpes zoster	Within solicited general symptoms: 206/278 (74.1%)	• 134/274 (48.9%)	Grade 3 headaches: 43/278 (15.5%)	Headache were combined with fatigue, myalgia and local injection site adverse events to consist of solicited general symptoms • Headache in the vaccine group was greater than the placebo group
17. Vink et al. [19]*	Herpes zoster	RZV vaccine: 45/112 (40%)	42/110 (38%)	• Grade 3 vaccine: 5% • Grade 3 placebo: 2%	• Headache was combined with fatigue, myalgia and local injection site adverse events • Headache in the vaccine group was greater than the placebo group
18. Curran et al. [20]	Herpes zoster	• Non-frail RZV group: 838 (41.8%) • Pre-frail RZV group: 676 (34.3%) • Frail RZV group: 147 (30.1%) • Unknown RZV group: 6 (28.6%)	• Non-frail placebo group: 287 (14.1%) • Pre-frail placebo group: 311 (15.8%) • Frail placebo group: 89 (19.0%) • Unknown placebo group: 3 (16.7%)	• Non-frail RZV grade 3 severity: 74 (3.7%) • Pre-frail RZV grade 3 severity: 53 (2.7%) • Frail RZV group grade 3 severity: 17 (3.5%) Unknown RZV group grade 3 severity: 0 • Non-frail placebo group grade 3 severity: 8 (0.4%) • Pre-frail placebo group grade 3 severity: 12 (0.6%) • Frail placebo group grade 3 severity: 10 (2.1%) • Unknown placebo group grade 3 severity: 0 (0%)	• Headache in all vaccine groups greater than all corresponding placebo groups
19. Ocran-Appiah et al. [21]	Herpes zoster	Overall: 679/8687 (7.8%) CI [7.3–8.4] • 50–59 year olds: 162/1040 (15.6% CI [13.4–17.9] • 60–69 year olds: 242/2189 (11.1%) CI [9.8–12.4] • 70–79 year olds: 205/3349 (6.1%) CI [5.3–7.0] 80 year olds and older: 70/2109 (3.3%) CI [2.6–4.2]	• No placebo group reported	• Overall grade 3: 98 (1.1%) CI [0.9–1.2] • 50–59 year olds grade 3: 28 (2.7%) CI [1.8–3.9] • 60–69 year olds grade 3: 34 (1.6%) CI [1.1–2.2] • 70–79 year olds grade 3: 28 (0.8%) CI [0.6–1.2] • 80 year olds and older grade 3: 8 (0.4%) CI [1.2–0.7]	• During 30 day post-vaccination period 5175 (59.6%) participants reported at least 1 VAE, 4422 (50.9%) were vaccine related • Headache was one of most common VAEs including injection site reactions and pyrexia Headache related to vaccine • Overall vaccine related: 563 (6.5%) CI [6.0–7.0 • 50–59 year olds vaccine related: 135 (13.0%) CI [11.0–15.2] • 60–69 year olds vaccine related: 207 (9.5%) CI 8.3–10.8 • 70–79 year olds vaccine related: 164 (4.9%) CI [4.2–5.7 • 80 year olds and older vaccine related: 57 (2.7%) CI [2.1–3.5]
20. Schmader et al. [22]*	Herpes zoster	37.5%	• No placebo group reported	Grade 3: 2.8% of vaccine participants	• Headache was most common solicited systemic VAE along with fatigue and myalgia • Post-vaccine 1: 30% headache • Post-vaccine 2: 38% headache
21. Schmader et al. [23]*	Herpes zoster	Overall participants: 28.3%	• No placebo group reported	• No grading system reported	• 6.5% of participants experienced Headache pre-vaccination • Headache was one of the most common solicited systemic reactions along with fatigue and myalgia
22. Lopez-Fauqued et al. [24]*	Herpes zoster	• RZV group: 954 (6.51%) CI [6.12–6.93]	• 445 (3.04%) CI [2.76–3.33]	• Grade 3 RZV group: 99 (0.7%) CI [0.5–0.8] • Grade 3 placebo group: 27 (0.2%) CI [0.1–0.3]	• Headache related to vaccine: 729 (5%) CI [4.6–5.3] • Headache related to placebo: 167 (1.1%) CI [1.0–1.3] • Headache in the vaccine group was greater than the placebo group
23. Mikamo et al. [25]	HPV vaccine	• 2/554 (0.4%)	• 7/559 (1.3%)	• No grading system reported	Headache in the placebo group was greater than the vaccine group • Headache was one of the most common vaccine-related VAEs along with pyrexia
24. Joura et al. [26]	HPV vaccine	• Women 16–26 years of age: 72/570 (12.6%) Women 27–45 years of age: 87/640 (13.6%)	• No placebo group reported	• No grading system reported	• Headache was one of the most common systemic VAEs including pyrexia and fatigue • Headache related to vaccine 16–26 year olds: 12.6% • Headache related to vaccine 27–45 year olds: 13.6%
25. Chen et al. [27]	HPV vaccine	218/1499 (14.5%)	193/1496 (12.9%)	Vaccine group severity • Grade 1: 203 (13.5%) • Grade 2: 14 (0.9%) • Grade 4: 1 (0.1%) Placebo group severity • Grade 1: 176 (11.7%) • Grade 2:17 (1.1%) • Grade 4: 0 (0%)	Difference in percent of the vaccine vs placebo group: 1.6% CI [− 0.8–4.1] Headache in the vaccine group was greater than the placebo group
26. Thiem et al. [28]	HPV vaccine	Overall: 7/200 (3.5%) headache VAEs	• No placebo group reported	• No grading system reported	• Headache was one of the most common systemic VAEs including dizziness and nasopharyngitis • Vaccine related dizziness and headache was reported in one participant — mild in intensity and resolved with no interruption to dosing schedule
27. Su et al. [29]	HPV vaccine	• Vaccine lot 1: 78/1229 (6.3%) • Vaccine lot 2:87/1229 (7.1%) • Vaccine lot 3: 94/1228 (7.7%)	• No placebo group reported	• 0 grade 3 headaches reported	P-value: 0.45 indicated no significant differences of headache among participants who received the three different lots of HPV vaccines
28. Dhingra et al. [30]	Meningococcal vaccine	• MenACYW-TT vaccine group: 27.9% (730/2618) • MCV4-DT vaccine group: 27.8% (171/615)	• No placebo group reported	• No specific grading system reported	• Headache was one of the most common solicited systemic reactions including myalgia • The majority of solicited reactions began within 3 days post-vaccination and resolved in 1 to 3 days • The majority of systemic reactions were a grade 1 or 2 in severity
29. Esteves-Jaramillo et al. [31]	Meningococcal vaccine	• MenACYW-TT vaccine group: 84/442 19.0 [15.5–23.0] • MPSV4 vaccine group: 66/451 14.5% [11.5–18.2]	• No placebo group reported	• Grade 3 MenACYW-TT: 3/442 0.7 [0.1–2.0] • Grade 3 MPSV4: 3/451 0.7% [0.1–1.9]	• Headache was one of the most common solicited systemic reactions along with myalgia and malaise
30. Group MMRS et al. [32]	Meningococcal vaccine With and without varicella/DTaP	• Sub-cohort 1 MMR-RIT: 0 • Sub-cohort 1 MMRII: 2 (0.7%) • Sub-cohort 2 MMR-RIT: 1 (0.1%) • Sub-cohort 2 MMRII: 0(0%) • Sub-cohort 3 MMR-RIT:0 (0%) • Sub-cohort 3 MMRII: 0 (0%)	• No placebo group reported	• Grade 3 sub-cohort 1 MMR-RIT: 0 (0%) • Grade 3 sub-cohort 1 MMRII: 0 (0%) • Grade 3 sub-cohort 2 MMR-RIT: 0 (0%) • Grade 3 sub-cohort 2 MMRII: 0 (0%) • Grade 3 sub-cohort 3 MMR-RIT: 0 (0%) • Grade 3 sub-cohort 3 MMRII: 0 (0%)	• Solicited VAEs were comparable across all vaccine groups
31. Baccarini et al. [33]	Meningococcal conjugate vaccine	• MenACYW-TT vaccine group: 61/487 12.5% CI [9.7–15.8] • MenACWY-CRM vaccine group: 56/486 11.5% CI [8.8– 14.7]	• No placebo group reported	• No grading system reported	• Headache measured was defined as pain or discomfort in the head or scalp but did not include migraine • Proportion of solicited systemic reactions and injection site reactions was similar in both vaccine groups • No systemic VAEs were considered related to vaccine in each vaccine group
32. Nolan et al. [34]	Meningococcal conjugate vaccine	• Primed group: 146/266 (55%) • Naïve group: 125/254 (49%)	• No placebo group reported	• Severe headache Primed group: 18/266 (7%) • Severe headache Naïve group: 19/254 (7%)	• Headache was one of the most frequently reported solicited systemic VAEs • Over 49% of participants experienced headache
33. Vesikari et al. [35]	Meningococcal conjugate vaccine	• MenACWY-TT toddler group: 4/67 (6.0%) • MenC-CRM toddler group: 1/67 (6.3%) • MenACWY-TT children group: 3/77 (3.9%) • MenACWY-PS children group: 0 (0%)	• No placebo group reported	• No grading system reported	• Headache was reported by 20.9–31.3% of participants across all study groups • Severe general events including headache were reported by less than or equal to 6.8% of subjects in each study group
34. Anez et al. [36]	Meningococcal conjugate vaccine	• MenACYW-TT vaccine group: 151/398 (37.9%) • MCV4-DT vaccine group: 156/402 (38.8%)	• No placebo group reported	• No specific grading system reported	Headache was the most common solicited systemic reaction • All headaches were either grade 1 or grade 2 and transient
35. Vesikari et al. [37]*	Meningococcal conjugate vaccine	• Primary series vaccine group: 77% after 0, 2, and 6 months • Booster group: 40% after 0, 2, and 6 months	• No placebo group reported	• No grading system reported	• Headache was combined with fever, vomiting, diarrhea, fatigue, chills, muscle pain, and joint pain to make up the systemic events category • Between 68.8 and 76.6% of subjects reported at least one systemic event depending on the study group after 0, 2, and 6 months
36. Tipton et al. [38]	Meningococcal conjugate vaccine	• Primed vaccine group: 31% • Naïve vaccine group: 20%	• No placebo group reported	• No grading system reported	• Possibly vaccine related medically attended VAEs associated with headache were reported in 3 participants in the primed vaccine group • Headache onset was on day 1 followed by myalgia at day 4 and anxiety onset at day 22
37. Nolan et al. [39]*	Meningococcal conjugate vaccine	• Less than 24.6% of all participants • HibMenC vaccine: 24% • HiB + MCC vaccine: 20%	• No placebo group reported	• Grade 3 HiB + MCC: about 5%	• Headache was one of the most common solicited general symptom along with fatigue and gastrointestinal symptoms • No VAEs were considered to be related to vaccine, study procedures, or concomitant medication
38. Jiang et al. [40]*	Varicella vaccine	5 (0.84%)	2 (0.67%)	Vaccine: • Grade one: 4 (0.67%) Headache • Grade 2: 1 (0.17%) • Grade 3: 0 (0%) Placebo: • Grade 1: 1 (0.34%) • Grade 2: 0 (0%) • Grade 3: 1 (0.34%)	Headache in the vaccine group was greater than the placebo group
39. Asatryan et al. [41]	Combined diphtheria, tetanus, pertussis vaccine	24.9% CI [20.9–29.3)	• No placebo group reported	• Grade 3: 2.1% [1.0–3.9]	• Headache related to the vaccine group: 18.9 CI [15.3–22.9] • Grade 3 headache was considered if headache prevented normal activity • Headache was one of two most common solicited VAEs • In participants 65 years and older, headache was unrelated to vaccine in 50% of cases
40. Vesikari et al. [42]*	Hepatitis B vaccine	• Tri-antigenic: 249/572 (31.3%) • Mono- antigenic: 238/811 (29.3%)	• No placebo group reported	• No specific grading system reported	There was no significant difference in headache reported between the two vaccine groups with a P-value of 0.678
41. Chaparro et al. [43]*	Hepatitis B vaccine	• Fendrix vaccine group: 17% • Engerix vaccine group: 4.3%	• No placebo group reported	• No grading system reported	Data reported only specified 18 participants presented mild VAEs related to the vaccine
42. Lee et al. [44]*	Adult tetanus diphtheria vaccine	• GC1107 vaccine: 22/250 (8.80%)	• Control group: 21/125 (16.80%)	• No grading system reported	• Incidence of all reported VAEs in the GC1107 vaccine group: 84.8% • Incidence of reported VAEs in the control group: 88.0% • Headache was grouped with pain, pressure, irritation, swelling, fever, vomiting, nausea diarrhea, fatigue and myalgia and reported as solicited VAEs Headache in the control group was greater than headache in the GC1107 vaccine group
43. Arredondo et al. [45]*	Concomitant dengue and HPV vaccine	• Concomitant vaccine group: 185/231 (80.1%) • Sequential Concomitant vaccine group: 196/234 (83.8%) • Sequential vaccine group: 129/151 (85.4%	• No placebo group reported	• No grading system reported	Headache was combined with fever, malaise, myalgia, and asthenia to make up solicited systemic reactions category • There was no difference in safety outcomes across vaccine groups
44. Shen et al. [46]	Rabies vaccine	• Zagreb group: 33/600 (5.5%) • Essen group: 37/598 (6.2%)	• 27/600 (4.5%)	• No grading system reported	• 97/598 (5.4%) of total adverse events were due to headache • Headache in both vaccine groups was greater than control
45. Matson et al. [47]*	Rabies vaccine	• HRIG vaccine group: 8/59 13.6% • Comparator vaccine group: 9/59 (15.3%) • Drug-related TEVAEs in HRIG: 3.4% • Drug-related TEVAEs in comparator group: 5.1%	• No placebo group reported	• No grading system reported	• Overall 17/118 (14.4%) reported headache in the trial • Overall 5/118 (4.2%) of participants reported drug related headache
46. de Bruyn et al. [48]*	C. diff vaccine candidate	• 302/1196 (25.3%) CI [21.5–26.4]	• 115/586 (19.6%) CI [16.5–23.1]	• No grading system reported	• Headache was combined with fever, malaise, myalgia, arthralgia to make up the systemic reaction category • Headache in the vaccine group greater than placebo
47. McCarty et al. [49]*	Oral cholera vaccine	• 60/296 (20.3%)	• 30/99 (30.3%)	Vaccine group severity • Mild headache: 41/296 (13.9%) • Moderate headache: 17/296 (5.8%) • Severe headache: 2/296 (0.7%) Placebo group severity • Mild headache: 19/99 (19.2%) • Moderate headache: 11 (11.1%) • Severe headache: 0 (0%)	• Headache in the placebo group was greater than the vaccine group • Headache in the placebo group was more severe with a greater percentage of participants experiencing mild and moderate headaches but severe headaches were only experienced in the vaccine group
48. Gray et al. [50]	HIV vaccine	• 0 (0%)	• 15.7%	• No grading system reported	Headache in the placebo group was greater than in the vaccine group
49. Brogan et al. [51]*	Canakinumab vaccine	CAPS vaccine: 6/17 (35%)	• No placebo group reported	• No grading system reported	• Headache was reported as a milder repeat symptom along with fever, chills, malaise, intense fatigue, conjunctivitis, diffuse rash, and generalized limb pain • Headache and migraine were reported equally
50. Riveau et al. [52]*	Schistosomiasis vaccine	23/787 (2.92%)	28/733 (3.82%)	• No grading system reported	Headache in the placebo group was greater than in the vaccine group
51. Markman et al. [53]	Pregabalin vaccine	12/274 (4.4%)	• 8/265 (3.0%)	• No grading system reported	Headache in the vaccine group was greater than the placebo group
52. Song et al. [54]	Hantaan virus vaccine	• 1st dose vaccine group: 21 (6.8%) • 2nd dose vaccine group: 12 (3.88%) • 3rd dose vaccine group: 12 (3.88%) • Booster vaccine group: 14 (4.53%)	• No placebo group reported	• No grading system reported	• Injection site pain and myalgia were the most frequently local and systemic VAEs • No vaccine-related severe VAE were reported • No significant differences in headache were noted with a P-value of 0.1818 across all doses • No significant differences in headache were noted when comparing headache in each subsequent dose to the primary dose
53. Halperin et al. [55]	Ebola virus envelope glycoprotein vaccine	ZEBOV-GP recipients reported higher rates of injection site pain, erythemia, swelling, fever, headache, arthralgia, pain, chills and fatigue recipients	• No placebo group reported	• No grading system reported	• The majority of reported VAEs were considered mild to moderate • No reported VAEs were related to vaccine

*Headache data reported from supplemental table and other information

Measurement and Report of Headache Occurrence and Frequency

Of these studies, about one fourth (40/148; 27.0%) reported headache as an individual VAE. Less (13/148; 8.8%) reported headache as combined with other common VAEs (including fatigue, fever, and myalgias): These were defined together as “solicited VAEs,” “solicited systemic VAEs,” “systemic events,” “solicited general symptoms,” “general symptoms,” “solicited systemic reactions,” and “systemic reaction categories.” Often, the specific frequency of headache was recorded in supplemental tables and materials (Table 1).

Measurement and Report of Headache Severity

Of the 53 studies reporting headache, 16 measured the intensity of headache as a grading scale. One study defined four grades (the most severe headache outcome as “grade 4”) [27], while all others defined three grades (the most severe and debilitating outcome as “grade 3”). Not all grading scale data was reported: One study reported grades 1, 2, and 4 but did not report grade 3 [27], and 14 studies reported grade 3 only (Table 1).

Additionally, two studies specified headache severity as “mild,” “moderate,” or “severe,” rather than using a grading scale [16, 49]. Three studies specified only when headaches were considered “severe” [13, 14, 34].

Within the RCTs with active comparison groups, 9 described headache using a grading severity system, 3 described headache using severity measures, and 22 did not specify grade/severity. Within the 19 placebo-controlled RCTs, 7 described headache using a grading system, 2 provided headache severity measures, and 10 did not specify headache grade/severity.

Measurement and Report of Headache Severity in COVID-19 Vaccination Studies

Because of significant interest due to the COVID-19 pandemic, we evaluated the FDA approved COVID-19 vaccinations separately. Among the six COVID-19 vaccine RCTs reviewed, all but one, CoronaVac, reported data on headache severity. However, the five trials that do report severity also lack consistency. The RCT involving COVID-19 vaccine BNT162b2 classified headache severity outcomes as “any,” “mild,” “moderate,” “severe,” and grade 4 among the “5 to 11,” “12 to 15,” “16 to 55,” and “55 and greater” age groups [56]. The RCT involving vaccine mRNA-1273 categorized headache severity in grades 1–4 and “any” among the “18 to 65” and “65 and greater” age groups [57, 58]. The RCT involving vaccine Ad26 CoV2.S only reported headache severity with grades 3 and 4 and these were assessed in the “18 to 59” and “59 and greater” age groups [59]. This study did not report data on headaches with a grade severity of 1 or 2. The RCT involving ChAdOx1nCoV-19/ADZ1222 vaccine also defined headache severity as “any,” “mild,” “moderate,” and “severe” but indicated whether headaches led to hospitalization across the “18 to 55,” “56–69,”, and “69 and greater” age groups [60]. Similarly, to the mRNA-1273 vaccine, the RCT involving NVX-CoV2373 also defined headache severity as “any” and grades 1–4, but these were only reported in the “18 to 84” age group [61, 62]. These severity definitions were assessed within 7 days of each vaccination dose except for the Ad26 CoV2.S vaccine RCT, which only administered one dose. All six studies reported headache as an individual VAE and were considered one of the “systemic” VAEs (Table 2).

Table 2.

Headache as an adverse event following COVID-19 vaccinations in clinical trials

Study	Vaccine/technology	Trial details	Within 7 days of first dose	Within 7 days of second dose	Overall headache results
1. Polack et al. [56, 63–65]	BNT162b2 Lipid nanoparticle-encapsulated nucleoside-modified mRNA encoding the prefusion stabilized full-length SARS-CoV2 spike protein [63, 66]	Randomized, observer-blinded, placebo-controlled trial of efficacy and safety Conducted in multiple nations	Age 5–11 years: • Any: 22.4% (placebo 24.1%) • Milda: 16.5% (placebo 17.5%) • Moderate: 5.8% (placebo 6.0%) • Severe: 0.1% (placebo 0.5%) • Grade 4: 0% (placebo 0%) Age 12–15 years: • Any: 55.3% (placebo 35.1%) • Mild: 32.0% (placebo 22.7%) • Moderate: 22.3% (placebo 11.6%) • Severe: 1.0% (placebo 0.8%) • Grade 4: 0% (placebo 0%) Age 16–55 years: • Any: 41.9% (placebo 33.7%) • Mild: 27.4% (placebo 20.3%) • Moderate: 19.9% (placebo 12.6%) • Severe: 1.4% (placebo 0.5%) • Grade 4: 0% (placebo 0%) Age > 55 years: • Any: 25.2% (placebo 18.1%) • Mild: 19.3% (placebo 13.5%) • Moderate: 22.9% (placebo 24.6%) • Severe: 0.4% (placebo 0.9%.) • Grade 4: 0% (placebo 0%)	Age 5–11 years: • Any: 28.0% (placebo 18.6%) • Mild: 18.7% (placebo 12.6%) • Moderate: 9.1% (placebo 6.1%) • Severe: 0.2% (placebo 0%) • Grade 4: 0% (placebo 0%) Age 12–15 years: • Any: 64.5% (placebo 24.4%) • Mild: 27.5% (placebo 15.7%) Moderate: 35.0% (placebo 8.6%) • Severe: 2.0% (placebo 0.1%) • Grade 4: 0% (placebo 0%) Age 16–55 years: ••••••Any: 51.7% (placebo 24.1%) ••••••Mild: 25.6% (placebo 15.3%) • Moderate: 5.8% (placebo 4.5%) • Severe: 0.1% (placebo 0.2%) • Grade 4: 0% (placebo 0%) Age > 55 years: • Any: 39.0% (placebo 13.9%) • Mild: 25.4% (placebo 10.0%) • Moderate: 13.0% (placebo 3.6%) • Severe: 0.5% (placebo 0.2%.) • Grade 4: 0% (placebo 0%)	Second most commonly occurring solicited systemic event (55.1%), behind fatigue (62.9%)
2. Baden et al. [57, 58]	mRNA-1273 Lipid nanoparticle-encapsulated nucleoside-modified mRNA encoding the prefusion stabilized full-length SARS-CoV2 spike protein	Randomized, observer-blinded, placebo-controlled trial of efficacy and safety Conducted at 99 centers across the USA	Age 18–65 years: • Any: 35.3% (placebo 29.0%) • Grade 1b: 27.8% (placebo 23.5%) • Grade 2: 5.6% (placebo 4.1%) • Grade 3: 1.9% (placebo 1.4%) • Grade 4: 0% (placebo 0%) Age > 65 years: • Any: 24.5% (19.3%) • Grade 1: 20.7% (placebo 16.8%) • Grade 2: 2.4% (placebo 1.6%) • Grade 3: 1.5% (placebo 0.9%) Grade 4: 0% (placebo 0%)	Age 18–65 years: • Any: 62.8% (placebo 25.3%) • Grade 1: 33.3% (placebo 20.0%) • Grade 2: 24.5% (placebo 4.1%) • Grade 3: 5.0% (placebo 1.2%) • Grade 4: 0% (placebo 0%) Age > 65 years: • Any: 46.2% (placebo 17.8%) • Grade 1: 31.1% (placebo 15.3%) • Grade 2: 12.3% (placebo 1.6%) • Grade 3: 2.9% (placebo 0.9%) • Grade 4: 0% (placebo 0%)	• Second most commonly occurring solicited systemic event (63.0%), behind fatigue (68.5%)
3. Sadoff et al. [59]	Ad26.COV2.S Recombinant, replication-incompetent human adenovirus type 26 vector encoding full-length SARS-CoV-2 spike protein in a prefusion-stabilized conformation	Randomized, double-blind, placebo-controlled trial of efficacy and safety Conducted in Argentina, Brazil, Chile, Colombia, Mexico, Peru, South Africa, and the USA	Age 18–59 years: • Any: • Grade 1: • Grade 2: • Grade 3: 0.2% (placebo 0.9%) • Grade 4: 0% (placebo 0%) Age > 59 years: • Any: • Grade 1: • Grade 2: • Grade 3: 0.3% (placebo 0.4%) • Grade 4: 0% (placebo 0%)	A single dose of this vaccines was studied	• Most commonly occurring solicited systemic event (38.9%)
4. Ramasamy et al. [60]	ChAdOx1 nCoV-19 / ADZ1222 Replication-defective chimpanzee adenovirus-vectored vaccine expressing the full-length SARS-CoV-2 spike glycoprotein gene	Randomized, single-blind, controlledd trial of safety and efficacy Conducted in two trial sites in the UK	Age 18–55 years: • Any: 65% • Mildc: 41% • Moderate: 20% • Severe: 4% • Hospitalization: 0% Age 56–69 years: • Any: 50% • Mild: 50% • Moderate: 0% • Severe: 0% • Hospitalization: 0% Age > 69 years: • Any: 41% • Mild: 35% • Moderate: 6% • Severe: 0% • Hospitalization: 0%	Age 18–55 years: • Any: 31% • Mild: 24% • Moderate: 4% • Severe: 1% • Hospitalization: 0% Age 56–69 years: • Any: 34% • Mild: 31% • Moderate: 3% • Severe: 0% • Hospitalization: 0% Age > 69 years: • Any: 20% • Mild: 16% • Moderate: 4% • Severe: 0% • Hospitalization: 0%	• Second most commonly occurring solicited systemic event, behind fatigue
5. Heath et al., Keech et al. [61, 62]	NVX-CoV2373 Recombinant nanoparticle contains the full-length spike glycoprotein of the SARS-CoV-2 prototype strain plus Matrix-M adjuvant	Randomized, observer-blinded, placebo-controlled trial of efficacy and safety Phase III trial conducted at 33 sites in the UK	Age 18–84 years: • Any: 23% (placebo 30%) • Grade 1b: 19.2% (placebo 21.7%) • Grade 2: 3.8% (placebo 8.7%) • Grade 3: 0% (placebo 0%) • Grade 4: 0% (placebo 0%)	Age 18–84 years: • Any: 46% (placebo 29%) • Grade 1: 38.5% (placebo 23.8%) • Grade 2: 7.7% (placebo 4.8%) • Grade 3: 0% (placebo 0%) • Grade 4: 0% (placebo 0%)	• Most commonly reported systemic adverse event after both the first (24.5%) and second (40.0%) doses
6. Tanriover et al. [67]	CoronaVac Inactivated whole-virion SARS-CoV-2 vaccine	Randomized, double-blind, placebo-controlled trial of efficacy and safety Phase III trial conducted in Brazil, Indonesia, Chile, and Turkey; data published from Turkey			• There was no significant difference in report of headache in vaccine (5.91%) versus placebo (5.94%) (P = 0.9538)

^aMild, does not interfere with activity; moderate, some interference with activity; severe, prevents daily activity; grade 4, emergency room visit or hospitalization for severe headache

^bGrade 1, does not interfere with daily activity; grade 2, repeated use of OTC pain reliever > 24 h to some interference with activity; grade 3, any use of prescription pain reliever or prevents daily activity; grade 4, requires emergency room visit or hospitalization

^cGrade 1 (mild), symptoms causing no or minimal interference with usual social and functional activities (minor headache not requiring medication); grade 2 (moderate), symptoms causing greater than minimal interference with usual social and functional activities (bad headache but able to do most activities with medication); grade 3 (severe), symptoms cause inability to perform usual social and functional activities (severe headache requiring medication and unable to do normal activities during the day); grade 4, symptoms causing inability to perform basic self-care functions OR hospitalization indicated OR headache with significant impairment of alertness or other neurologic function (emergency department or hospital admission required)

^dVaccine was compared with a meningococcal conjugate vaccine (MenACWY) as control

Results

Findings on Headache Reported Post-Vaccination

Of the 148 (non-COVID-19) studies reviewed, the top five infectious agents which measured and reported headache as a VAE included herpes zoster, influenza, HPV, meningococcal, and pneumococcal. Of those using placebo as control, 8 of 13 (61.5%) herpes zoster vaccine trials, 11 of 27 (40.7%) of influenza vaccine trials, and 5 of 16 (31.4%) of HPV vaccine trials reported headache as a VAE. Of those using active control, 10 of 26 (38.5%) meningococcal vaccine trials and 3 of 10 (30.0%) of pneumococcal conjugate vaccine trials reported headache as a VAE.

Over a third (38.5%; 19 /53) of RCTs reporting headache were placebo controlled. In 13 of these, headache was more common after vaccination than placebo. These included studies of vaccines against herpes zoster, influenza, varicella, rabies, and c. difficile. In the remaining six, headache was more common in the placebo than vaccine group. These included studies of vaccines against influenza, HPV, diphtheria, HIV, and schistosomiasis (Table 1). In one study, more than one vaccine group was compared to a single placebo group [3]. Headache was greater in the quadrivalent virus-like particle vaccine group in adults 18–64 than in the placebo group. However, headache was greater in the placebo group when compared to the quadrivalent virus-like particle vaccine with adults 65 plus and quadrivalent inactivated vaccine of both age groups [3]. In another, one vaccine group was compared to two different control groups [12]. Headache was greater in the vaccine group than in the control 2 trivalent inactivated subunit group but was less than headache in the control 1 trivalent inactivated subunit group.

Of the herpes zoster vaccine trials, five of eight found post-vaccination headache to be more common in the vaccine group compared to placebo: 33.5% (active) vs. 18.6% (placebo) [17]; 74.1% (active) vs. 48.9% (placebo) [18]; 40% (active) vs. 38% (placebo) [19]; 41.8% (active) vs.14.1% (placebo), 34.3% (active) vs. 15.8% (placebo), 30.1% (active) vs. 19.0% (placebo), 28.6% (active) vs. 16.7% (placebo) [20]; 6.51% (active) vs. 3.04% (placebo) [24] while the others found no significant difference. Of the influenza vaccine trials, 27.3% (3/11): 20.1% (active) vs. 19.1% (placebo) [3]; 14.1% (active) vs. 12.3% (placebo) [12]; and 19.2% (active) vs. 6.3% (placebo) [13] found headache to be more common in the vaccine group and 9.1% (1/11): 16.4% (active) vs. 19.6% (placebo) [8] found headache to be more common in the placebo group. Of the HPV vaccine trials, 20% (1/5):14.5% (active) vs. 12.9% (placebo) [27] found headache more common in the vaccine group and 20% (1/5): 0.4% (active) vs. 1.3% (placebo) [25] found headache more common in the placebo group. Overall, median rate of headache in non-COVID-19 vaccines was 15.6% (IQR: 6.4–30.6%) (active) vs. 15.7% (IQR: 5.4–19.1%) (placebo) (Table 1).

Headache as an Adverse Event Following COVID-19 Vaccination Studies

The coronavirus disease (COVID-19) pandemic resulting from infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has affected and continues to affect hundreds of millions of people. In response, multiple vaccines were developed, of which clinical trial and prospective data have revealed headache to be one of the most commonly reported VAEs (Table 2). Headache was the third most common symptom after vaccination [68].

The initial messenger RNA-based COVID-19 vaccines were the first of their approach to be approved [56, 57]. For these vaccines, the majority of headache events were rated as “mild” or “grade 1” across doses and age groups and systemic reactogenicity (including headache) was more common and severe after the second dose than after the first dose and among younger than older recipients [56, 57, 61]. The median rate of headache post-vaccination for mRNA COVID-19 vaccines dose one, two, and combined was 30.3% (IQR: 4.7–40.3%) (active) vs. 26.6% (IQR: 20.5–32.5%) (placebo), 49% (IQR: 40.8–60%) (active) vs. 21.4% (IQR: 18–24.3%) (placebo), and 40.5% (IQR: 27.3–52.6%) (active) vs. 24.1% (IQR: 18.5–26.2%) (placebo) respectively. When compared, median rate of headache due to placebo was lower by 3.7%, 27.6%, and 16.4%. In the BNT162b2 study, headache was one of only two systemic events reported as severe after either dose in at least 2% of recipients [57].

Data from the mRNA-1273 study reveal headache to have a mean duration of 2.1 days after the first dose and 2.3 days after the second dose, with only 4.8% persisting beyond 7 days [57]. Similarly, mean duration of headache was 1.6 days after the first and 2.0 days after the second dose in the NVX-CoV2373; no headache extended past 7 days after the second dose [61].

The median rate of headache vaccination of vaccines using a recombinant nanoparticle was calculated for dose 1, 23% (active) vs. 30% (placebo), dose 2, 46% (active) vs. 29% (placebo), and combined, 34.5% (active) vs. 29.5% (placebo). When compared, median rate of headache due to placebo was 7% higher for dose one, yet was 17% lower for dose two, and 5% lower for both doses combined [61, 62].

The median rate of headache vaccination for adenovirus vectored vaccines [59, 60] was calculated for dose 1, 45.5% (IQR: 40.5–53.8%), dose 2, 31% (IQR: 25.5–32.5%), and combined, 38.9% (IQR: 32.5–45.5%). No rate of headache due to placebo was reported for comparison.

For the COVID-19 vaccines reviewed (Table 2), overall median rate of headache vaccination and IQR was calculated among first, second, and both doses combined. This resulted in medians: 38.9% (IQR: 24.9–46%) (active) vs. 29% (IQR: 21.7–31.9%) (placebo), 42.5% (IQR: 31.8–50.3%) (active) vs. 24.1% (IQR: 18.2–24.9%) (placebo), and 39% (IQR: 28–50%) (active) vs. 24.3% (IQR: 18.8–29%) (placebo). This demonstrates a 10%, 18.4%, and 14.7% increase in headache post-vaccine when compared to placebo.

VAE Case Description: Headache Associated with COVID-19 Vaccination

A 23-year-old woman presented for follow up of migraine with aura and menstrual migraine; she had been diagnosed 3 years prior and had comorbid anxiety and irritable bowel syndrome. She had reported two migraine attacks in the 6 months prior to COVID-19 vaccination. Following vaccination, she experienced increased severity and frequency. Of note, she did have a history of chronic migraine (up to 22 headache days per month) in years prior.

The patient received the first dose of the BNT162b2 mRNA vaccine on January 14, 2021. Two days after, she experienced a series of severe migraine attacks for with pain intensity of 7–10 out of 10 on a 0–10 numeric rating scale. The attacks were lasting 7 to 8 h with reoccurrence, for 1.5 weeks. The migraine attacks alternated between unilateral and bilateral locations and were throbbing and sharp in pain quality. Symptoms occurring with her post-vaccination headache included more severe photophobia and nausea and vomiting compared to baseline, as well as her typical phonophobia, sensitivity to movement, lightheadedness, confusion, and difficulty thinking and concentrating. She reported an increased frequency of visual auras consisting of flashing lights with about half of these migraine attacks. The visual auras lasted about 4 h and were prolonged compared to her usual episodes of 45 min duration. Numbness with tingling also occurred in the face, arms, and sometimes legs during her attacks. In the past, she had experienced word substitution and weakness but had not had these symptoms for 6 years.

She treated her migraine attacks with rizatriptan, metoclopramide, and NSAIDs daily; however, they were treatment resistant. To alleviate the pain, the patient stayed in a dark room but had difficulty falling asleep. Due to the constant pain, she was not able to work or socialize. After 1.5 weeks, the migraine attacks subsided.

The patient received dose 2 of the vaccine three weeks later. A few hours after the vaccine, she experienced a mild headache in the center frontal region of the head, with pressure-like pain that lasted 2 h in duration and did not interrupt her daily activities. She did not have any associated symptoms and did not require treatment. About 15 h following the second dose, she experienced mild chills, a low-grade fever, and mild myalgias which resolved 5 h later. About 10 days after receiving dose 2, the patient reported no new symptoms or recurrences in headaches or migraine attacks.

In clinical practice, the risk of is getting a headache after vaccination is a commonly asked question. A recent systematic review and meta-analysis of 84 papers concluded that COVID-19 vaccines are associated with a two-fold risk of developing headache within 7 days from injection (compared with placebo) [68].

Similar trends have been shown in real-world, cross-sectional survey-based studies conducted after vaccine approval: “Headache/fatigue” was the most common systemic side effect (48.1% in mRNA-based vaccines and 74.4% in viral vector-based vaccines) in one [69] and the third most common (45.6%) behind fatigue in another [70]. Data according to the database of Adverse Drug Reactions in Italy has been compared to epidemiologic data according to the Global Health Data Exchange and revealed that the cumulative rate of headache/migraine episodes after receiving all COVID-19 vaccines was 2.25-fold higher than the daily frequency of headache disorders [71].

Discussion

Pathophysiology of Headache Post-Vaccination

Headache secondary to vaccination is likely due to systemic reactogenicity, the physical and systemic manifestations of the immune response to the vaccine. Headache following vaccination is proposed to occur via prostaglandin E production, release of cytokines such as IL-6, and C-reactive protein [72] which could lead to activation of trigeminal nociceptors. In a similar fashion, immune mediators and products of inflammation could exacerbate symptoms and induce headache persistence in patients with primary headache disorder. Taken together, individuals with migraine have been shown to have clinical evidence of peripheral and central sensitization of the trigeminovascular system, in addition to enhanced sensitivity to inflammatory stimuli [73, 74]. Although inflammation is debated as a mechanism of migraine, our case suggests that the immune response to vaccination may induce cortical spreading depression in individuals with a predisposition to migraine aura. The association between headache, other non-headache symptoms of reactogenicity such as fever, fatigue, and malaise, and immunogenicity should be evaluated in future studies.

Characteristics of Post-Vaccination Headache

Prior to the emergence of COVID-19 vaccinations, specific characteristics of headache following vaccination were not systematically examined. Still, HPV vaccination had been identified as a trigger for new daily persistent headache (NDPH) [75]. In our clinical practice, persistent and unremitting headache of at least 3-month duration, consistent with NDPH following vaccination has also been seen in rare circumstances.

An understanding of the characteristics and risk factors related to post-vaccination headache has been further elucidated with recent investigations focused on COVID-19 vaccination. Three questionnaire-based studies have revealed similar timelines with mean intervals of 1.8 ± 3.5 days [76], 18.0 ± 27.0 h [77], and 14.5 ± 21.6 h [78] following vaccination. The mean duration of the attacks has been reported as 14.2 ± 21.3 h [77], 16.3 ± 30.4 h [78], and majority less than 3 days [76]. There is one published case report of status migrainosus lasting 11 days following receipt of vaccination in a patient with history of migraine [79], and status migrainosus following vaccine has also been seen in our clinical practice. According to a recent systematic review and meta-analysis, post-vaccination headache tends to develop within 24-h from injection and usually resolves in less than 24 h [68].

The characteristics of headache after vaccination included a majority with bilateral location [76–78] and often at the forehead and temples [77, 78]. Commonly described pain qualities included pressing, throbbing, and dull [76–78]. Pain intensity was reported most often as moderate (46.2%) or severe (32.1%) in one study [77] and most often as severe (38.7%) or moderate (35.2%) in another [78]. In studies of COVID-19 vaccine, migraine-like features were present in one third of the cases (pulsating quality, phonophobia, and photophobia), and in 40–60% of the cases aggravation with activity was observed [68]. Interestingly, in a cohort of individuals with prior diagnosis of migraine, over half perceived the post-vaccination headache attacks as “different” from those usually experienced; this included higher pain intensity, longer duration, and reduced responsiveness to usually effective painkillers [80].

Of note, post-vaccination headache was found to be less severe and shorter than COVID-19-related headache [76]. There is one case reporting transient unilateral hemiparesis, sensory deficit, and visual phenomenon followed by headache and lasting 5 days without evidence of cerebral insult on brain imaging which was ultimately attributed to migraine pathology with cortical spreading depression [81]. Another report describes a case of new-onset visual aura phenomenon without headache, although this occurred 127 days after injection; magnetic resonance imaging (MRI) of brain and intracranial vessel imaging were normal [82]. There is one series of 8 patients who experienced lateralized sensory deficits, motor deficits, or both, of 2–14 day duration following CoronaVac vaccination; a history of migraine, female predominance, and abnormal functional brain imaging without structural changes was found and suggestive of migraine aura as pathophysiology [83]. The incidence of aura symptoms related to post-vaccination headache remains unclear at this time.

Risk Factors for Post-Vaccination Headache

In a web-based questionnaire study, potential risk factors identified for development of headache included female sex, pre-existing primary headaches (including migraine and tension-type), thyroid disorders, headache during COVID-19, and headache related to the influenza vaccine [76]. However, our review of recent influenza vaccine RCTs includes reported results of trivalent inactivated vaccine and quadrivalent inactivated vaccine, which was mixed.

Another questionnaire-based study also found headache to be more commonly reported in participants who had a prior history of migraine or non-migraine headache compared with healthy controls [84]. Patients who reported headache were more likely to report other systemic VAEs including fever, chills, fatigue, myalgias, joint pain, and nausea or vomiting [76–78].

Other Secondary Etiologies

As in the evaluation of all patients presenting with headache complaint, other secondary causes for a post-vaccination headache must be thoroughly considered. Headache was the most common presenting symptom of cerebral venous sinus thrombosis (CVST) following SARS-CoV-2 vaccination, a very rare but severe and potentially fatal complication [85].

There is accumulating evidence supporting an association between (CVST) and adenovirus vector-based vaccines against SARS-CoV-2 (including ChAdOx1 nCov-19 and Ad26.COV2.S); although, one cohort study found no significant association [86]. Development of CVST following vaccination may be mediated by the development of thrombosis and thrombocytopenia syndrome (TTS); one cohort study found that over two thirds of patients who developed CVST within 28 days of SARS-CoV-2 met diagnostic criteria for TTS [87]. A meta-analysis revealed that these thrombotic complications tended to affect predominantly women (69%; 95% CI 60–77%) under age 45, even in the absence of prothrombotic risk factors [88]. Headache related to CVST tended to be delayed compared to the time interval observed in the vaccine safety studies: Studies found the development of CVST-related headache at mean intervals of 8 days [89] and 10 days (within 2 weeks) [88] after exposure.

Suspicion for such an etiology is critical as the pooled mortality rate of TTS-associated CVST was 38% (95% CI 27–49%) [88]. Healthcare providers should be familiar with “red flags” in clinical presentations and the diagnostic criteria for this potential complication and other secondary etiologies (Fig. 1). When suspected, early diagnosis including brain imaging and prompt initiation of treatment can result in more favorable neurologic outcomes.

Fig. 1.

Comparison of headache as an adverse event to common COVID-19 vaccinations in clinical trials. Legend: Headache according to grade (scoring) following vaccination with COVID-19 vaccination for middle-aged range of patients (age 16–55 years for A BNT162b2, age 18–65 years for B mRNA-1273, and age 18–55 years for C ChAdOx1 nCoV-19). The results of Ad26.COV2.S and CoronaVac (due to missing data), in addition to NVX-CoV2373 (recent emergency use authorization only), are not shown here. There were no reports of headache scored as grade 4. A Mild, does not interfere with activity; moderate, some interference with activity; severe, prevents daily activity; grade 4, emergency room visit or hospitalization for severe headache. B Grade 1, does not interfere with daily activity; grade 2, repeated use of OTC pain reliever > 24 h to some interference with activity; grade 3, any use of prescription pain reliever or prevents daily activity; grade 4, requires emergency room visit or hospitalization. C Grade 1 (mild), symptoms causing no or minimal interference with usual social and functional activities (minor headache not requiring medication); grade 2 (moderate), symptoms causing greater than minimal interference with usual social and functional activities (bad headache but able to do most activities with medication); grade 3 (severe), symptoms cause inability to perform usual social and functional activities (severe headache requiring medication and unable to do normal activities during the day); grade 4, symptoms causing inability to perform basic self-care functions OR hospitalization indicated OR headache with significant impairment of alertness or other neurologic function (emergency department or hospital admission required)

Nocebo Effects of Vaccination Trials

The frequency of headache as a VAE in vaccination trials may be associated with several additional factors, including nocebo effects inherent to clinical trials. VAEs resulting from placebo administration are called nocebo effects. Overall, 12 studies reported headache as a VAE greater within the vaccine group than the placebo. However, 6 studies reported greater headache outcomes in the placebo group than the vaccine group. This may be due to differing sample sizes between the vaccine and the placebo group, with the placebo group being considerably smaller.

The “nocebo effect” has been defined as a negative effect experienced due to the belief that an intervention will cause harm. There is concern that this effect may occur when safety information of a vaccine is updated regularly with spontaneous VAEs, whether they are truly vaccine-related or not [90]. While the nocebo effect is more widely recognized among long-term vaccination efforts of well-described diseases, it has also been observed in recent COVID-19 vaccine trials as a potential factor for bias. In a meta-analysis of VAEs in COVID-19 RCTs, the incidence of nocebo responses was 16.4% while the magnitude was determined to be 0.3% [66]. Nocebo was attributed as a possible contribution for lowered vaccination rates in European countries due to public perception of the vaccine as less effective [91]. Additionally, a nationally representative cross-sectional survey in the UK also documented that side-effect expectation was associated with believing that COVID-19 vaccination was unsafe and ineffective [92].

Treatment Recommendations

Given the multitude of potential mediators contributing to vaccine-related headache, these events may require different treatment approaches. In the BNT162b2 mRNA COVID-19 vaccine trial, younger recipients were more likely to report taking an antipyretic or pain medication in response to a moderate or severe headache than older recipients [56]. Based on expert opinion, there is no contraindication to use of NSAIDs and acetaminophen for treatment of a headache following vaccination; triptans may also be helpful. Infusion therapies for treatment of status migrainosus may be of particular benefit; anecdotally, we have seen 30–100% response rates with intravenous dihydroergotamine and neuroleptics.

Oral corticosteroids can also be considered after expected immunogenicity is established, especially if other severe non-headache symptoms are also present. There is no consensus on the amount and duration of steroids that will result in suppression of an immunocompetent person [93] but CDC warns of active treatment with high-dose corticosteroids (i.e., 20 or more mg of prednisone or equivalent per day when administered for 2 or more weeks). Moreover, some theoretical guidance is provided by both the Pfizer-BioNTech BNT162b2 mRNA COVID-19 vaccine (28 days after dose 1 and 7 days after dose 2) and the Moderna mRNA-1273 (42 days after day 1 and 14 days after dose 2) [94, 95]. Greater occipital nerve blocks with corticosteroid may also be effective and corticosteroid sparing when administered peripherally. In general, it is reasonable to delay use for at least 2 weeks, especially in the case of live-virus vaccines [96].

Our clinical practice has shown that it may be beneficial to address the possibility of acute headache triggering after vaccination in patients with a pre-existing primary headache disorder in preparation for vaccination. In addition, for patients with migraine, there are no contraindications to the use of preventive therapies including onabotulinumtoxinA and monoclonal antibodies against calcitonin gene-related peptide [97]. It may be helpful to have a plan to escalate treatment as needed depending on response, including the potential treatment of status migrainosus. Longer term preventive therapies may be indicated for rare cases of headache persistence (e.g., amitriptyline and venlafaxine); treatment options should be guided by the headache phenotype.

Conclusion

As both passive surveillance and RCTs have shown, headache is a common although mostly mild and transient VAE following vaccination. There is heterogeneity among randomized controlled trials regarding the grading and scoring of headache severity; therefore, comparison is limited. Often, especially in pediatric trials, headache is not considered or is grouped with other systemic VAEs, which is a limiting factor towards understanding headache as a VAE post-vaccination.

There may be triggering of attacks in patients with baseline primary headache disorders or de novo headache. De novo headache post-vaccination should be considered for inclusion in the next iteration of the International Classification of Headache Disorders. Standardized grading methods, risk factors for persistence, and treatment are warranted in clinical trials, including in open-label phases.

Clinicians including headache specialists play a major role in helping people assess their personal eligibility for a vaccine and weigh the risks and benefits. Communication regarding the relative safety of vaccination and the transient and benign nature of the majority of potential systemic effects including headache can be crucial in the promotion of public health.

Declarations

Conflict of Interest

Kimberly Garces and Alexandra Cocores do not report any significant disclosures or conflicts of interest. Peter James Goadsby reports, over the last 36 months, grants and personal fees from Eli-Lilly and Company, grant from Celgene, and personal fees from Aeon Biopharma, Allergan/Abbvie, Amgen, Biodelivery Sciences International, Biohaven Pharmaceuticals Inc., CoolTech LLC, Dr Reddys, Epalex, GlaxoSmithKline, Impel Neuropharma, Lundbeck, Novartis, Praxis, Sanofi, Satsuma and Teva Pharmaceuticals, and personal fees for advice through Gerson Lehrman Group, Guidepoint, SAI Med Partners, Vector Metric, and fees for educational materials from CME Outfitters, Omnia Education, WebMD, and publishing royalties or fees from Massachusetts Medical Society, Oxford University Press, UptoDate and Wolters Kluwer, and for medicolegal advice in headache. Teshamae Monteith has received personal compensation for serving on advisory boards for Biohaven, Allegan/Abbvie, Lundbeck, Amgen, Teva, Linpharma and Impel Neuropharmaceuticals. She has also served as a site principal investigator without direct compensation for Teva, Eli Lilly, Electrocore, Amgen, Novartis.