Abstract
This cohort study compares the sex- and age-adjusted incidence of cerebral venous sinus thrombosis before the COVID-19 pandemic with that during the first 92 days after Ad26.COV2.S vaccination.
Recent reports1,2,3,4 suggest a possible association between Ad26.COV2.S (Johnson & Johnson/Janssen) COVID-19 vaccination and cerebral venous sinus thrombosis (CVST). Estimates of postvaccination CVST risk require accurate age- and sex-specific prepandemic CVST incidence rates; however, reported rates vary widely.5 We compared the age- and sex-specific CVST rates after Ad26.COV2.S vaccination with the prepandemic CVST rate in the population.
Methods
In this population-based cohort study, to estimate the risk of CVST after Ad26.COV2.S vaccination, we first identified all incident cases of CVST in Olmsted County, Minnesota from January 1, 2001, through December 31, 2015 (eMethods in the Supplement). Sex-and age-adjusted incidence rates were adjusted to the 2010 US census population. We used CDC Vaccine Adverse Event Reporting System (VAERS) data from February 28, 2021 (vaccine approval date) to May 7, 2021, to estimate the incidence of CVST after Ad26.COV2.S vaccination assuming 3 (15, 30, and 92 days) plausible postvaccination periods during which individuals were considered to be at risk of CVST. We then compared post-Ad26.COV2.S vaccination CVST rates with prepandemic rates to estimate postvaccination CVST risk. This study was approved by the Mayo Clinic institutional review board. Medical records of Olmsted County residents with CVST were reviewed only if the residents had signed an authorization for accessing their medical records for research purposes. SAS, version 9.4 (SAS Institute Inc) and R, version 4.0.3 (R Project for Statistical Computing) were used for statistical analyses. Significance was set at a 2-sided P < .05.
Results
From 2001 through 2015, 39 Olmsted County residents developed acute incident CVST. A total of 29 patients (74.4%) had a predisposing venous thromboembolism risk factor (eg, infection, active cancer, or oral contraceptives [for women]) within 92 days before the event. The median age at diagnosis was 41 years (range, 22-84 years); 22 residents with CVST (56.4%) were female. The overall age- and sex-adjusted CVST incidence was 2.34 per 100 000 person-years (PY) (95% CI, 1.60-3.08 per 100 000 PY). Age-adjusted CVST rates for female and male individuals were 2.46 per 100 000 PY (95% CI, 1.43-3.49 per 100 000 PY) and 2.34 per 100 000 PY (95% CI, 1.22-3.46 per 100 000 PY), respectively. Men aged 65 years or older had the highest CVST rate (6.22 per 100 000 PY; 95% CI, 2.50-12.82 per 100 000 PY), followed by women aged 18 to 29 years (4.71 per 100 000 person-years; 95% CI, 2.26-8.66 per 100 000 PY) (Table 1).
Table 1. Annual Incidence of CVST Among Residents of Olmsted County, Minnesota, From 2001 to 2015 by Age and Sex.
| Sex and age, y | CVST cases, No. | Population, person-years | Incidence, per 100 000 person-years (95% CI) |
|---|---|---|---|
| Female | |||
| 18-29 | 10 | 212 441 | 4.71 (2.26-8.66) |
| 30-39 | 4 | 156 541 | 2.56 (0.70-6.54) |
| 40-49 | 2 | 157 433 | 1.27 (0.15-4.59) |
| 50-64 | 4 | 195 110 | 2.05 (0.56-5.25) |
| ≥65 | 2 | 148 204 | 1.35 (0.16-4.88) |
| Total | 22 | 869 729 | 2.53 (1.59-3.83) |
| Age-adjusted ratea | NA | NA | 2.46 (1.43-3.49) |
| Male | |||
| 18-29 | 2 | 181 342 | 1.10 (0.13-3.99) |
| 30-39 | 3 | 147 386 | 2.04 (0.42-5.95) |
| 40-49 | 2 | 145 879 | 1.37 (0.16-4.96) |
| 50-64 | 3 | 175 760 | 1.71 (0.35-4.99) |
| ≥65 | 7 | 112 508 | 6.22 (2.50-12.82) |
| Total | 17 | 762 875 | 2.23 (1.30-3.57) |
| Age-adjusted ratea | NA | NA | 2.34 (1.22-3.46) |
| All | |||
| 18-29 | 12 | 393 783 | 3.05 (1.57-5.32) |
| 30-39 | 7 | 303 927 | 2.30 (0.92-4.74) |
| 40-49 | 4 | 303 312 | 1.32 (0.36-3.38) |
| 50-64 | 7 | 370 870 | 1.89 (0.76-3.89) |
| ≥65 | 9 | 260 712 | 3.45 (1.58-5.53) |
| Total | 39 | 1 632 604 | 2.39 (0.61-1.67) |
| Age-adjusted ratea | NA | NA | 2.38 (1.63-3.13) |
| Age- and sex-adjusted ratea | NA | NA | 2.34 (1.60-3.08) |
Abbreviations: CVST, cerebral venous sinus thrombosis; NA, not applicable.
Adjusted to the US census 2010 population.
As of May 7, 2021, 8 727 851 Ad26.COV2.S vaccine doses had been administered in the US; 46 potential CVST events occurring within 92 days after Ad26.COV2.S vaccination were reported to VAERS. Eight events were excluded because they were potentially duplicate reports (4) or were not objectively diagnosed (4). Twenty-seven of 38 objectively diagnosed cases of CVST after Ad26.COV2.S vaccination (71.1%) occurred in female individuals. The median patient age was 45 years (range, 19-75 years). The median time from vaccination to CVST was 9 days (IQR, 6-13 days; range, 1-51 days); 31 of 38 cases of CVST (81.6%) occurred within 15 days after vaccination, and 36 (94.7%) occurred within 30 days.
The overall incidence rate of post–Ad26.COV2.S vaccination CVST was 8.65 per 100 000 PY (95% CI, 5.88-12.28 per 100 000 PY) at 15 days, 5.02 per 100 000 PY (95% CI, 3.52-6.95 per 100 000 PY) at 30 days, and 1.73 per 100 000 PY (95% CI, 1.22-2.37 per 100 000 PY) at 92 days (Table 2). The 15-day postvaccination CVST incidence rates for female and male individuals were 13.01 per 100 000 PY (95% CI, 8.24-19.52 per 100 000 PY) and 4.41 per 100 000 PY (95% CI, 1.90-8.68 per 100 000 PY), respectively. The postvaccination CVST rate among females was 5.1-fold higher compared with the pre-COVID-19 pandemic rate (13.01 vs 2.53 per 100 000 PY; P < .001) (Table 2). This risk was highest among women aged 40 to 49 years (29.50 per 100 000 PY; 95% CI, 13.50-55.95 per 100 000 PY), followed by women aged 30 to 39 years (26.50 per 100 000 PY; 10.65-54.63 per 100 000 PY).
Table 2. Incidence Rate of CVST Occurring After the Administration of the Ad26.COV2.S Vaccine.
| Risk period, sex, and age, y | Observed CVST cases, No. | Doses administered, No. | Person-years at risk | Incidence, per 100 000 person-years (95% CI) | Expected CVST cases, No.a | Incidence rate ratio (95% CI)b | P valuec |
|---|---|---|---|---|---|---|---|
| 15 d | |||||||
| Female | |||||||
| 18-29 | 2 | 641 510 | 26 346 | 7.59 (0.91-27.40) | 1.24 | 1.61 (0.17-7.57) | .63 |
| 30-39 | 7 | 642 745 | 26 397 | 26.52 (10.65-54.63) | 0.67 | 10.38 (2.64-48.33) | <.001 |
| 40-49 | 9 | 743 256 | 30 525 | 29.48 (13.50-55.95) | 0.39 | 23.21 (4.80-221.05) | <.001 |
| 50-64 | 5 | 1 463 416 | 60 101 | 8.32 (2.70-19.42) | 1.23 | 4.06 (0.87-20.45) | .04 |
| ≥65 | 0 | 814 947 | 33 469 | 0.00 (0.00-11.03) | 0.45 | 0.00 (0.004-23.58) | >.99 |
| Total | 23 | 4 305 874 | 176 837 | 13.01 (8.24-19.52) | 4.47 | 5.14 (2.74-9.68) | <.001 |
| Male | |||||||
| 18-29 | 1 | 714 458 | 29 342 | 3.41 (0.10-18.98) | 0.32 | 3.09 (0.05-59.36) | .36 |
| 30-39 | 0 | 728 699 | 29 927 | 0.00 (0.00-12.33) | 0.61 | 0.00 (0.00-11.92) | >.99 |
| 40-49 | 3 | 775 390 | 31 844 | 9.42 (1.95-27.54) | 0.44 | 6.87 (0.79-82.34) | .04 |
| 50-64 | 3 | 1 505 505 | 61 829 | 4.85 (1.00-14.18) | 1.06 | 2.84 (0.38-21.32) | .19 |
| ≥65 | 1 | 697 925 | 28 663 | 3.49 (0.10-19.43) | 1.78 | 0.56 (0.01-4.36) | >.99 |
| Total | 8 | 4 421 977 | 181 606 | 4.41 (1.90-8.68) | 4.05 | 1.98 (0.74-4.83) | .12 |
| 30 d | |||||||
| Female | |||||||
| 18-29 | 2 | 641 510 | 52 692 | 3.80 (0.46-13.70) | 2.48 | 0.81 (0.09-3.78) | >.99 |
| 30-39 | 8 | 642 745 | 52 794 | 15.15 (6.53-29.85) | 1.35 | 5.93 (1.59-26.93) | .003 |
| 40-49 | 10 | 743 256 | 61 049 | 16.38 (7.86-30.12) | 0.78 | 12.89 (2.75-120.81) | <.001 |
| 50-64 | 6 | 1 463 416 | 120 202 | 4.99 (1.83-10.87) | 2.46 | 2.43 (0.58-11.73) | .20 |
| ≥65 | 0 | 814 947 | 66 938 | 0.00 (0.00-5.51) | 0.90 | 0.00 (0.00-11.79) | >.99 |
| Total | 26 | 4 305 874 | 353 675 | 7.35 (4.80-10.77) | 8.95 | 2.91 (1.58-5.38) | <.001 |
| Male | |||||||
| 18-29 | 1 | 714 458 | 58 684 | 1.70 (0.05-9.49) | 0.65 | 1.55 (0.03-29.68) | .56 |
| 30-39 | 0 | 728 699 | 59 854 | 0.00 (0.00-6.17) | 1.22 | 0.00 (0.00-5.96) | .56 |
| 40-49 | 3 | 775 390 | 63 689 | 4.71 (0.97-13.77) | 0.87 | 3.44 (0.39-41.17) | .16 |
| 50-64 | 5 | 1 505 505 | 123 659 | 4.04 (1.31-9.44) | 2.11 | 2.37 (0.46-15.26) | .29 |
| ≥65 | 1 | 697 925 | 57 326 | 1.74 (0.05-9.72) | 3.57 | 0.28 (0.01-2.18) | .28 |
| Total | 10 | 4 421 977 | 363 211 | 2.75 (1.32-5.06) | 8.09 | 1.24 (0.51-2.86) | .54 |
| 92 d | |||||||
| Female | |||||||
| 18-29 | 2 | 641 510 | 161 589 | 1.24 (0.15-4.47) | 7.61 | 0.26 (0.03-1.23) | .08 |
| 30-39 | 8 | 642 745 | 161 901 | 4.94 (2.13-9.73) | 4.14 | 1.93 (0.52-8.78) | .39 |
| 40-49 | 10 | 743 256 | 187 218 | 5.34 (2.56-9.82) | 2.38 | 4.20 (0.90-39.39) | .05 |
| 50-64 | 6 | 1 463 416 | 368 619 | 1.63 (0.60-3.54) | 7.56 | 0.79 (0.19-3.82) | .75 |
| ≥65 | 1 | 814 947 | 205 276 | 0.49 (0.01-2.71) | 2.77 | 0.36 (0.01-6.93) | .58 |
| Total | 27 | 4 305 874 | 1 084 603 | 2.49 (1.64-3.62) | 27.44 | 0.98 (0.54-1.81) | >.99 |
| Male | |||||||
| 18-29 | 1 | 714 458 | 179 964 | 0.56 (0.02-3.10) | 1.98 | 0.50 (0.01-9.68) | >.99 |
| 30-39 | 0 | 728 699 | 183 551 | 0.00 (0.00-2.01) | 3.74 | 0.00 (0.00-1.94) | .09 |
| 40-49 | 3 | 775 390 | 195 312 | 1.54 (0.32-4.49) | 2.68 | 1.12 (0.13-13.43) | >.99 |
| 50-64 | 6 | 1 505 505 | 379 220 | 1.58 (0.58-3.44) | 6.47 | 0.93 (0.20-5.72) | >.99 |
| ≥65 | 1 | 697 925 | 175 800 | 0.57 (0.02-3.17) | 10.94 | 0.09 (0.00-0.71) | .007 |
| Total | 11 | 4 421 977 | 1 113 848 | 0.99 (0.49-1.77) | 24.82 | 0.44 (0.19-1.00) | .05 |
Abbreviation: CVST, cerebral venous sinus thrombosis.
Based on the population of Olmsted County, Minnesota.
Observed vs expected.
The exact binomial test P value was calculated using the binom.test() function in the R, version 4.0.3, with the probability of an observed CVST case being calculated as K2/(K1+K2), where K1 was the number of prepandemic CVST cases in the general population (expected) and K2 was the number of postvaccination CVST cases (observed).
Discussion
In this population-based cohort study, we found that the CVST incidence rate 15 days after Ad26.COV2.S vaccination was significantly higher than the prepandemic rate. However, the higher rate of this rare adverse effect must be considered in the context of the effectiveness of the vaccine in preventing COVID-19 (absolute reduction of severe or critical COVID-19 of 940 per 100 000 PY).6
Most CVST events occurred within 15 days after vaccination, which is likely the highest at-risk period. The postvaccination CVST rate among females was higher than the prepandemic rate among females. The highest risk was among women aged 30 to 49 years, but the absolute CVST risk was still low in this group (up to 29.5 per 100 000 PY among women aged 40-49 years). The reason that women had a higher incidence of postvaccination CVST is unclear; concomitant CVST risk factors or autoantibody production might have been involved.2 The overall prepandemic CVST incidence rate was slightly higher in our study than in other studies (0.22-1.57 per 100 000 PY)5 likely because we captured all objectively diagnosed incident CVST cases in a well-defined population, including those discovered at autopsy.
The present study avoided referral bias and included only objectively diagnosed and confirmed cases. Only cases with adequate details or imaging findings reported on VAERS were used. Study limitations include possible ascertainment bias by including only objectively diagnosed CVST cases. VAERS reporting is voluntary and subject to reporting biases. VAERS monitors vaccine adverse events but does not prove causality.
eMethods.
References
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Associated Data
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Supplementary Materials
eMethods.
