Evaluation of COVID-19 vaccine breakthrough infections among immunocompromised patients fully vaccinated with BNT162b2

Figures & data

Figure 1. Algorithm to define IC cases. ^aIndex date was defined as the date of receipt of the 1st BNT162b2 dose; ^bbased on a review of ICD-10 diagnosis codes and keyword search including immune, malignancy, neoplasm, rheumatoid, and kidney, excluding encounter/screening test. Abbreviations. AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus; IC, immunocompromised; IS, immunosuppressive.

Figure 2. Study selection criteria. IC, Immunocompromised.

Table 1. Characteristics of the IC and non-IC cohorts and overall study population that received 2 BNT162b2 doses.

	IC cohort N = 225,796	Non-IC cohort N = 1,051,951	Overall study population N = 1,277,747
Age on index date (years), mean (SD)	55.4 (15.2)	44.1 (16.9)	46.1 (17.1)
Median (Q1–Q3)	58 (47–64)	45 (30–58)	48 (32–60)
Age group (years), N (%)
16–17	2,962 (1.3)	57,188 (5.4)	60,140 (4.7)
18–29	12,591 (5.6)	196,915 (18.7)	209,506 (16.4)
30–39	18,244 (8.1)	169,258 (16.1)	187,502 (14.7)
40–49	30,880 (13.7)	181,533 (17.3)	212,413 (16.6)
50–64	109,136 (48.3)	349,742 (33.3)	458,878 (35.9)
65–74	33,964 (15.0)	72,973 (6.9)	106,937 (8.4)
75–84	13,495 (6.0)	18,583 (1.8)	32,078 (2.5)
≥85	4,524 (2.0)	5,769 (0.6)	10,293 (0.8)
Sex, N (%)
Female	127,101 (56.3)	558,164 (53.1)	685,265 (53.6)
Male	96,835 (42.9)	476,804 (45.3)	573,639 (44.9)
Unknown	1,860 (0.8)	16,983 (1.6)	18,843 (1.5)
US census region of residence, N (%)
Northeast	20,574 (9.1)	99,040 (9.4)	119,614 (9.4)
Midwest	65,094 (28.8)	321,679 (30.6)	386,773 (30.3)
South	79,862 (35.4)	368,579 (35.0)	448,441 (35.1)
West	21,214 (9.4)	140,221 (13.3)	161,435 (12.6)
Other	8 (0.0)	74 (0.0)	82 (0.0)
Missing	39,044 (17.3)	122,358 (11.6)	161,402 (12.6)
Payer on index date, N (%)
Commercial	168,142 (74.5)	843,469 (80.2)	1,011,611 (79.2)
Medicaid	31,446 (13.9)	158,082 (15.0)	189,528 (14.8)
Medicare	22,951 (10.2)	34,673 (3.3)	57,624 (4.5)
Unknown	3,224 (1.4)	15,649 (1.5)	18,873 (1.5)
Missing	33 (0.0)	78 (0.0)	111 (0.0)
At risk of severe COVID-19,^a N (%)	141,105 (62.5)	203,491 (19.3)	344,596 (27.0)
Vaccine administration setting, N (%)
Office	34,655 (15.4)	118,281 (11.2)	152,936 (12.0)
Other place of service	5,583 (2.5)	30,077 (2.9)	35,660 (2.8)
Public health clinic	2,322 (1.0)	5,990 (0.6)	8,312 (0.7)
Urgent care facility	574 (0.3)	3,500 (0.3)	4,074 (0.3)
Pharmacy	126,408 (56.0)	699,313 (66.5)	825,721 (64.6)
Inpatient	6 (0.0)	1 (0.0)	7 (0.0)
Other	5,122 (2.3)	18,964 (1.8)	24,086 (1.9)
Unknown	51,126 (22.6)	175,825 (16.7)	226,951 (17.8)
Time interval between vaccine doses (days), mean (SD)	22.0 (3.8)	22.0 (3.6)	22.0 (3.7)
Median (Q1–Q3)	21 (21–22)	21 (21–22)	21 (21–22)
Month of receipt of 1st vaccine dose, N (%)
December	4,088 (1.8)	22,537 (2.1)	26,625 (2.1)
January	26,947 (11.9)	85,870 (8.2)	112,817 (8.2)
February	41,423 (18.4)	126,174 (12.0)	167,597 (13.1)
March	102,813 (45.5)	415,507 (39.5)	518,320 (40.6)
April	35,369 (15.7)	263,415 (25.0)	298,784 (23.4)
May	11,910 (5.3)	108,734 (10.3)	120,644 (9.4)
June	3,244 (1.4)	29,712 (2.8)	32,956 (2.6)
July	2 (0.0)	2 (0.0)	4 (0.0)
Month of receipt of 1st vaccine dose (cumulative), N (%)
December or January	31,035 (13.7)	108,407 (10.3)	139,442 (10.9)
February	72,458 (32.1)	234,581 (22.3)	307,039 (24.0)
March	175,271 (77.6)	650,088 (61.8)	825,359 (64.6)
April	210,640 (93.3)	913,503 (86.8)	1,124,143 (88.0)
May	222,550 (98.6)	1,022,237 (97.2)	1,244,787 (97.4)
June	225,794 (100)	1,051,949 (100)	1,277,743 (100)
July	225,796 (100)	1,051,951 (100)	1,277,747 (100)
Healthcare prevention seeking behavior in the baseline period, N (%)
≥1 Telehealth/telephone visit	218,222 (96.7)	689,687 (65.6)	907,909 (71.1)
≥1 COVID-19 laboratory test	25,195 (11.2)	78,155 (7.4)	103,350 (8.1)
≥1 Influenza vaccine	60,229 (26.7)	196,137 (18.7)	256,366 (20.1)
Follow-up duration post second dose (days), mean (SD)	103.5 (39.6)	95.8 (40.2)	97.1 (40.2)
Median (Q1–Q3)	107 (78–127)	99 (68–120)	100 (69–121)

^aThe list of medical conditions that determine whether or not an individual is at risk of severe COVID-19 was based on guidance from the Advisory Committee on Immunization Practices (ACIP) of the CDC and FDA Sentinel Master Protocol^35,36, and included cancer, chronic kidney disease, chronic obstructive pulmonary disease, Down syndrome, congestive heart failure, coronary artery disease, other cardiomyopathies, immunocompromised state from solid organ transplant, obesity (body mass index [BMI]: ≥30 kg/m² but <40 kg/m²), severe obesity (BMI ≥40 kg/m²), pregnancy, sickle cell disease, smoking, and type 2 diabetes.

Abbreviations. CDC, Centers for Disease Control and Prevention; FDA, Food and Drug Administration; IC, immunocompromised; SD, standard deviation.

Table 2. Incidence rates of COVID-19 vaccine breakthrough infections per 100 person-years among individuals fully vaccinated^a with BNT162b2, by IC condition and age <65 and ≥65 years.

Study population	N	Breakthrough infections	Proportion (%)	Person- years^b	IR per 100 person-years	Lower 95% CI	Upper 95% CI
Non-IC cohort	963,962	604	0.06	175101.5	0.34	0.32	0.37
IC cohort	212,945	374	0.18	42069.2	0.89	0.80	0.98
12 IC cohorts
HIV/AIDS	2103	3	0.14	424.4	0.71	0.15	2.07
Solid malignancy	68,545	77	0.11	13780.2	0.56	0.44	0.70
Bone marrow transplant	12	0	0.00	2.6	0.00	–	–
Organ transplant (excluding bone marrow)	675	5	0.74	136.6	3.66	1.19	8.54
Rheumatologic/other inflammatory condition	35,475	57	0.16	6980.7	0.82	0.62	1.06
Primary immunodeficiency	3190	7	0.22	619.7	1.13	0.45	2.33
Other immune condition^c	3684	2	0.05	729.5	0.27	0.03	0.99
CKD or ESRD	41,597	77	0.19	8084.6	0.95	0.75	1.19
Hematological malignancy	1814	4	0.22	366.4	1.09	0.30	2.80
IS medication usage ≥14 days in baseline period	19,074	17	0.09	3563.1	0.48	0.28	0.76
Antimetabolite usage ≥14 days in baseline period	659	2	0.30	135.1	1.48	0.18	5.35
>1 IC condition	36,117	123	0.34	7246.5	1.70	1.41	2.03
<65 years of age
Non-IC cohort	871,022	485	0.06	156666.6	0.31	0.28	0.34
IC cohort	163,235	228	0.14	32321.4	0.71	0.62	0.80
12 IC cohorts
HIV/AIDS	2000	3	0.15	400.5	0.75	0.15	2.19
Solid malignancy	52,900	46	0.09	10581.7	0.43	0.32	0.58
Bone marrow transplant	11	0	0.00	2.2	0.00	–	–
Organ transplant (excluding bone marrow)	538	4	0.74	109.9	3.64	0.99	9.31
Rheumatologic/other inflammatory condition	29,382	39	0.13	5800.0	0.67	0.48	0.92
Primary immunodeficiency	2729	7	0.26	523.7	1.34	0.54	2.75
Other immune condition^c	3269	1	0.03	644.8	0.16	0.00	0.86
CKD or ESRD	29,760	39	0.13	5863.2	0.67	0.47	0.91
Hematological malignancy	1315	2	0.15	271.1	0.74	0.09	2.67
IS medication usage ≥14 days in baseline period	15,950	15	0.09	2947.6	0.51	0.28	0.84
Antimetabolite usage ≥14 days in baseline period	552	2	0.36	112.8	1.77	0.21	6.40
>1 IC condition	24,829	70	0.28	5063.8	1.38	1.08	1.75
≥65 years of age
Non-IC cohort	92,940	119	0.13	18434.9	0.65	0.53	0.77
IC cohort	49,710	146	0.29	9747.8	1.50	1.26	1.76
12 IC cohorts
HIV/AIDS	103	0	0.00	23.9	0.00	–	–
Solid malignancy	15,645	31	0.20	3198.4	0.97	0.66	1.38
Bone marrow transplant	1	0	0.00	0.3	0.00	–	–
Organ transplant (excluding bone marrow)	137	1	0.73	26.7	3.75	0.09	20.90
Rheumatologic/other inflammatory condition	6093	18	0.30	1180.6	1.52	0.90	2.41
Primary immunodeficiency	461	0	0.00	96.0	0.00	–	–
Other immune condition^c	415	1	0.24	84.7	1.18	0.03	6.58
CKD or ESRD	11,837	38	0.32	2221.4	1.71	1.21	2.35
Hematological malignancy	499	2	0.40	95.3	2.10	0.25	7.58
IS medication usage ≥14 days in baseline period	3124	2	0.06	615.5	0.32	0.04	1.17
Antimetabolite usage ≥14 days in baseline period	107	0	0.00	22.2	0.00	–	–
>1 IC condition	11,288	53	0.47	2182.7	2.43	1.82	3.18

^aFully vaccinated was defined as ≥14 days after receipt of the 2nd BNT162b2 dose.

^bPerson time was calculated starting from 14 days after the receipt of the 2nd dose of BNT162b2 until a COVID-19 vaccine breakthrough infection case or end of continuous enrollment, whichever occurred earlier.

^cOther immune conditions are described in Supplementary Table 1.

Abbreviations. AIDS, acquired immunodeficiency syndrome; CI, confidence interval; CKD, chronic kidney disease; ESRD, end stage renal disease; HIV, human immunodeficiency virus; IC, immunocompromised; IR, incidence rate; IS, immunosuppressive.

Table 3. Characteristics of fully vaccinated^a individuals with COVID-19 vaccine breakthrough infections.

	IC cohort N = 374	Non-IC cohort N = 604	Overall study population N = 978
Age (years), mean (SD)	61 (15.1)	50 (17.5)	54 (17.3)
Median (Q1–Q3)	61 (52–69)	51 (38–62)	55 (42–65)
<65 years, N (%)	227 (60.7)	485 (80.3)	712 (72.8)
≥65 years, N (%)	147 (39.3)	119 (19.7)	266 (27.2)
Sex, N (%)
Female	217 (58.0)	363 (60.0)	580 (59.3)
Male	157 (42.0)	239 (39.7)	396 (40.5)
Unknown	0 (0.0)	2 (0.3)	2 (0.2)
US Census region of residence, N (%)
Northeast	54 (14.4)	93 (15.4)	147 (15.0)
Midwest	70 (18.7)	147 (24.3)	217 (22.2)
South	142 (38.0)	200 (33.1)	342 (35.0)
West	20 (5.3)	37 (6.1)	57 (5.8)
Missing	88 (23.5)	127 (21.0)	215 (22.0)
Time from 2nd BNT162b2 dose to a COVID-19 vaccine breakthrough infection (days)	34.5 (22–58)	33 (20.5–58)	34 (21–58)
Full cohort, per IC algorithm, median (Q1–Q3) in days
CDC recommended IC groups^c	31 (21–56.5)	–	–
Additional IC groups^d	35 (22–58)	–	–
Median (Q1-Q3) by IC condition
HIV/AIDS	94 (35–127)	–	–
Solid malignancy	36 (25–66)	–	–
Bone marrow transplant	–	–	–
Organ transplant (excluding bone marrow)	16 (16–23)	–	–
Rheumatologic/other inflammatory condition	30 (21–57)	–	–
Primary immunodeficiency	29 (17–44)	–	–
Other immune condition^b	52 (47–57)	–	–
CKD or ESRD	33 (19–51)	–	–
Hematological malignancy	47.5 (26–72)	–	–
IS medication usage ≥14 days in baseline period	29 (23–49)	–	–
Antimetabolite usage ≥14 days in baseline period	57 (15–99)	–	–
>1 IC condition	38 (22–59)	–	–
HCRU after 1st COVID-19 diagnosis, N (%)
Any outpatient encounter	361 (96.5)	589 (97.5)	950 (97.1)
ED visits	95 (25.4)	72 (11.9)	167 (17.1)
Other outpatient hospital visits	146 9 (39.0)	164 (27.2)	310 (31.7)
Other outpatient services	309 (82.6)	527 (87.3)	836 (85.5)
Any 1st hospitalization	74 (19.8)	50 (8.3)	124 (12.7)
No ICU admission and no IMV usage	50 (13.4)	40 (6.6)	90 (9.2)
With ICU admission and no IMV usage	15 (4.0)	9 (1.5)	24 (2.5)
With ICU admission and IMV usage	8 (2.1)	1 (0.2)	9 (0.9)
No ICU admission with IMV usage	1 (0.3)	0 (0.0)	1 (0.1)
Inpatient death	2 (0.5)	0 (0.0)	2 (0.2)

^aFully vaccinated was defined as ≥14 days after receipt of the 2nd BNT162b2 dose.

^bOther immune conditions are described in Supplementary Table 1.

^cThe CDC recommended IC groups include HIV/AIDS, solid organ/stem cell transplantation with active IS medication treatment, primary immunodeficiency, hematologic malignancy with active cancer treatment, and active IS medication/antimetabolite treatment²⁸.

^dThe additional IC groups included all the IC groups identified per the algorithm, minus the CDC evaluated IC groups.

Abbreviations. AIDS, acquired immunodeficiency syndrome; CDC, Centers for Disease Control and Prevention; CKD, chronic kidney disease; ED, emergency department; ESRD, end stage renal disease; HCRU, healthcare resource utilization; HIV, human immunodeficiency virus; IC, immunocompromised; ICU, intensive care unit; IMV, invasive mechanical ventilation; IS, immunosuppressive; SD, standard deviation.

Figure 3. COVID-19 vaccine breakthrough infections: subgroup analysis of CDC recommended IC groups by active treatment status. Active treatment was defined as evidence of medication usage ≤14 days before a 1st BNT162b2 dose, except for hematological malignancy, where active treatment status was defined as evidence of any IS medication (including radiotherapy) usage within 6 months before a 1st BNT162b2 dose. Abbreviations. CDC, Centers for Disease Control and Prevention; IC, immunocompromised; IS, immunosuppressive.

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Data availability statement

Data generated or analyzed during this study are available upon request.