Effectiveness of BNT162b2 Vaccine Booster Against SARS-CoV-2 Infection and Breakthrough Complications, Israel

Aharona Glatman-Freedman; Michal Bromberg; Yael Hershkovitz; Hanna Sefty; Zalman Kaufman; Rita Dichtiar; Lital Keinan-Boker

Disclosures

Emerging Infectious Diseases. 2022;28(5):948-956.

Methods

Study Design

We conducted a retrospective longitudinal cohort study using 2 MOH national repositories: the COVID-19 vaccine repository and the SARS-CoV-2 test repository. The national COVID-19 vaccine repository includes vaccine type, vaccine lot number, and date of dose administration for each person vaccinated in Israel. The national SARS-CoV-2 PCR test database includes the results of each test performed, the date of testing, and the date results were obtained for each person. It also includes the date of hospitalization, severity of illness, and date of death of persons with COVID-19, if applicable. Personal identifiers such as unique personal identity number, age, and sex of each person registered in the repositories (because of PCR testing or vaccination) are included in both databases. We retrieved individual deidentified data from both databases and matched persons by using twice-encrypted unique personal identity numbers.

During the first stage of our study, we determined VE for booster dose vaccine recipients against SARS-CoV-2 infection by using unvaccinated persons as controls. During the second stage, we determined the rate reduction for hospitalizations, severe or critical disease, and deaths among persons who tested positive for SARS-CoV-2 after the booster dose (i.e., breakthrough cases).

We defined as index dates the dates on which third-dose vaccine recipients in our study received the booster dose (Figure 1, panel A). Booster dose recipients and unvaccinated controls included in each index date represented a single cohort. We performed analyses for persons 16–59 years of age across 14 consecutive cohorts with the index dates August 29, 2021–September 11, 2021. These dates were selected because, by that period, persons 16–59 years of age had already been approved by the MOH to receive the booster dose (Appendix Figure 1). Analyses for persons ≥60 years of age were performed across 14 consecutive cohorts with index dates occurring during August 1, 2021–August 14, 2021. These dates were chosen for this age group because this group was the first to receive the booster dose (Figure 1, panel B) and because most persons ≥60 years of age received the third dose before August 29, 2021 (Appendix Figure 1). We followed each cohort through January 1, 2022.

(Enlarge Image)

Figure 1.

Estimations of effectiveness of BNT162b2 vaccine booster (Pfizer, https://www.pfizer.com) against SARS-CoV-2 infection and breakthrough complications, Israel. A) Epidemic curve of new PCR-confirmed SARS-CoV-2–positive persons, June 1, 2021–January 1, 2022. Index dates are highlighted in orange (for persons ≥60 years of age) and light blue (for persons 16–59 years of age). B) Daily booster dose recipients by age group. C) Graphic illustration of the booster dose vaccine effectiveness evaluation method for a single cohort of persons ≥60 years of age that received the booster dose on August 1, 2021. Orange bars represent the number of persons who received the booster dose each day; light blue asterisk represents the date persons ≥60 years of age included in cohort 1 received the booster dose. D) Graphic illustration of the booster dose vaccine effectiveness evaluation method for a single cohort of persons 16–59 years of age who received the booster dose on August 29, 2021. Light blue bars represent the number of persons who received the booster dose each day; orange asterisk represents the date persons 16–59 years of age included in cohort 1 received the booster dose.

Estimation of VE

We excluded residents of Israel who tested positive for SARS-CoV-2 by PCR before the evaluation periods from the analyses (Appendix Table 1, Figures 2, 3). We estimated VE for the 16–59-year and ≥60-year age groups, as well as for age groups 16–29 years, 30–39 years, 40–49 years, and 50–59 years (Appendix Figures 2, 3). We first estimated VE for each cohort starting week 2 after the index date. We then estimated VE for all 14 cohorts combined. Because of the different index dates for these age groups, we followed persons 16–59 years of age for 16 weeks and persons ≥60 years of age for 20 weeks (Figure 1, panels C, D; Appendix Table 2).

(Enlarge Image)

Figure 2.

Adjusted vaccine effectiveness against severe acute respiratory syndrome coronavirus 2 infection in persons 16–59 years of age, by week, September 6, 2021–January 1, 2022 (A), and ≥60 years of age, by week, August 9, 2021–January 1, 2022 (B), Israel. Adjustments were performed for sex, age, and epidemiologic week. Error bars represent 95% CIs.

(Enlarge Image)

Figure 3.

Percentage of sequenced severe acute respiratory syndrome coronavirus 2 samples by variant and reporting date, Israel, November 15, November 29, December 13, and December 27, 2021. Based on (9). Numbers within the figure represent percentages of sequenced samples.

Hospitalizations, Severe Disease, and Death Among SARS-CoV-2–Positive Booster Dose Recipients

We determined rates of SARS-CoV-2–related hospitalizations, severe or critical disease, and deaths for booster-dose recipients and for unvaccinated persons who tested positive for SARS-CoV-2 by PCR during the evaluation period described previously (breakthrough cases). The time allotted for the occurrence of hospitalization and severe or critical disease after the first positive PCR test was 14 days.^[6] We did not set a time limit for death after the first positive PCR test. We determined disease severity in accordance with US National Institutes of Health guidelines.^[7]

Statistics

We determined VE and 95% CI using the formula (1 – incidence rate ratio [IRR]) × 100. The IRR represents the ratio of PCR-confirmed SARS-CoV-2 infection rate in the group of booster-dose recipients to the corresponding rate in the unvaccinated control group. For persons who tested positive for SARS-CoV-2 by PCR several times during the evaluation period, we included only the first positive test result in the analysis.

We excluded persons who had a positive SARS-CoV-2 PCR test before the evaluation periods from the analysis, regardless of their vaccination status. Unvaccinated persons included in the study who were vaccinated during the cohort evaluation period were censored (removed from the study) on their vaccination dates.

We computed the number of unvaccinated controls by age and sex for each cohort by subtracting the number of residents of Israel, by age and sex, who were vaccinated with any number of BNT162b2 vaccine doses before or on the cohort vaccination date (index date) from the number of residents who did not have a recorded positive SARS-CoV-2 PCR test by that date. We calculated the number of person-days each person contributed as unvaccinated during each evaluation period. The number of residents (total, by age and by sex) was based on the 2021 Central Bureau of Statistics statistical abstract.^[8] We took into account unvaccinated participants who were included in >1 cohort when calculating VEs and CIs.

VE was first calculated for each age group daily cohort by week starting the second week after the booster dose. VE was estimated separately for each week that passed since the index date. For the combined VE estimate (for all 14 cohorts together), we took several steps. First, we summed the number of booster-vaccinated and unvaccinated SARS-CoV-2–positive cases for the evaluation period. Second, we counted the days at risk for each age-group cohort on the basis of the number of person-days for each booster-vaccinated and unvaccinated person from the start of the study until the person became SARS-CoV-2–positive or until the end of follow-up, whichever date was earlier. Third, we summed the days at risk for each age group cohort during the evaluation period to provide the total number of person-days at risk in the booster-vaccinated or unvaccinated status for all age group cohorts. Finally, we calculated IRR for the age group cohorts combined.

We evaluated the reduction in SARS-CoV-2–related hospitalizations, illness severity during hospitalizations, and death in persons who received 3 BNT162b2 vaccine doses compared with unvaccinated persons using the formula (1 – IRR) × 100. We performed adjustment of IRR and 95% CI for age group (16–29, 30–39, 40–49, and 50–59 years for persons 16–59 years of age; 60–79 and ≥80 years for persons ≥60 years of age), sex and epidemiologic week, provided the data sizes were sufficiently large, by using Poisson regression. Statistical analysis was performed using SAS Enterprise Guide 7.1 software (SAS Institute, https://www.sas.com). The study was approved by the superior ethical committee of the Israel MOH (protocol no. CoR-MOH-081–2021) with exemption from informed consent.

1 2 3 4

Next Section

Table 1. Rate reduction of hospitalizations among SARS-CoV-2–positive persons who received the BNT162b2 COVID-19 vaccine booster dose, Israel*
Age group, y	Time of first positive SARS-CoV-2 PCR test after index date, wk	Unvaccinated SARS-CoV-2–positive persons		Vaccinated SARS-CoV-2–positive persons		Adjusted 1 – IRR, % (95% CI)†
Age group, y		Hospitalized	Total	Hospitalized	Total	Adjusted 1 – IRR, % (95% CI)†
16–59	2	889	22,545	4	1,343	92.2 (77.9–97.3)
	3	770	18,232	3	455	83.9 (46.7–95.1)
	4	590	12,962	2	293	84.6 (47.1–95.5)
	5	414	8,555	1	210	90.1 (44.5–98.2)
	6	259	5,531	1	138	84.3 (15.1–97.1)
	7	175	3,573	0	131	100.0
	8	120	2,626	1	83	74.0 (−52.5 to 95.6)
	9	92	2,013	0	54	100.0
	10	72	1,714	0	57	100.0
	11	69	1,401	0	66	100.0
	12	68	1,385	0	90	100.0
	13	72	1,442	0	118	100.0
	14	62	1,569	1	154	84.4 (5.9–97.4)
	15	64	2,145	4	351	62.8 (−0.6 to 86.2)
	16	71	4,088	1	884	94.0 (47.9–99.3)
	2–16 combined	1,662	41,135	18	4,427	89.2 (79.1–94.4)
>60	2	644	1,985	98	1,314	77.5 (71.5–82.3)
	3	666	2,200	39	464	73.0 (64.4–79.5)
	4	647	2,160	36	375	68.2 (52.7–78.6)
	5	619	2,164	25	319	73.2 (48.2–86.2)
	6	593	2,033	20	296	77.3 (62.5–86.3)
	7	501	1,724	29	271	64.5 (50.2–74.7)
	8	375	1,276	23	221	65.3 (40.2–79.9)
	9	254	869	6	147	86.7 (72.6–93.6)
	10	163	577	10	86	64.1 (27.1–82.3)
	11	108	376	9	63	54.9 (−35.9 to 85.1)
	12	80	258	4	44	71.0 (21.5–89.3)
	13	56	208	3	52	80.2 (54.4–91.4)
	14	56	183	3	49	81.9 (45.8–94.0)
	15	58	170	6	47	67.5 (32.6–84.4)
	16	53	162	5	44	65.7 (23.4–84.6)
	17	46	151	1	56	94.4 (57.3–99.2)
	18	42	147	1	69	95.0 (72.1–99.1)
	19	38	184	5	125	82.6 (57.7–92.8)
	20	46	305	13	432	81.4 (67.0–89.5)
	2–20 combined	1,976	6,673	336	4,474	75.1 (71.3–78.5)

*COVID-19, coronavirus disease; IRR, incidence rate ratio; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
†Adjusted for sex and epidemiologic week.

Table 2. Rate reduction of severe or critical disease among SARS-CoV-2–positive persons who received the BNT162b2 COVID-19 vaccine booster dose, Israel*
Age group, y	Time of first positive SARS-CoV-2 PCR test after index date, wk	Unvaccinated SARS-CoV-2–positive persons		Vaccinated SARS-CoV-2–positive persons		Adjusted 1 – IRR, % (95% CI)†
Age group, y		Severe or critical disease	Total	Severe or critical disease	Total	Adjusted 1 – IRR, % (95% CI)†
16–59	2	422	22,545	2	1,343	92.0 (70.0–97.9)
	3	358	18,232	0	455	100.0
	4	262	12,962	0	293	100.0
	5	170	8,555	0	210	100.0
	6	113	5,531	0	138	100.0
	7	63	3,573	0	131	100.0
	8	40	2,626	0	83	100.0
	9	32	2,013	0	54	100.0
	10	27	1,714	0	57	100.0
	11	29	1,401	0	66	100.0
	12	24	1,385	0	90	100.0
	13	25	1,442	0	118	100.0
	14	21	1,569	0	154	100.0
	15	30	2,145	0	351	100.0
	16	30	4,088	0	884	100.0
	2–16 combined	727	41,135	2	4,427	97.3 (89.7–99.3)
≥60	2	450	1,985	56	1,314	81.9 (75.4–86.7)
	3	470	2,200	27	464	73.5 (61.0–82.0)
	4	464	2,160	18	375	77.8 (63.1–86.8)
	5	469	2,164	15	319	78.9 (66.8–86.6)
	6	447	2,033	9	296	86.6 (74.2–93.0)
	7	390	1,724	12	271	81.4 (63.1–90.6)
	8	299	1,276	13	221	75.6 (54.1–87.0)
	9	207	869	2	147	94.6 (85.3–98.0)
	10	128	577	9	86	58.6 (11.1–80.7)
	11	78	376	2	63	86.2 (39.1–96.9)
	12	52	258	3	44	69.0 (−15.3 to 91.7)
	13	40	208	1	52	91.0 (63.8–97.8)
	14	42	183	2	49	84.0 (44.8–95.3)
	15	45	170	3	47	78.5 (49.3–90.8)
	16	37	162	3	44	70.3 (30.0–87.4)
	17	32	151	1	56	91.7 (43.4–98.8)
	18	28	147	0	69	100.0
	19	33	184	4	125	83.6 (47.0–94.9)
	20	42	305	7	432	89.0 (75.8–95.0)
	2–20 combined	1,465	6,673	187	4,474	81.6 (78.3–84.3)

*COVID-19, coronavirus disease; IRR, incidence rate ratio; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
†Adjusted for sex and epidemiologic week.

Table 3. Rate reduction of deaths among SARS-CoV-2–positive persons who received the BNT162b2 COVID-19 vaccine booster dose, Israel*
Age group, y	Time of first positive SARS-CoV-2 PCR test after index date, wk	Unvaccinated SARS-CoV-2–positive persons		Vaccinated SARS-CoV-2–positive persons		Adjusted 1 – IRR, % (95% CI)†
Age group, y		Deaths	Total	Deaths	Total	Adjusted 1 – IRR, % (95% CI)†
16–59	2	45	22,545	0	1,343	100
	3	36	18,232	0	455	100
	4	27	12,962	0	293	100
	5	17	8,555	0	210	100
	6	11	5,531	0	138	100
	7	6	3,573	0	131	100
	8	5	2,626	0	83	100
	9	4	2,013	0	54	100
	10	3	1,714	0	57	100
	11	3	1,401	0	66	100
	12	3	1,385	0	90	100
	13	2	1,442	0	118	100
	14	1	1,569	0	154	100
	15	1	2,145	0	351	100
	16	1	4,088	0	884	100
	2–16 combined	72	41,135	0	4,427	100
≥60	2	243	1,985	31	1,314	81.9 (70.4–88.9)
	3	246	2,200	13	464	76.0 (55.3–87.2)
	4	226	2,160	13	375	68.1 (49.6–79.8)
	5	229	2,164	11	319	68.7 (42.7–82.9)
	6	201	2,033	7	296	76.5 (55.9–87.4)
	7	166	1,724	8	271	70.5 (29.4–87.7)
	8	122	1,276	8	221	63.1 (29.4–80.7)
	9	89	869	2	147	87.6 (53.7–96.7)
	10	59	577	5	86	49.1 (−44.3 to 82.1)
	11	30	376	0	63	100.0
	12	19	258	1	44	67.7 (−189.8 to 96.4)
	13	19	208	1	52	78.7 (−89.9 to 97.6)
	14	22	183	1	49	85.0 (8.5–97.5)
	15	21	170	1	47	85.3 (−21.3 to 98.2)
	16	17	162	0	44	100.0
	17	11	151	1	56	74.6 (−225.9 to 98.0)
	18	10	147	0	69	100.0
	19	7	184	2	125	56.5 (−144.3 to 92.3)
	20	8	305	3	432	70.7 (−2.7 to 91.7)
	2–20 combined	686	6,673	108	4,474	77.1 (71.2–81.8)

*COVID-19, coronavirus disease; IRR, incidence rate ratio; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
†Adjusted for sex and epidemiologic week.