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Protection by a Fourth Dose of BNT162b2 against Omicron in Israel
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Design
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Cohort Study, Database Analysis
N= 623,355
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Objective
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To use data from the Israeli Ministry of Health national database to study the relative effectiveness of a fourth dose as compared with only three doses against confirmed infection and severe illness among older persons in the Israeli population.
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Study Groups
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Intervention Group: 4-dose group
Control Group 1: 3-dose group
Control Group 2: Internal control group
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Inclusion Criteria
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60 years of age or older by 01/01/22 and had received three doses of the BNT162b2 vaccine at least four months before the end of the study period (03/02/22)
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Exclusion Criteria
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those who had died before the beginning of the study period (01/10/22); those who had had a confirmed SARS-CoV-2 infection before the beginning of the study; those who had received a third dose before its approval for all older residents; those who had been abroad for the entire study period; and those who had received a vaccine other than BNT162b2.
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Methods
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The rate of confirmed infection and severe COVID-19 was estimated as a function of time starting at 8 days after receipt of a fourth dose.
For patients who received the fourth dose, sub-treatment groups were defined by number of weeks passed since dose received, starting from the second week (8 to 14 days after vaccination).
These four-dose groups were compared with two control groups. The first control group included persons who were eligible for a fourth dose but had not yet received it (three-dose group). A second control group was defined as persons who had received a fourth dose 3 to 7 days earlier (internal control group).
Quasi-Poisson regression was used to calculate the estimation of rates of confirmed infection and severe COVID-19 per 100,000 person-days for each study group, adjusting for age, sex, demographic group, and calendar day.
A SARS-CoV-2 infection was confirmed either by state-regulated rapid antigen test or by PCR. Severe COVID-19 was defined as a resting respiratory rate of >30 breaths per minute, an oxygen saturation of <94% while breathing ambient air, or a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of <300) during the 14 days after confirmation of infection.
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Duration
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Confirmed infection: 01/10/22 – 03/02/22
Severe infection: 02/18/22 – 03/02/22
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Outcome Measures
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Unadjusted and adjusted rates of infection (number of cases of infection per 100,000 person-days)
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Baseline Characteristics
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| Population |
Aggregated Four-Dose Groups |
Three-Dose Group |
Internal Control Group |
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% Person- Days at Risk |
No. of Infections (Cases per 100,000 Person-Days) |
No. of Severe Cases (Cases per 100,000 Person-Days) |
% Person- Days at Risk |
No. of Infections (Cases per 100,000 Person-Days) |
No. of Severe Cases (Cases per 100,000 Person-Days) |
% Person- Days at Risk |
No. of Infections (Cases per 100,000 Person-Days) |
No. of Severe Cases (Cases per 100,000 Person-Days) |
| Total |
100 |
42,325 (177) |
355 (1.5) |
100 |
111,780 (361) |
1210 (3.9) |
100 |
10,531 (388) |
114 (4.2) |
| Women |
51.8 |
20,646 (166) |
154 (1.2) |
55.1 |
62,531 (366) |
499 (2.9) |
52.6 |
5,135 (360) |
54 (3.8) |
| Men |
48.2 |
21,679 (188) |
201 (1.7) |
44.9 |
49,249 (354) |
711 (5.1) |
47.4 |
5,396 (419) |
60 (4.7) |
| Age group: |
| 60–69 yr |
32.5 |
16,701 (214) |
41 (0.5) |
52.0 |
69,198 (429) |
193 (1.2) |
33.6 |
4,302 (471) |
8 (0.9) |
| 70–79 yr |
42.5 |
16,349 (161) |
102 (1.0) |
31.8 |
30,817 (313) |
363 (3.7) |
41.3 |
3,965 (353) |
33 (2.9) |
| ≥80 yr |
24.9 |
9,275 (155) |
212 (3.6) |
16.2 |
11,765 (235) |
654 (13.0) |
25.1 |
2,264 (332) |
73 (10.7) |
| Population: |
| General Jewish |
94.2 |
39,886 (177) |
319 (1.4) |
84.4 |
95,708 (366) |
965 (3.7) |
93.7 |
9,688 (381) |
98 (3.9) |
| Ultra-Orthodox Jewish |
2.7 |
1,119 (176) |
12 (1.9) |
4.6 |
5,262 (372) |
67 (4.7) |
2.7 |
500 (676) |
5 (6.8) |
| Arab |
3.1 |
1,320 (176) |
24 (3.2) |
11.1 |
10,810 (315) |
178 (5.2) |
3.6 |
343 (349) |
11 (11.2) |
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Results
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| Confirmed Cases |
| Group |
# of cases per 100,000 person-days (unadjusted) |
| 4-dose |
177 |
| 3-dose |
361 |
| Internal Control Group |
388 |
| Severe COVID-19 |
| Group |
# of cases per 100,000 person-days (unadjusted) |
| 4-dose |
1.5 |
| 3-dose |
3.9 |
| Internal Control Group |
4.2 |
Quasi-Poisson Analysis of Confirmed Cases:
| Group (Days since Dose 4) |
No. of Confirmed Infections (Person-Days at Risk) |
Adjusted Rate Ratio (95% CI) |
Adjusted Rate Difference (95% CI) |
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Comparison with Three- Dose Group |
Comparison with Internal Control Group |
Comparison with Three- Dose Group |
Comparison with Internal Control Group |
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cases/100,000 person-days at risk |
| Three-dose group |
111,780 (31,000,299) |
Reference |
— |
Reference |
— |
| Internal control group (3–7) |
10,531 (2,717,489) |
1.1 (1.1 to 1.1) |
Reference |
33 (23 to 42) |
Reference |
| Four-dose groups: |
| Week 2 (8–14) |
12,840 (4,181,768) |
1.5 (1.5 to 1.6) |
1.4 (1.3 to 1.4) |
115 (109 to 121) |
82 (72 to 93) |
| Week 3 (15–21) |
8,926 (4,041,309) |
2.1 (2.0 to 2.1) |
1.9 (1.8 to 1.9) |
175 (169 to 181) |
142 (132 to 152) |
| Week 4 (22–28) |
7,225 (3,883,824) |
2.0 (1.9 to 2.1) |
1.8 (1.7 to 1.9) |
170 (162 to 176) |
137 (125 to 148) |
| Week 5 (29–35) |
5,611 (3,701,580) |
1.7 (1.6 to 1.7) |
1.5 (1.4 to 1.6) |
136 (127 to 145) |
103 (90 to 115) |
| Week 6 (36–42) |
3,686 (3,479,549) |
1.5 (1.4 to 1.6) |
1.4 (1.3 to 1.5) |
116 (103 to 127) |
83 (68 to 100) |
| Week 7 (43–49) |
2,666 (3,040,564) |
1.2 (1.2 to 1.3) |
1.1 (1.0 to 1.2) |
67 (50 to 83) |
35 (15 to 53) |
| Week 8 (50–56) |
1,304 (1,547,985) |
1.1 (1.0 to 1.2) |
1.0 (0.9 to 1.1) |
22 (−10 to 52) |
−10 (−43 to 20) |
Quasi-Poisson Analysis of Severe COVID-19:
| Group (Days from Vaccination) |
No. of Severe Cases (Person-Days at Risk) |
Adjusted Rate Ratio (95% CI) |
Adjusted Rate Difference (95% CI) |
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Comparison with Three- Dose Group |
Comparison with Internal Control Group |
Comparison with Three- Dose Group |
Comparison with Internal Control Group |
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cases/100,000 person-days at risk |
| Three-dose group |
1210 (24,857,976) |
Reference |
— |
Reference |
— |
| Internal control group (3–7) |
114 (2,673,746) |
1.5 (1.2–1.9) |
Reference |
1.8 (0.9–2.6) |
Reference |
| Four-dose groups: |
| Week 2 (8–14) |
125 (4,073,168) |
2.4 (2.0–2.9) |
1.6 (1.2–2.1) |
3.2 (2.7–3.7) |
1.3 (0.6–2.2) |
| Week 3 (15–21) |
99 (3,868,314) |
2.9 (2.3–3.6) |
1.9 (1.4–2.6) |
3.6 (3.1–4.2) |
1.7 (1.0–2.7) |
| Week 4 (22–28) |
66 (3,639,393) |
3.5 (2.7–4.6) |
2.3 (1.7–3.3) |
3.9 (3.4–4.5) |
2.1 (1.4–3.0) |
| Week 5 (29–35) |
47 (3,277,662) |
3.4 (2.5–4.7) |
2.3 (1.6–3.3) |
3.9 (3.3–4.5) |
2.0 (1.2–3.0) |
| Week 6 (36–42) |
18 (2,133,014) |
4.3 (2.6–7.1) |
2.8 (1.6–4.9) |
4.2 (3.4–4.9) |
2.4 (1.3–3.4) |
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Adverse Events
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Not reported |
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Study Author Conclusions
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A fourth dose appeared to increase the protection against severe illness relative to three doses that were administered more than 4 months earlier.
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InpharmD Researcher Critique
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Further randomized, controlled studies need to be done before applying the results to a larger population.
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