Target Trial: Booster Long-term effectivity against infection and severe cases on Omicron-dominant period in Navarra
Francisco Sánchez Sáez
2022-08-30
1 Introduction
The omicron (B.1.1.529) variant of SARS-CoV-2 has increased capacity to elude immunity and cause breakthrough infections. The long-term effectivity against infection and severe cases of the booster vaccination is assessed on Omicron-dominant period in Navarra. This has been done following the Target trial emulation methodology1. The results of infections from January 3 to February 6 are compared with2 and then the period of the study is enlarged in order to assess the long-term effects.
2 Methods
In this population cohort study, we linked data from three population registries in Navarra (Vaccination Registry, Laboratory Results Registry, and BARDENA-Population registry) to select:
Non-residents.
Non-educational workers.
Non health-care workers.
Community-dwelling individuals aged 40 years or older.
Who completed their primary vaccine schedule at least 3 months before the start of follow-up.
Had not tested positive for SARS-CoV-2 since the start of the pandemic.
On each day between Jan 3, and Feb 6, 2022, we matched individuals who received a booster mRNA vaccine and controls of the same:
Age (5-years group).
Sex.
Number of previous negative test (0, 1, 2, 3+).
Type of primary vaccine (homologous or Janssen).
Time since complete vaccination.
Basic zone.
Migrant.
Flu vaccine (2020).
Flu vaccine (2021).
Number of people at home.
We estimated risk of laboratory-confirmed SARS-CoV-2 infection using the Kaplan-Meier method and compared groups using risk ratios (RR) and risk differences. Vaccine effectiveness was calculated as one minus RR.
3 Results
3.1 Comparison with the study of Omicron in Spain
In the study of Omicron in Spain2, the estimated effectiveness from day 7 to 34 after a booster was 51·3% (95% CI 50·2–52·4).
In Navarra, we have the following results shown in Tables 3.1, 3.2 and 3.3.
| Variable | No booster group (n = 30962*) | Booster group (n = 30962) |
|---|---|---|
| Age group (years), n (%) | ||
| 40-44 | 6788 (21.9%) | 6788 (21.9%) |
| 45-49 | 9669 (31.2%) | 9669 (31.2%) |
| 50-54 | 7986 (25.8%) | 7986 (25.8%) |
| 55-59 | 6262 (20.2%) | 6262 (20.2%) |
| 60-64 | 182 (0.6%) | 182 (0.6%) |
| 65-69 | 39 (0.1%) | 39 (0.1%) |
| 70-74 | 22 (0.1%) | 22 (0.1%) |
| 75-79 | 7 (0.0%) | 7 (0.0%) |
| 80-84 | 0 (0.0%) | 0 (0.0%) |
| 85-89 | 6 (0.0%) | 6 (0.0%) |
| ≥ 90 | 1 (0.0%) | 1 (0.0%) |
| Sex, n (%) | ||
| Men | 18561 (59.9%) | 18561 (59.9%) |
| Women | 12401 (40.1%) | 12401 (40.1%) |
| Number of previous SARS-CoV-2 tests, n (%) | ||
| 0 | 17139 (55.4%) | 17139 (55.4%) |
| 1 | 6389 (20.6%) | 6389 (20.6%) |
| 2 | 3806 (12.3%) | 3806 (12.3%) |
| ≥ 3 | 3628 (11.7%) | 3628 (11.7%) |
| Type of previous vaccination, n (%) | ||
| BioNTech/Pfizer | 27232 (88.0%) | 27232 (88.0%) |
| J&J / Janssen | 63 (0.2%) | 63 (0.2%) |
| Moderna/Lonza | 3461 (11.2%) | 3461 (11.2%) |
| Oxford/AstraZeneca | 206 (0.7%) | 206 (0.7%) |
| Time since primary vaccine schedule, n (%) | ||
| 91-150 days | 1 (0.0%) | 1 (0.0%) |
| 151-180 days | 89 (0.3%) | 89 (0.3%) |
| ≥ 181 days | 30872 (99.7%) | 30872 (99.7%) |
| Type of booster, n (%) | ||
| BioNTech/Pfizer | NA | 4097 (13.2%) |
| Moderna/Lonza | NA | 26865 (86.8%) |
| Note: NA = not applicable, *21161 unique individuals in the no booster group. | ||
| Events | Risk per 10 000 individuals | Events | Risk per 10 000 individuals | |||
|---|---|---|---|---|---|---|
| Overall | 962 | 624 | 512 | 330 | 47.1 % (41.4, 52.3) | 294 (244, 340) |
| Age group (years) | ||||||
| 40-54 | 852 | 678 | 456 | 361 | 46.7 % (40.8, 52.7) | 316 (261, 377) |
| ≥ 55 | 110 | 379 | 56 | 186 | 50.9 % (32.8, 65.2) | 193 (104, 281) |
| Sex | ||||||
| Male | 541 | 574 | 277 | 293 | 48.9 % (41.3, 55.5) | 281 (220, 336) |
| Female | 421 | 702 | 235 | 387 | 44.8 % (36, 54) | 315 (241, 414) |
| Type of previous vaccination | ||||||
| BioNTech/Pfizer | 889 | 644 | 465 | 336 | 47.8 % (41.4, 53.1) | 308 (255, 357) |
| J&J / Janssen | 2 | 426 | 1 | 189 | 55.7 % (-Inf, 100) | 237 (-514, 977) |
| Moderna/Lonza | 68 | 472 | 42 | 278 | 41.1 % (15.4, 60.4) | 194 (62, 337) |
| Oxford/AstraZeneca | 3 | 203 | 4 | 267 | -31.8 % (-Inf, 80.6) | -65 (-411, 275) |
| Time since vaccination completed | ||||||
| 91-195 days | 321 | 1009 | 184 | 578 | 42.7 % (31.2, 52.7) | 431 (293, 579) |
| 196-220 days | 592 | 556 | 303 | 282 | 49.4 % (41.9, 55.5) | 275 (222, 322) |
| ≥ 221 days | 45 | 325 | 21 | 153 | 52.9 % (24.4, 73) | 172 (63, 275) |
| Type of booster | ||||||
| BioNTech/Pfizer | 151 | 705 | 81 | 372 | 47.3 % (33.9, 59.7) | 334 (213, 462) |
| Moderna/Lonza | 811 | 611 | 431 | 323 | 47.1 % (41.1, 53.4) | 288 (237, 339) |
| Note: Analyses based on 19825 matched pairs who remained under follow-up by day 7 after the booster dose | ||||||
| 1–risk ratio (95% CI) | Risk difference per 10 000 individuals (95% CI) | |
|---|---|---|
| Main analysis | 47.1 % (41.4, 52.3) | 294 (244, 340) |
| Restricting to people with ≥ 1 negative lab test at enrolment | 45.3 % (36.7, 52.4) | 345 (261, 428) |
| Restricting to persons with no tests in the 7 days before enrolment | 48.8 % (43.2, 54.1) | 304 (255, 352) |
| Censoring matched pairs 7 days after the control receives a booster rather than 0 days | 41.2 % (35.5, 46.4) | 246 (203, 290) |
| Adding 2 days to the PCR test date rather than the PCR collection date | 46 % (41.2, 50.3) | 359 (308, 404) |
| Selecting matched controls without replacement | 45 % (39, 50.2) | 288 (239, 337) |
| Exact matching by age (year by year vs 5-year groups) | 50.4 % (43, 57.4) | 352 (283, 430) |
3.2 Long-term infection (fcv1)
Now, the period has been extended from January 3 to April 13 and 60 days of follow-up has been selected. The results are shown in Tables 3.4 and 3.5
## Se está analizando el outcome: fcv1 mediante la emulación de un ensayo clínico con múltiples inicios de tiempo. Se ha utilizado matching por: gen, czbs, tvc1, migran, vgp20, vgp21, ucn8, n_0, fpauta_90 (in weeks), age (in 5-years groups).
##
## Análisis de supervivencia días 0-60
## caso
## exposicion 0 1 Total
## 0 30030 2261 32291
## 1 30998 1293 32291
## Total 61028 3554 64582##
## # Estimated effectiveness in Navarra for fcv1 is : 45.2 % (41.3 - 48.8 %)## Warning: Removed 19 row(s) containing missing values (geom_path).## Warning: Removed 19 rows containing missing values (geom_point).## Warning: Removed 19 row(s) containing missing values (geom_path).## Warning: Removed 19 rows containing missing values (geom_point).
##
## ########################################################################
##
## Análisis de supervivencia días 7-60
## caso
## exposicion 0 1 Total
## 0 19903 1188 21091
## 1 20450 641 21091
## Total 40353 1829 42182
##
## # Estimated effectiveness in Navarra for fcv1 is : 47.4 % (42.1 - 52.2 %)| Variable | No booster group (n = 32291*) | Booster group (n = 32291) |
|---|---|---|
| Age group (years), n (%) | ||
| 40-44 | 7340 (22.7%) | 7340 (22.7%) |
| 45-49 | 10176 (31.5%) | 10176 (31.5%) |
| 50-54 | 8188 (25.4%) | 8188 (25.4%) |
| 55-59 | 6310 (19.5%) | 6310 (19.5%) |
| 60-64 | 195 (0.6%) | 195 (0.6%) |
| 65-69 | 45 (0.1%) | 45 (0.1%) |
| 70-74 | 22 (0.1%) | 22 (0.1%) |
| 75-79 | 7 (0.0%) | 7 (0.0%) |
| 80-84 | 1 (0.0%) | 1 (0.0%) |
| 85-89 | 6 (0.0%) | 6 (0.0%) |
| ≥ 90 | 1 (0.0%) | 1 (0.0%) |
| Sex, n (%) | ||
| Men | 19483 (60.3%) | 19483 (60.3%) |
| Women | 12808 (39.7%) | 12808 (39.7%) |
| Number of previous SARS-CoV-2 tests, n (%) | ||
| 0 | 18015 (55.8%) | 18015 (55.8%) |
| 1 | 6600 (20.4%) | 6600 (20.4%) |
| 2 | 3921 (12.1%) | 3921 (12.1%) |
| ≥ 3 | 3755 (11.6%) | 3755 (11.6%) |
| Type of previous vaccination, n (%) | ||
| BioNTech/Pfizer | 28419 (88.0%) | 28419 (88.0%) |
| J&J / Janssen | 80 (0.2%) | 80 (0.2%) |
| Moderna/Lonza | 3572 (11.1%) | 3572 (11.1%) |
| Oxford/AstraZeneca | 220 (0.7%) | 220 (0.7%) |
| Time since primary vaccine schedule, n (%) | ||
| 91-150 days | 1 (0.0%) | 1 (0.0%) |
| 151-180 days | 102 (0.3%) | 102 (0.3%) |
| ≥ 181 days | 32188 (99.7%) | 32188 (99.7%) |
| Type of booster, n (%) | ||
| BioNTech/Pfizer | NA | 4978 (15.4%) |
| Moderna/Lonza | NA | 27313 (84.6%) |
| Note: NA = not applicable, *21873 unique individuals in the no booster group. | ||
| Events | Risk per 10 000 individuals | Events | Risk per 10 000 individuals | |||
|---|---|---|---|---|---|---|
| Overall | 1188 | 755 | 641 | 406 | 46.3 % (41.2, 51) | 349 (301, 400) |
| Age group (years) | ||||||
| 40-54 | 1066 | 822 | 574 | 440 | 46.4 % (40.3, 51.6) | 381 (316, 444) |
| ≥ 55 | 122 | 427 | 67 | 234 | 45.3 % (28.8, 59.3) | 194 (111, 285) |
| Sex | ||||||
| Male | 677 | 700 | 351 | 363 | 48.2 % (41.2, 54.8) | 337 (272, 400) |
| Female | 511 | 843 | 290 | 474 | 43.8 % (35, 50.9) | 369 (277, 451) |
| Type of previous vaccination | ||||||
| BioNTech/Pfizer | 1098 | 778 | 581 | 411 | 47.2 % (41.8, 52.4) | 367 (313, 424) |
| J&J / Janssen | 2 | 318 | 1 | 145 | 54.4 % (-Inf, 100) | 173 (-296, 668) |
| Moderna/Lonza | 84 | 587 | 53 | 361 | 38.5 % (13.7, 57.3) | 226 (70, 395) |
| Oxford/AstraZeneca | 4 | 267 | 6 | 400 | -49.6 % (-753.5, 61.3) | -133 (-505, 280) |
| Time since vaccination completed | ||||||
| 91-195 days | 362 | 1190 | 210 | 688 | 42.2 % (31.2, 51.3) | 502 (348, 642) |
| 196-220 days | 746 | 731 | 385 | 373 | 49 % (42.4, 54.7) | 358 (298, 419) |
| ≥ 221 days | 75 | 338 | 41 | 191 | 43.7 % (19.8, 62.4) | 148 (58, 247) |
| Type of booster | ||||||
| BioNTech/Pfizer | 198 | 706 | 108 | 381 | 46 % (33.9, 58.8) | 325 (211, 458) |
| Moderna/Lonza | 990 | 766 | 533 | 411 | 46.3 % (41.2, 51.2) | 355 (302, 407) |
| Note: Analyses based on 21091 matched pairs who remained under follow-up by day 7 after the booster dose | ||||||
3.3 Long-term hospitalisation (fih1)
Now, the admission in hospital due to covid in the period from January 3 to April 13 and 60 days of follow-up has been selected. The results are shown in Tables 3.6 and 3.7
## Se está analizando el outcome: fih1 mediante la emulación de un ensayo clínico con múltiples inicios de tiempo. Se ha utilizado matching por: gen, czbs, tvc1, n_0, fpauta_90 (in weeks), age (in 5-years groups).
##
## Análisis de supervivencia días 0-60
## caso
## exposicion 0 1 Total
## 0 61228 25 61253
## 1 61248 5 61253
## Total 122476 30 122506
##
## # Estimated effectiveness in Navarra for fih1 is : 80 % (47.8 - 92.3 %)
##
## ########################################################################
##
## Análisis de supervivencia días 7-60
## caso
## exposicion 0 1 Total
## 0 44937 18 44955
## 1 44950 5 44955
## Total 89887 23 89910
##
## # Estimated effectiveness in Navarra for fih1 is : 72.2 % (25.2 - 89.7 %)| Variable | No booster group (n = 61253*) | Booster group (n = 61253) |
|---|---|---|
| Age group (years), n (%) | ||
| 40-44 | 14019 (22.9%) | 14019 (22.9%) |
| 45-49 | 16757 (27.4%) | 16757 (27.4%) |
| 50-54 | 15065 (24.6%) | 15065 (24.6%) |
| 55-59 | 13660 (22.3%) | 13660 (22.3%) |
| 60-64 | 1112 (1.8%) | 1112 (1.8%) |
| 65-69 | 435 (0.7%) | 435 (0.7%) |
| 70-74 | 108 (0.2%) | 108 (0.2%) |
| 75-79 | 53 (0.1%) | 53 (0.1%) |
| 80-84 | 11 (0.0%) | 11 (0.0%) |
| 85-89 | 25 (0.0%) | 25 (0.0%) |
| ≥ 90 | 8 (0.0%) | 8 (0.0%) |
| Sex, n (%) | ||
| Men | 34211 (55.9%) | 34211 (55.9%) |
| Women | 27042 (44.1%) | 27042 (44.1%) |
| Number of previous SARS-CoV-2 tests, n (%) | ||
| 0 | 28693 (46.8%) | 28693 (46.8%) |
| 1 | 13627 (22.2%) | 13627 (22.2%) |
| 2 | 9356 (15.3%) | 9356 (15.3%) |
| ≥ 3 | 9577 (15.6%) | 9577 (15.6%) |
| Type of previous vaccination, n (%) | ||
| BioNTech/Pfizer | 50947 (83.2%) | 50947 (83.2%) |
| J&J / Janssen | 544 (0.9%) | 544 (0.9%) |
| Moderna/Lonza | 8362 (13.7%) | 8362 (13.7%) |
| Oxford/AstraZeneca | 1400 (2.3%) | 1400 (2.3%) |
| Time since primary vaccine schedule, n (%) | ||
| 91-150 days | 11 (0.0%) | 11 (0.0%) |
| 151-180 days | 580 (0.9%) | 580 (0.9%) |
| ≥ 181 days | 60662 (99.0%) | 60662 (99.0%) |
| Type of booster, n (%) | ||
| BioNTech/Pfizer | NA | 10365 (16.9%) |
| Moderna/Lonza | NA | 50888 (83.1%) |
| Note: NA = not applicable, *35874 unique individuals in the no booster group. | ||
| Events | Risk per 10 000 individuals | Events | Risk per 10 000 individuals | |||
|---|---|---|---|---|---|---|
| Overall | 18 | 5 | 5 | 1 | 73.2 % (37.1, 94.3) | 4 (1, 7) |
| Age group (years) | ||||||
| 40-54 | 12 | 5 | 3 | 1 | 76.3 % (31.5, 100) | 3 (1, 6) |
| ≥ 55 | 6 | 8 | 2 | 3 | 66.5 % (-44.3, 100) | 5 (-1, 12) |
| Sex | ||||||
| Male | 13 | 6 | 4 | 2 | 69 % (15.9, 93.3) | 4 (1, 8) |
| Female | 5 | 4 | 1 | 1 | 82.8 % (8.1, 100) | 3 (0, 7) |
| Type of previous vaccination | ||||||
| BioNTech/Pfizer | 16 | 6 | 5 | 2 | 70.1 % (22.2, 93.5) | 4 (1, 7) |
| J&J / Janssen | 1 | 20 | 0 | 0 | 100 % (100, 100) | 20 (0, 59) |
| Moderna/Lonza | 1 | 3 | 0 | 0 | 100 % (100, 100) | 3 (0, 11) |
| Oxford/AstraZeneca | 0 | 0 | 0 | 0 | NaN % (NA, NA) | 0 (0, 0) |
| Time since vaccination completed | ||||||
| 91-195 days | 2 | 3 | 2 | 3 | -2.6 % (-Inf, 100) | 0 (-6, 5) |
| 196-220 days | 9 | 5 | 1 | 1 | 88.7 % (52.7, 100) | 4 (1, 7) |
| ≥ 221 days | 7 | 10 | 2 | 3 | 71.3 % (-19, 100) | 7 (-1, 16) |
| Type of booster | ||||||
| BioNTech/Pfizer | 5 | 7 | 1 | 1 | 80.3 % (-2.4, 100) | 6 (0, 13) |
| Moderna/Lonza | 13 | 5 | 4 | 1 | 70.6 % (26.4, 94.8) | 3 (1, 7) |
| Note: Analyses based on 44955 matched pairs who remained under follow-up by day 7 after the booster dose | ||||||
4 References
1
Danaei G, Rodríguez LAG, Cantero OF, Logan R, Hernán MA. Observational data for comparative effectiveness research: an emulation of randomised trials to estimate the effect of statins on primary prevention of coronary heart disease. Statistical methods in medical research 2013; 22: 70.
2
Monge S, Rojas-Benedicto A, Olmedo C, et al. Effectiveness of mRNA vaccine boosters against infection with the SARS-CoV-2 omicron (B.1.1.529) variant in Spain: a nationwide cohort study. The Lancet Infectious Diseases 2022; published online June. DOI:10.1016/S1473-3099(22)00292-4.