MESSAGE
| DATE | 2021-05-08 |
| FROM | Ruben Safir
|
| SUBJECT | Subject: [Hangout - NYLXS] Vaccine Safety data and effectiveness - origianl
|
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00947-8/fulltext
Summary
Background
Following the emergency use authorisation of the Pfizer–BioNTech mRNA
COVID-19 vaccine BNT162b2 (international non-proprietary name
tozinameran) in Israel, the Ministry of Health (MoH) launched a campaign
to immunise the 6·5 million residents of Israel aged 16 years and older.
We estimated the real-world effectiveness of two doses of BNT162b2
against a range of SARS-CoV-2 outcomes and to evaluate the nationwide
public-health impact following the widespread introduction of the vaccine.
Methods
We used national surveillance data from the first 4 months of the
nationwide vaccination campaign to ascertain incident cases of
laboratory-confirmed SARS-CoV-2 infections and outcomes, as well as
vaccine uptake in residents of Israel aged 16 years and older. Vaccine
effectiveness against SARS-CoV-2 outcomes (asymptomatic infection,
symptomatic infection, and COVID-19-related hospitalisation, severe or
critical hospitalisation, and death) was calculated on the basis of
incidence rates in fully vaccinated individuals (defined as those for
whom 7 days had passed since receiving the second dose of vaccine)
compared with rates in unvaccinated individuals (who had not received
any doses of the vaccine), with use of a negative binomial regression
model adjusted for age group (16–24, 25–34, 35–44, 45–54, 55–64, 65–74,
75–84, and ≥85 years), sex, and calendar week. The proportion of spike
gene target failures on PCR test among a nationwide convenience-sample
of SARS-CoV-2-positive specimens was used to estimate the prevelance of
the B.1.1.7 variant.
Findings
During the analysis period (Jan 24 to April 3, 2021), there were 232 268
SARS-CoV-2 infections, 7694 COVID-19 hospitalisations, 4481 severe or
critical COVID-19 hospitalisations, and 1113 COVID-19 deaths in people
aged 16 years or older. By April 3, 2021, 4 714 932 (72·1%) of 6 538 911
people aged 16 years and older were fully vaccinated with two doses of
BNT162b2. Adjusted estimates of vaccine effectiveness at 7 days or
longer after the second dose were 95·3% (95% CI 94·9–95·7; incidence
rate 91·5 per 100 000 person-days in unvaccinated vs 3·1 per 100 000
person-days in fully vaccinated individuals) against SARS-CoV-2
infection, 91·5% (90·7–92·2; 40·9 vs 1·8 per 100 000 person-days)
against asymptomatic SARS-CoV-2 infection, 97·0% (96·7–97·2; 32·5 vs 0·8
per 100 000 person-days) against symptomatic COVID-19, 97·2% (96·8–97·5;
4·6 vs 0·3 per 100 000 person-days) against COVID-19-related
hospitalisation, 97·5% (97·1–97·8; 2·7 vs 0·2 per 100 000 person-days)
against severe or critical COVID-19-related hospitalisation, and 96·7%
(96·0–97·3; 0·6 vs 0·1 per 100 000 person-days) against COVID-19-related
death. In all age groups, as vaccine coverage increased, the incidence
of SARS-CoV-2 outcomes declined. 8006 of 8472 samples tested showed a
spike gene target failure, giving an estimated prevalence of the B.1.1.7
variant of 94·5% among SARS-CoV-2 infections.
Interpretation
Two doses of BNT162b2 are highly effective across all age groups (≥16
years, including older adults aged ≥85 years) in preventing symptomatic
and asymptomatic SARS-CoV-2 infections and COVID-19-related
hospitalisations, severe disease, and death, including those caused by
the B.1.1.7 SARS-CoV-2 variant. There were marked and sustained declines
in SARS-CoV-2 incidence corresponding to increasing vaccine coverage.
These findings suggest that COVID-19 vaccination can help to control the
pandemic.
Funding
None.
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Introduction
As of April 3, 2021, the SARS-CoV-2 pandemic has resulted in more than
131 million cases and more than 2·8 million deaths worldwide,1
including 821 748 cases and 6236 deaths in Israel2
(population 9·1 million). Among the SARS-CoV-2 strains characterised
globally in 2020, the D614G variant was dominant.3
More recently, the SARS-CoV-2 variant B.1.1.7, first identified in the
UK and associated with increased transmissibility, has emerged in
several countries.3
B.1.1.7 was first reported in Israel on Dec 23, 2020.4
Research in context
Evidence before this study
The Pfizer–BioNTech mRNA COVID-19 vaccine BNT162b2, administered as two
doses 21 days apart, was authorised for emergency use in Israel in
December, 2020, after it was shown to have high efficacy against
symptomatic laboratory-confirmed COVID-19 in a randomised controlled
trial of individuals aged 16 years and older. Since the initiation of
vaccine rollout, we have been closely monitoring the scientific
literature (including preprint servers) and press coverage to identify
reports of BNT162b2 vaccine effectiveness. Although observational
studies have estimated the effectiveness of BNT162b2, precise nationwide
effectiveness estimates of two doses of BNT162b2 against SARS-CoV-2
outcomes are lacking. More data are particularly needed regarding the
vaccine's effectiveness against severe disease and deaths, and
effectiveness in older adults. Finally, no country has yet described the
nationwide public health impact of a national COVID-19 vaccination campaign.
Added value of this study
This analysis of nationwide surveillance data, done in a period when
SARS-CoV-2 variant B.1.1.7 was the dominant strain, provides precise
real-world estimates of the high effectiveness of two doses of BNT162b2
against a range of SARS-CoV-2 outcomes, including symptomatic and
asymptomatic infection and hospitalisation or death due to COVID-19. The
median follow-up time of 7 weeks after the second dose for vaccinated
individuals was longer than that in previous reports. Marked and
sustained declines in the incidence of SARS-CoV-2 infections were
observed in all age groups as the percentage of individuals vaccinated
with two BNT162b2 doses began to rise, thereby showing, at a national
level, the beneficial public health impact of a nationwide vaccination
campaign.
Implications of all the available evidence
Vaccination with two doses of BNT162b2 has high efficacy and
effectiveness against a range of SARS-CoV-2 outcomes, including among
older adults (aged ≥85 years), offering hope that COVID-19 vaccination
will eventually control the pandemic. These findings are of
international importance as vaccination programmes ramp up across the
rest of the world, suggesting that other countries can similarly achieve
marked and sustained declines in SARS-CoV-2 incidence if they can
achieve high vaccine uptake.
In a randomised controlled trial (RCT), two doses of the Pfizer–BioNTech
mRNA COVID-19 vaccine BNT162b2 (international non-proprietary name
tozinameran) had 95% efficacy against symptomatic laboratory-confirmed
COVID-19 at least 7 days after the second dose in people aged 16 years
or older with no evidence of existing or previous SARS-CoV-2 infection.5
After emergency use authorisation of BNT162b2 in Israel on Dec 6, 2020,
the Ministry of Health (MoH) launched a nationwide vaccination campaign
to administer two doses of BNT162b2 to the 6·5 million people aged 16
years and older (71% of the population). On April 3, 2021, 61% of the
population of Israel had received at least one dose of a COVID-19
vaccine, a proportion higher than that of any other country in the world.6
Preliminary estimates of the effectiveness of one dose of BNT162b2 have
been reported from Denmark,7
Israel,8
, 9
the UK,10
, 11
and the USA,12
and estimates for two doses of BNT162b2 have been described for a subset
of the Israeli population enrolled in a health maintenance organisation.13
However, no estimates of the effectiveness of two doses of BNT162b2
against a range of SARS-CoV-2 outcomes, including among older adults,
have been reported. Furthermore, population-level estimates of the
impact of a COVID-19 vaccine on the incidence of SARS-CoV-2 infections
have not been reported.
In this study, we provide nationwide estimates of the effectiveness of
two doses of BNT162b2 against a range of SARS-CoV-2 outcomes and to
evaluate the nationwide public-health impact following the widespread
introduction of the vaccine.
Methods
Study design and population
In this observational study, we analysed nationwide surveillance data
from Jan 24 to April 3, 2021, to assess the effectiveness of the
BNT162b2 vaccine against various SARS-CoV-2 outcomes. The study
population consisted of residents of Israel (ie, the census population)
aged 16 years and older. The start of the study period corresponded to
14 days after the first individuals received their second BNT162b2 dose.
Health care in Israel is universal, with government-funded participation
in one of four nationwide medical insurance programmes that operate as
health maintenance organisations:14
Clalit (in which 54% of the population are enrolled), Maccabi (26%),
Meuhedet (12%), and Leumit (8%).15
All Israeli residents are assigned a unique identification number that
enables data linkage in the national medical records database.
The Israel MoH planned, organised, and continues to lead the nationwide
vaccination campaign, which began on Dec 20, 2020, and was initially
targeted at people aged 65 years and older, health-care workers, and
residents of long-term care facilities. Vaccine availability was
subsequently expanded, approximately weekly, to younger age cohorts in
5-year intervals. Until Feb 28, 2021, because of an insufficient vaccine
supply, individuals with a previous diagnosis of laboratory-confirmed
SARS-CoV-2 infection were instructed to not seek vaccination, unless
they were a resident of a long-term care facility. However, an unknown
number of previously diagnosed people received vaccine. Immunisations
were given at around 400 vaccination sites. At these sites, information
about the administered vaccine was entered into the patient's electronic
health record and reported to the national database.
Surveillance of COVID-19 and vaccine uptake are part of the national
pandemic response and are collected under Public Health Ordinance number
40. Only aggregate data, with no personal identifiers, were used in this
analysis.
The analysis plan for this study was internally reviewed by senior
management in the MoH Public Health Services and found to be compliant
with all regulatory requirements including the MoH guidelines for human
subject research. As no regulatory issues were identified, it was
decided that a full ethical review was not necessary. The study followed
the Strengthening the Reporting of Observational studies in Epidemiology
guidelines.16
Testing for SARS-CoV-2, including variant B.1.1.7
SARS-CoV-2 testing is free-of-charge and widely available in Israel.
Testing is required for people returning from travel abroad, in close
contact with an infected person, or with suggestive symptoms such as
fever or acute respiratory illness. When seeking testing, individuals
provide their identification number and a specimen is collected via
nasal or nasopharyngeal swab. Specimens are tested, using national
testing standards, at one of 48 clinical diagnostic laboratories with
use of real-time PCR tests. B.1.1.7 prevalence was estimated on the
basis of swabs tested at Leumit with the TaqPath COVID-19 test (Thermo
Fisher Scientific, Pleasanton, CA, USA), which identifies spike gene
target failure (SGTF) associated with gene mutations that cause
deletions of amino acids 69 and 70 in the spike protein. Because these
mutations are found in B.1.1.7, SGTF is used to estimate the prevalence
of this variant.17
, 18
Public health surveillance
MoH conducts surveillance for laboratory-confirmed SARS-CoV-2
infections, with mandatory daily reporting of PCR results by all
diagnostic laboratories. An epidemiological investigation, including an
interview about COVID-19 symptoms, is done for each SARS-CoV-2
infection, usually within 2 days of diagnosis. MoH also conducts
surveillance of COVID-19-associated hospitalisations. Daily updates are
received from all hospitals and linked to the national database using
patients' identification numbers. Hospitalisations are classified as
severe (if a patient has a resting respiratory rate of >30 breaths per
minute, oxygen saturation on room air of <94%, or a ratio of PaO2 to
FiO2 of <300) or critical (in the event of mechanical ventilation,
shock, or cardiac, hepatic, or renal failure). In accordance with
national guidelines, health-care providers attributed any
hospitalisations and deaths among individuals with laboratory-confirmed
SARS-CoV-2 infection to COVID-19.2
, 19
Outcomes
Vaccine effectiveness estimates were assessed against six SARS-CoV-2
outcomes, comprising asymptomatic infections and five other hierarchical
laboratory-confirmed outcomes: all SARS-CoV-2 infections (symptomatic
and asymptomatic), symptomatic COVID-19 cases, and COVID-19-related
hospitalisations, severe or critical hospitalisations (including those
who died), and deaths. Asymptomatic infection was defined as a person
with laboratory-confirmed SARS-CoV-2 infection who reported no fever and
no respiratory symptoms during the symptom interview portion of the
epidemiological investigation, and who was not subsequently hospitalised
for or did not die from COVID-19.
Statistical analysis
Individuals were defined as unvaccinated if they had not received any
doses of BNT162b2, and as fully vaccinated if at least 7 days had passed
since receiving the second dose of BNT162b2. Incidence rates were
calculated for unvaccinated and fully vaccinated individuals aged 16
years and older for each SARS-CoV-2 outcome after excluding people with
previous laboratory-confirmed SARS-CoV-2 infection. Data were stratified
by age group (16–24, 25–34, 35–44, 45–54, 55–64, 65–74, 75–84, and ≥85
years, based on 2020 census data), sex, and calendar week. In the
primary analysis, cases were categorised as vaccinated if the date of
laboratory confirmation of infection occurred at least 7 days after the
second dose of BNT162b2. Cases were excluded from the analysis if they
had received only one dose, or had received two doses of BNT162b2 and
fewer than 7 days had passed since the second dose. Person-days for the
fully vaccinated group were ascertained each day by multiplying the
proportion of people who were fully vaccinated with two doses of
BNT162b2 by the census estimates for each age stratum. Person-days for
the unvaccinated group were determined each day by subtracting the
number of person-days contributed by those who were vaccinated from the
total census population for each age stratum; this process was repeated,
summed, and aggregated for each day of the study period. Individuals
with previous SARS-CoV-2 infection were excluded from person-day
estimates. Using STATA (version 15), a negative binomial regression
model (nbreg command), which is better suited for over-dispersion of
variance than the traditional Poisson regression method,20
was used to derive incidence rate ratios (IRRs) with 95% CIs for each
outcome adjusted for age group, sex, and calendar week. The exposure
command was used to account for varying patient-days across strata.21
Vaccine effectiveness estimates were calculated as (1 – IRR) × 100. In
sensitivity analyses, vaccine effectiveness estimates were also
calculated with the same method for people who had received two BNT162b2
doses and for whom at least 14 days had passed after the second dose, as
well as for those who had received one dose and for whom 14–21 days had
passed after the first dose.
Role of the funding source
The Israel MoH and Pfizer separately provided in-kind support to this
study. No funding was exchanged between the Israel MoH and Pfizer. MoH
and Pfizer were involved in the study design and writing of the report,
and approved the decision to submit for publication.
Results
The vaccination campaign was launched on Dec 20, 2020, around the time
of a surge in SARS-CoV-2 infections in Israel that resulted in a
nationwide lockdown on Dec 27, 2020 (figure 1). Additional lockdown
restrictions were implemented on Jan 8, 2021. Daily SARS-CoV-2
infections increased in December, 2020, peaking at 10 213 on Jan 20,
2021. Phased reopening occurred on Feb 7 and Feb 21, 2021, and the
lockdown was lifted on March 7, 2021.
Figure thumbnail gr1
Figure 1Daily laboratory-confirmed SARS-CoV-2 infections in Israel (Nov
1, 2020, to April 3, 2021)
View Large Image Figure ViewerDownload Hi-res image Download (PPT)
From Jan 24 to April 3, 2021 (the study period), there were 232 268
SARS-CoV-2 infections. 213 919 (92·1%) of infected individuals were
interviewed and 186 109 (87·1%) answered the questions about the
presence or absence of symptoms. People aged 16 years or older accounted
for 154 648 (66·6%) infections, among which 31 548 (20·4%) were in the
Arab sector, 24 280 (15·7%) in the ultra-Orthodox sector, and 98 220
(63·9%) in the general Jewish (non-ultra-Orthodox) sector. During the
study period, 7694 COVID-19 hospitalisations, 4481 severe or critical
COVID-19 hospitalisations, and 1113 COVID-19 deaths occurred in people
aged 16 years or older. 8472 (60%) of Leumit PCR tests used TaqPath
during the study period, of which 8006 had an SGTF, giving an estimated
prevalence of 94·5% for the B.1.1.7 variant.
As of April 3, 2021, BNT162b2 was the only COVID-19 vaccine available in
Israel, and more than 10·0 million doses were administered to more than
5·2 million people. Overall, 4 714 932 (72·1%) of 6 538 911 people aged
16 years or older and 1 015 620 (90·0%) of 1 127 965 people aged 65
years or older were fully vaccinated with two doses (table 1). By
sector, among those aged 16 years or older, 669 542 (54·6%) of 1 226 788
in the Arab population, 228 479 (42·8%) of 534 146 in the ultra-Orthodox
population, and 3 816 911 (79·9%) of 4 777 977 in the general Jewish
population were fully vaccinated with two doses. Median follow-up for
people who received two doses was 48 days (IQR 30–60).
Table 1Numbers and proportions of people fully vaccinated with BNT162b2
in the Israel population aged 16 years and older (Jan 24 to April 3, 2021)
Population Fully vaccinated*
Age-groups, years
16–44 3 646 848 2 290 820 (62·8%)
45–64 1 764 098 1 408 492 (79·8%)
≥65 1 127 965 1 015 620 (90·0%)
Sex†
Female 3 337 693 2 398 547 (71·9%)
Male 3 201 218 2 310 788 (72·2%)
Sector
Arab 1 226 788 669 542 (54·6%)
Ultra-Orthodox 534 146 228 479 (42·8%)
General Jewish (non-ultra-Orthodox) 4 777 977 3 816 911 (79·9%)
Calendar week in 2021
Jan 17 to 23 .. 248 196
Jan 24 to 30 .. 773 331
Jan 31 to Feb 6 .. 767 416
Feb 7 to 13 .. 285 272
Feb 14 to 20 .. 412 001
Feb 21 to 27 .. 443 542
Feb 28 to March 6 .. 408 882
March 7 to 13 .. 391 983
March 14 to 20 .. 415 510
March 21 to 27 .. 382 569
March 28 to April 3 .. 186 230
Overall 6 538 911 4 714 932 (72·1%)
Data are n or n (%).
* Defined as people for whom at least 7 days had passed after the second
dose of BNT162b2 vaccine.
† Sex was not recorded for 5597 fully vaccinated individuals.
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Among 154 648 SARS-CoV-2 infections in those aged 16 years and older,
109 876 (71·0%) were unvaccinated and 6266 (4·1%) were fully vaccinated
(with ≥7 days after the second dose). Among 54 677 people aged 16 years
and older who had symptomatic COVID-19, 39 065 (71·4%) were unvaccinated
and 1692 (3·1%) received two doses (with ≥7 days after the second dose).
Among 7694 people aged 16 years and older who were hospitalised with
COVID-19, 5526 (71·8%) were unvaccinated and 596 (7·7%) received two
doses with ≥7 days after the second dose. 4481 COVID-19-related severe
or critical hospitalisations occurred in people aged 16 years and older,
among which 3201 (71·4%) people were unvaccinated and 364 (8·1%) were
fully vaccinated. Of the 1113 people aged 16 years and older who died
from COVID-19, 715 (64·2%) were unvaccinated and 138 (12·4%) were fully
vaccinated.
The incidence rate of SARS-CoV-2 infections among adults aged 16 years
and older was 91·5 per 100 000 person-days in the unvaccinated group and
3·1 per 100 000 person-days in the fully vaccinated group, with an
estimated vaccine effectiveness (adjusted for age group, sex, and
calendar week) against SARS-CoV-2 infection of 95·3% (95% CI 94·9–95·7%;
table 2, appendix p 3). The adjusted estimates of vaccine effectiveness
were 91·5% (90·7–92·2%) against asymptomatic SARS-CoV-2 infection, 97·0%
(96·7–97·2%) against symptomatic COVID-19, 97·2% (95% CI 96·8–97·5%)
against COVID-19 hospitalisation, 97·5% (97·1–97·8%) against severe or
critical hospitalisation, and 96·7% (95% CI 96·0–97·3%) against death
(table 2). Adjusted vaccine effectiveness estimates against all COVID-19
outcomes were higher than 96% among people aged 75 years and older and
people aged 85 years and older (table 3). Vaccine effectiveness
estimates adjusted for each day of the study period (rather than
calendar week) yielded similar results (data not shown).
Table 2Estimated effectiveness of two doses of BNT162b2 (≥7 days after
the second dose) against laboratory-confirmed SARS-CoV-2 outcomes by age
group (Jan 24 to April 3, 2021)
Unvaccinated Fully vaccinated*
Vaccine effectiveness
Cases Incidence rate per 100 000 person-days†
Cases Incidence rate per 100 000 person-days‡
Unadjusted Adjusted§
SARS-CoV-2 infection¶
Age 16–44 years 84 611 95·1 1801 2·3 95·4% (94·0–96·5) 96·1% (95·7–96·5)
Age 45–64 years 18 579 86·1 2264 3·4 93·6% (91·4–95·3) 94·9% (94·2–95·5)
Age ≥65 years 5686 67·7 2201 3·8 93·4% (91·3–95·0) 94·8% (93·9–95·5)
All ages 109 876 91·5 6266 3·1 94·2% (93·2–95·1) 95·3% (94·9–95·7)
Asymptomatic SARS-CoV-2 infection
Age 16–44 years 40 088 45·1 1174 1·5 92·8% (90·3–94·7) 93·6% (92·8–94·4)
Age 45–64 years 7414 32·6 1343 2·0 89·1% (84·7–92·3) 90·8% (89·6–91·9)
Age ≥65 years 1636 19·5 1115 1·9 85·9% (80·2–89·9) 88·5% (86·4–90·3)
All ages 49 138 40·9 3632 1·8 90·1% (88·0–91·8) 91·5% (90·7–92·2)
Symptomatic COVID-19
Age 16–44 years 28 196 31·7 352 0·5 97·8% (97·0–98·3) 97·6% (97·3–97·8)
Age 45–64 years 7790 34·3 560 0·8 96·3% (95·0–97·3) 96·7% (96·3–97·0)
Age ≥65 years 3079 36·6 780 1·4 96·1% (94·8–97·1) 96·4% (95·9–97·0)
All ages 39 065 32·5 1692 0·8 96·6% (95·8–97·2) 97·0% (96·7–97·2)
COVID-19-related hospitalisation
Age 16–44 years 2043 2·3 33 <0·01 98·1% (97·1–98·8) 98·1% (97·3–98·7)
Age 45–64 years 1687 7·4 112 0·2 97·6% (96·9–98·2) 97·6% (97·1–98·1)
Age ≥65 years 1826 21·7 451 0·8 96·6% (95·3–97·6) 96·8% (96·2–97·3)
All ages 5526 4·6 596 0·3 96·7% (95·5–97·6) 97·2% (96·8–97·5)
Severe or critical COVID-19-related hospitalisation
Age 16–44 years 644 0·7 7 0·01 98·8% (97·3–99·5) 98·9% (97·6–99·5)
Age 45–64 years 1132 5·0 62 0·1 98·1% (97·2–98·6) 98·1% (97·5–98·5)
Age ≥65 years 1425 17·0 295 0·5 97·2% (95·9–98·1) 97·3% (96·8–97·8)
All ages 3201 2·7 364 0·2 97·2% (95·9–98·1) 97·5% (97·1–97·8)
COVID-19-related death
Age 16–44 years 36 0·04 0 0·0 100 100
Age 45–64 years 125 0·5 14 <0·01 96·2% (92·6–98·0) 95·8% (92·6–97·6)
Age ≥65 years 554 6·6 124 0·2 96·8% (94·6–98·1) 96·9% (96·0–97·6)
All ages 715 0·6 138 0·1 96·6% (93·9–98·1) 96·7% (96·0–97·3)
Numbers and incidence rates of outcomes are shown for unvaccinated and
fully vaccinated individuals. Vaccine effectiveness estimates are % (95%
CI).
* Defined as people for whom at least 7 days had passed after the second
dose of BNT162b2 vaccine.
† Total person-days for all outcomes were 88 938 455 for age 16–44
years, 22 734 025 for age 45–64 years, 8 403 760 for age ≥65 years, and
120 076 240 for all ages.
‡ Total person-days for all outcomes were 77 280 720 for age 16–44
years, 67 027 505 for age 45–64 years, 57 573 640 for age ≥65 years, and
201 881 865 for all ages.
§ Model is adjusted for age group (16–24, 25–34, 35–44, 45–54, 55–64,
65–74, 75–84, and ≥85 years), sex, and calendar week.
¶ Includes asymptomatic and symptomatic infections, as well as cases
with positive SARS-CoV-2 tests for which the symptom interview portion
of the epidemiological investigation was not completed.
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Table 3Estimated effectiveness of two doses of BNT162b2 (≥7 days after
the second dose) against laboratory-confirmed SARS-CoV-2 outcomes in the
oldest age groups (Jan 24 to April 3, 2021)
Vaccine effectiveness*
Age ≥65 years Age ≥75 years Age ≥85 years
SARS-CoV-2 infection†
94·8% (93·9–95·5) 95·1% (93·9–96·0) 94·1% (91·9–95·7)
Asymptomatic SARS-CoV-2 infection 88·5% (86·4–90·3) 87·5% (84·2–90·1)
83·2% (76·3–88·1)
Symptomatic COVID-19 96·4% (95·9–97·0) 96·7% (95·9–97·4) 96·6% (95·2–97·6)
COVID-19-related hospitalisation 96·8% (96·2–97·3) 97·0% (96·2–97·7)
96·9% (95·5–97·9)
Severe or critical COVID-19-related hospitalisation 97·3% (96·8–97·8)
97·6% (96·8–98·1) 97·4% (95·9–98·3)
COVID-19-related death 96·9% (96·0–97·6) 97·1% (96·0–97·9) 97·0% (94·9–98·3)
Estimates are % (95% CI).
* Model is adjusted for age group (16–24, 25–34, 35–44, 45–54, 55–64,
65–74, 75–84, and ≥85 years), sex, and calendar week.
† Includes asymptomatic and symptomatic infections, as well as cases
with positive SARS-CoV-2 tests for which the symptom interview portion
of the epidemiological investigation was not completed.
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Adjusted vaccine effectiveness estimates against all SARS-CoV-2 outcomes
were slightly higher at 14 days or longer after the second dose (table
4; appendix p 4) and somewhat lower at 14–21 days after the first dose
(appendix p 5) compared with those at 7 days or longer after the second
dose. Vaccine effectiveness against deaths was estimated to be 98·1% at
14 days or longer after the second dose and 77·0·% at 14–21 days after
the first dose (in contrast to 96·7% at 7 days or longer after the
second dose).
Table 4Estimated effectiveness of two doses of BNT162b2 (≥14 days after
the second dose) against laboratory-confirmed SARS-CoV-2 outcomes by age
group (Jan 24 to April 3, 2021)
Unvaccinated Fully vaccinated*
Vaccine effectiveness
Number of cases Incidence rate per 100 000 person-days†
Number of cases Incidence rate per 100 000 person-days‡
Unadjusted Adjusted§
SARS-CoV-2 infection¶
Age 16–44 years 84 611 95·1 1066 1·7 97·2% (96·3–97·8) 97·1% (96·7–97·3)
Age 45–64 years 19 579 86·1 1292 2·2 96·5% (95·6–97·2) 96·5% (96·3–96·7)
Age ≥65 years 5686 67·7 1284 2·5 96·1% (95·1–96·9) 95·9% (95·5–96·3)
All ages 109 876 91·5 3642 2·1 96·6% (96·1–97·0) 96·5% (96·3–96·8)
Asymptomatic SARS-CoV-2 infection
Age 16–44 years 40 088 45·1 666 1·1 95·8% (94·4–96·9) 95·2% (94·6–95·8)
Age 45–64 years 7414 32·6 729 1·3 94·3% (92·4–95·7) 94·0% (93·4–94·4)
Age ≥65 years 1636 19·5 633 1·2 91·7% (88·8–93·8) 91·5% (90·4–92·5)
All ages 49 138 40·9 2028 1·2 94·4% (93·3–95·3) 93·8% (93·3–94·2)
Symptomatic COVID-19
Age 16–44 years 28 196 31·7 230 0·4 98·4% (97·7–98·8) 97·8% (97·5–98·1)
Age 45–64 years 7790 34·3 333 0·6 97·9% (97·2–98·4) 97·7% (97·4–97·9)
Age ≥65 years 3079 36·6 437 0·9 97·9% (97·3–98·4) 97·5% (97·2–97·8)
All ages 39 065 32·5 1000 0·6 98·0% (97·6–98·3) 97·7% (97·5–97·9)
COVID-19-related hospitalisation
Age 16–44 years 2043 2·3 26 0·0 98·1% (97·0–98·8) 98·1% (97·1–98·7)
Age 45–64 years 1687 7·4 74 0·1 98·3% (97·6–98·7) 98·2% (97·7–98·6)
Age ≥65 years 1826 21·7 259 0·5 98·2% (97·6–98·7) 97·9% (97·6–98·1)
All ages 5556 4·6 359 0·2 98·2% (97·5–98·7) 98·0% (97·7–98·3)
Severe or critical COVID-19-related hospitalisation
Age 16–44 years 644 0·7 5 0·01 98·9% (97·3–99·6) 99·0% (97·5–99·6)
Age 45–64 years 1132 5·0 41 0·1 98·6% (97·9–99·0) 98·5% (97·9–98·9)
Age ≥65 years 1425 17·0 160 0·3 98·7% (98·1–99·1) 98·3% (98·0–98·6)
All ages 3201 2·7 206 0·1 98·6% (98·0–99·0) 98·4% (98·1–98·6)
COVID-19-related death
Age 16–44 years 36 0·04 0 0 100 100
Age 45–64 years 125 0·5 10 <0·01 96·9% (93·5–98·5) 96·5% (93·2–98·2)
Age ≥65 years 554 6·6 61 0·1 98·7% (97·8–99·2) 98·2% (97·7–98·7)
All ages 715 0·6 71 <0·01 98·5% (97·4–99·2) 98·1% (97·6–98·5)
Numbers and incidence rates of outcomes are shown for unvaccinated and
fully vaccinated individuals. Vaccine effectiveness estimates are % (95%
CI).
* Defined as people for whom at least 14 days had passed after the
second dose of BNT162b2 vaccine.
† Total person-days for all outcomes were 88 938 455 for age 16–44
years, 22 734 025 for age 45–64 years, 8 403 760 for age ≥65 years, and
120 076 240 for all ages.
‡ Total person-days for all outcomes were 77 280 720 for age 16–44
years, 67 027 505 for age 45–64 years, 57 573 640 for age ≥65 years, and
201 881 865 for all ages.
§ Model is adjusted for age group (16–24, 25–34, 35–44, 45–54, 55–64,
65–74, 75–84, and ≥85 years), sex, and calendar week.
¶ Includes asymptomatic and symptomatic infections, as well as cases
with positive SARS-CoV-2 tests for which the symptom interview portion
of the epidemiological investigation was not completed.
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Overall, as cumulative vaccination coverage increased, the 7-day daily
moving average of incident cases of SARS-CoV-2 infection (per 100 000
people) markedly declined across all age groups (figure 2). Notably,
steeper and earlier declines were observed in older age groups, which
had higher and earlier vaccine coverage. Specifically, although some
declines in incident infections were evident around 2 weeks following
the implementation of lockdown, sharper declines followed increased
vaccine uptake. For example, steep reductions in incident cases of
SARS-CoV-2 infections were observed for people aged 65 years and older
starting in mid-January, 2021, but were not observed until 3–4 weeks
later among people aged 16–24 years, when vaccine coverage for this age
group began to increase. Similar marked declines in all age groups,
corresponding to increasing vaccine coverage, were seen in the incidence
of COVID-19 hospitalisations, severe or critical hospitalisations, and
deaths (appendix pp 6–11). It is also noteworthy that the declines
continued even after the two phases of reopening and the final lifting
of the lockdown.
Figure thumbnail gr2
Figure 2Incident cases of SARS-CoV-2 infection and prevalence of
BNT162b2 vaccination by age group in Israel (Dec 1, 2020, to March 6, 2021)
Show full caption
View Large Image Figure ViewerDownload Hi-res image Download (PPT)
Discussion
This nationwide observational study, with a median follow-up period of
almost 7 weeks after receipt of the second vaccine dose, showed high
effectiveness of two doses of BNT162b2, including among older adults,
against SARS-CoV-2 infections and COVID-19 cases, hospitalisations,
severe disease, and deaths. Corroborating the high effectiveness
observed, marked declines in incident cases of SARS-CoV-2 infection were
observed as vaccine coverage increased. Although population-level
vaccine effectiveness data are ecological, and teasing apart the impact
of a vaccination programme from the impact of non-pharmaceutical
interventions (including a nationwide lockdown) is complex, it is
noteworthy that declines in incident cases of SARS-CoV-2 for each age
group corresponded with achieving high vaccine coverage in that age
group rather than initiation of the nationwide lockdown. These findings
suggest that the primary driver of reductions in the incidence of
SARS-CoV-2 infections was high vaccine coverage, not implementation of
the lockdown. Furthermore, even after reopenings occurred, SARS-CoV-2
incidence remained low, suggesting that high vaccine coverage might
provide a sustainable path towards resuming normal activity. These data
provide nationwide evidence of the beneficial public health impact of a
COVID-19 vaccination campaign.
During the study period, 95% of 8472 tested specimens showed an SGTF,
associated with SARS-CoV-2 variant B.1.1.7, thereby providing evidence
that BNT162b2 is effective against B.1.1.7. These findings are
consistent with laboratory studies that indicated that BNT162b2 was
likely to be effective against B.1.1.7.22
Notably, another clinically important variant, B.1.351, which was
initially identified in South Africa, has recently been identified in
Israel.23
Vaccine effectiveness against B.1.351, however, could not be estimated
in our study because of the small number of B.1.351 infections
identified in Israel during the study period.
This study also suggests that two doses of BNT162b2 are effective
against asymptomatic SARS-CoV-2 infections (with vaccine effectiveness
estimates of 92% at ≥7 days after the second dose and 94% at ≥14 after
the second dose). Estimates of effectiveness against asymptomatic
infections were slightly lower than those against COVID-19, which could
suggest a higher threshold of protection for asymptomatic infection
compared with symptomatic illness. We conservatively defined
asymptomatic infections as SARS-CoV-2 infections in interviewees who
reported no fever and no respiratory symptoms at the time of the
interview. Additionally, it is possible that some SARS-CoV-2-infected
individuals who reported being asymptomatic at the time of interview
might have instead been presymptomatic (ie, developed symptoms later).
Although we made efforts to avoid this type of misclassification by
excluding the small number of people who were initially reported to be
asymptomatic but were later hospitalised for or died from COVID-19, some
presymptomatic individuals who later developed symptoms without being
hospitalised or dying might still have been included. This type of
misclassification, however, was probably uncommon and would be unlikely
to substantially influence the vaccine effectiveness estimate against
asymptomatic infection.
Notably, Israel's SARS-CoV-2 testing policy was different for
unvaccinated and vaccinated individuals during the study period. At 7
days after the second dose, vaccinated individuals were exempt from the
SARS-CoV-2 testing required of individuals who either had contact with a
laboratory-confirmed case or returned from travel abroad. This testing
policy might have resulted in a differential bias that would cause
overestimation of vaccine effectiveness against asymptomatic infection
(ie, asymptomatic people who received two doses were less likely to be
tested than unvaccinated asymptomatic people). However, 19% of the 4·4
million PCR tests conducted during the study period were done on
exempted individuals (MoH, unpublished data). Additionally, symptomatic
individuals might have been reluctant to report symptoms for fear of
being blamed for infecting other individuals, in which case asymptomatic
vaccine effectiveness would also be overestimated. Conversely,
individuals who were hesitant to receive a COVID-19 vaccine might also
have been reluctant to seek SARS-CoV-2 testing, which would lead to
underestimation of vaccine effectiveness against asymptomatic infection.
Further studies are needed to confirm the magnitude of BNT162b2
protection against asymptomatic infection that we observed.
Specifically, studies are needed to evaluate testing behaviour of
vaccinated and unvaccinated people and to determine the extent to which
prevention of asymptomatic infection leads to interruption of transmission.
Two-dose BNT162b2 vaccine effectiveness estimates from this
observational study align with the 95% efficacy against symptomatic
SARS-CoV-2 infections shown in the pivotal RCT.5
Our study adds important new data about the effectiveness of BNT162b2
derived from outside of the RCT setting. We found high vaccine
effectiveness against a wider range of SARS-CoV-2 outcomes (including
severe COVID-19 and deaths) than were evaluated in the RCT, as well as
high effectiveness in older adults with a level of precision not
available in the RCT. In addition, although pregnant women and
immunocompromised individuals were excluded from the RCT, these groups
were recommended to receive BNT162b2 in Israel and an unknown number
would, therefore, have been vaccinated. Finally, unlike the clinical
trial, our study provides evidence that achieving high population-level
coverage with BNT162b2 can lead to marked declines in the incidence of
SARS-CoV-2 infections and COVID-19 outcomes.
In the primary analysis of the Israel MoH surveillance data, we
evaluated the effectiveness of two doses of BNT162b2, given Israel's
adherence to the authorised two-dose 21-day vaccine schedule. In the
sensitivity analysis, we showed moderate effectiveness of the vaccine
against all SARS-CoV-2 outcomes at 14–21 days after the first dose. This
finding is similar to those of studies from Israel8
, 9
early in the vaccine campaign and in the UK.10
, 11
Estimated effectiveness against all outcomes at 14–21 days after the
first dose was lower than that of two doses at 7 days or longer or at 14
days or longer after the second dose, demonstrating the importance of
fully vaccinating adults. Furthermore, despite indications of at least
partial effectiveness after one dose of BNT162b2, relying on protection
against COVID-19 from a single dose might not be prudent; BNT162b2 was
developed and evaluated in the RCT as a two-dose schedule,5
and substantially lower levels of neutralising antibodies were observed
after one dose compared with after two doses.24
Additionally, little is known about the duration of protection of one
dose and how it compares with the durability after two doses. It is
possible that one dose will provide a shorter duration of protection
than two doses, particularly in an environment where new SARS-CoV-2
variants continue to emerge.
Our study has some limitations. In the absence of randomisation, there
could have been unmeasured differences between vaccinated and
unvaccinated persons (eg, different test-seeking behaviours or levels of
adherence to non-pharmaceutical interventions) which might have
confounded our vaccine effectiveness estimates.25
Although we adjusted our estimates for age, sex, and calendar week, the
effect of additional covariates such as location, comorbidities, race or
ethnicity, socioeconomic status, and likelihood of seeking SARS-CoV-2
testing should be evaluated in future studies. Preliminary findings from
a study in Israel, for example, indicate that neighbourhood might be an
important confounder.9
Misclassification of exposures and outcomes in our study are potentially
more common than in the RCT, although misclassification was probably
limited by Israel's readily available SARS-CoV-2 testing and
comprehensive surveillance system. Misclassification of vaccine history
in our study was also unlikely because of comprehensive recording of
vaccine administration in Israel. With nearly 7 weeks of follow-up after
the second dose, our study has the longest follow-up reported so far,
although longer-term data on effectiveness are needed. Another
limitation is that the time from symptom onset to hospitalisation and
death might have prevented identification of all hospitalisations and
deaths during the study period. Such unidentified hospitalisations and
deaths are unlikely, however, to be differential between the vaccinated
and unvaccinated groups. Finally, given differences between countries in
how vaccines are rolled out and in how the pandemic evolves, caution
should be used in extrapolating our findings to other populations.
Further real-world effectiveness studies of BNT162b2, and other COVID-19
vaccines, in other populations and settings are needed.
Israel provides a unique opportunity to observe the nationwide impact on
SARS-CoV-2 transmission of a rapidly increasing percentage of the
population with vaccine-derived immunity. SARS-CoV-2 transmission is
likely to continue until the proportion of the population with immunity
exceeds a herd immunity threshold,26
which has been estimated to be at least 60%,27
although the emergence of more transmissible SARS-CoV-2 variants could
result in higher herd immunity thresholds. Achieving the SARS-CoV-2 herd
immunity threshold might not be reached, however, without vaccinating
some individuals younger than 16 years. In addition, the duration of
immunity to SARS-CoV-2, either from infection or immunisation, is not
known, and progress towards herd immunity in Israel could be disrupted
by the emergence of new SARS-CoV-2 variants if those variants are less
susceptible to the current vaccine-induced immune response and if they
were to become broadly disseminated. Further studies are needed to
monitor the population level of immunity, identify disruption of viral
transmission, and detect and evaluate the effects of emerging SARS-CoV-2
variants.
This study showed that two doses of BNT162b2 were highly effective,
including in older adults, against laboratory-confirmed SARS-CoV-2
infections and COVID-19 hospitalisations, severe disease, and deaths in
a nationwide observational study where variant B.1.1.7 was the dominant
strain. Marked nationwide declines in the incidence of SARS-CoV-2
infections and COVID-19 outcomes corresponded with increasing vaccine
coverage, and these declines were sustained even after societal
reopening. Finally, the high effectiveness against all SARS-CoV-2
infections and apparent effectiveness against infections that were
asymptomatic at the time of epidemiological investigation suggest that
BNT162b2 might reduce SARS-CoV-2 transmission. Taken together, these
findings suggest that high vaccine uptake can meaningfully stem the
pandemic and offers hope for eventual control of the SARS-CoV-2 outbreak
as vaccination programmes ramp up across the rest of the world.
Contributors
EJH and SA-P conceived the study, conducted the analysis, and edited the
final manuscript. EJH, FJA, JMM, and DLS wrote the first draft of the
protocol. EJH, JMM, FK, and KP cleaned and analysed the data. All
authors contributed to study design, drafting the protocol, and revising
the manuscript for important intellectual content, were responsible for
the decision to submit for publication, and approved the final submitted
version of the manuscript. All authors had full access to the
deidentified and aggregated data in the study. EJH, JMM, and FK accessed
and verified the data underlying the study and take responsiblity for
the data.
Data sharing
The individual-level data used in this study are sensitive and cannot be
publicly shared. Requests for data should be made to the Ministry of
Health of Israel. Aggregated surveillance data are freely available
online at https://data.gov.il/dataset/covid-19.
Declaration of interests
FJA, JMM, FK, GM, KP, JS, DLS, and LJ hold stock and stock options in
Pfizer. All other authors declare no competing interests.
Acknowledgments
We thank Natalia Bilenko, Tal Brosh, Dani Cohen, Ron Dagan, Aharona
Glatman-Freedman, Michael Gdalevich, Manfred Green, Yoram Hamu, Amit
Huppert, Udi Kaliner, Boaz Lev, Ella Mendelson, Ami Mizrachi, Walid
Salliba, Avigdor Shafferman, Chen Stein-Zamir, Michal Stein, Dana Wolf,
and Gidon Zuriely of the Israel Advisory Council for COVID-19 Vaccine
Effectiveness for their guidance and feedback on data management and
analysis. We also thank Rona Kaiser, Hanna Levi, Gilad Saar, Osnath
Dreyfuss, and Natalia Pertsovsky from the Israel MoH for data management
and programming assistance; Yotam Shenhar from Leumit Health Services
and Ron Milo and Yinon Bar On from the Weizmann Institute of Science for
assistance with data on SARS-CoV-2 variant B.1.1.7 in Israel; and Marc
Lipsitch and Miguel Hernan from Harvard University for epidemiological
guidance. We acknowledge Ugur Sahin and Özlem Türeci from BioNTech, the
holder of the emergency use authorisation for BNT162b2 in Israel;
BNT162b2 is produced using BioNTech proprietary mRNA technology and was
developed by BioNTech and Pfizer.
Supplementary Material
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Supplementary appendix
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