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Importante estudio sobre efectos secundarios de las vacunas ARNm tras 300 millones de dosis
Importante estudio sobre efectos secundarios de las vacunas ARNm tras 300 millones de dosis (¡300!). La inmensa mayoría de efectos 2 son leves y de corta duración. No hay datos que de otros efectos relevantes distintos de los conocidos (miopericarditis)
Safety
of mRNA vaccines administered during the initial 6 months of the US
COVID-19 vaccination programme: an observational study of reports to the
Vaccine Adverse Event Reporting System and v-safe
In
December, 2020, two mRNA-based COVID-19 vaccines were authorised for
use in the USA. We aimed to describe US surveillance data collected
through the Vaccine Adverse Event Reporting System (VAERS), a passive
system, and v-safe, a new active system, during the first 6 months of
the US COVID-19 vaccination programme.
Methods
In
this observational study, we analysed data reported to VAERS and v-safe
during Dec 14, 2020, to June 14, 2021. VAERS reports were categorised
as non-serious, serious, or death. Reporting rates were calculated using
numbers of COVID-19 doses administered as the denominator. We analysed
v-safe survey reports from days 0–7 after vaccination for
reactogenicity, severity (mild, moderate, or severe), and health impacts
(ie, unable to perform normal daily activities, unable to work, or
received care from a medical professional).
Findings
During
the study period, 298 792 852 doses of mRNA vaccines were administered
in the USA. VAERS processed 340 522 reports: 313 499 (92·1%) were
non-serious, 22 527 (6·6%) were serious (non-death), and 4496 (1·3%)
were deaths. Over half of 7 914 583 v-safe participants self-reported
local and systemic reactogenicity, more frequently after dose two
(4 068 447 [71·7%] of 5 674 420 participants for local reactogenicity
and 4 018 920 [70·8%] for systemic) than after dose one (4 644 989
[68·6%] of 6 775 515 participants for local reactogenicity and 3 573 429
[52·7%] for systemic). Injection-site pain (4 488 402 [66·2%] of
6 775 515 participants after dose one and 3 890 848 [68·6%] of 5 674 420
participants after dose two), fatigue (2 295 205 [33·9%] participants
after dose one and 3 158 299 participants [55·7%] after dose two), and
headache (1 831 471 [27·0%] participants after dose one and 2 623 721
[46·2%] participants after dose two) were commonly reported during days
0–7 following vaccination. Reactogenicity was reported most frequently
the day after vaccination; most reactions were mild. More reports of
being unable to work, do normal activities, or of seeking medical care
occurred after dose two (1 821 421 [32·1%]) than after dose one (808 963
[11·9%]); less than 1% of participants reported seeking medical care
after vaccination (56 647 [0·8%] after dose one and 53 077 [0·9%] after
dose two).
Interpretation
Safety
data from more than 298 million doses of mRNA COVID-19 vaccine
administered in the first 6 months of the US vaccination programme show
that most reported adverse events were mild and short in duration.
In
December, 2020, two mRNA COVID-19 vaccines (BNT162b2 [Pfizer-BioNTech];
and mRNA-1273 [Moderna]) were granted emergency use authorisation (EUA)
by the US Food and Drug Administration (FDA) as two-dose series and
recommended for use by the Advisory Committee on Immunization Practices
(ACIP).
the most frequently reported local and systemic symptoms were
injection-site pain, fatigue, and headache. Reactogenicity was more
frequently reported after dose two than after dose one and among
participants younger than 65 years than among older participants.
Phased administration of COVID-19 vaccines in the USA began with
health-care workers and long-term care-facility residents and was
expanded to the general population during spring 2021; however,
implementation plans varied by state.
a new active monitoring system. VAERS was established in 1990 as the US
early warning system to rapidly detect adverse events that might occur
following vaccinations. V-safe was established in 2020 specifically for
monitoring COVID-19 vaccine safety in the USA and collects information
on reactogenicity and effects on health following COVID-19 vaccination.
Previous reports from these systems have been issued.
We aimed to review VAERS and v-safe data during the first 6 months of
the US vaccination programme, when more than 298 million doses of mRNA
COVID-19 vaccines were administered, to better characterise the safety
profile of mRNA vaccines.
Methods
VAERS
VAERS is a national spontaneous reporting system for detecting potential adverse events for authorised or licensed US vaccines.
VAERS is co-administered by the US Centers for Disease Control and
Prevention (CDC) and the US FDA. VAERS accepts reports from health-care
providers and other members of the public primarily through online
submissions and from vaccine manufacturers through electronic
transmissions. The volume of mail, fax, and telephone reports is trivial
compared with public online and manufacturer electronic submissions.
Reports include information about the vaccinated person, type of vaccine
administered, and adverse events experienced. A VAERS report can be
submitted for any event experienced following receipt of a vaccine. We
included all VAERS reports that were submitted for US residents who
received mRNA vaccines and processed from Dec 14, 2020, to June 14,
2021, including any interval from vaccination to event report. Processed
reports were quality checked, and submitted text on the adverse event
was coded using Medical Dictionary for Regulatory Activities (MedDRA)
terminology.
Each VAERS report was assigned at least one and possibly more than one
MedDRA preferred term; preferred terms do not necessarily indicate
medically confirmed diagnoses and they include signs and symptoms of
illness and the ordering and results of diagnostic tests.
VAERS reports were classified as serious if any of the following
outcomes were documented: inpatient hospitalisation, prolongation of
hospitalisation, permanent disability, life-threatening illness,
congenital anomaly or birth defect, or death. Prespecified adverse
events of special interest were selected for enhanced monitoring of
COVID-19 vaccine safety on the basis of biological plausibility,
previous vaccine safety experience, and theoretical concerns related to
COVID-19, such as vaccine-mediated enhanced disease.
VAERS staff requested death certificates and autopsy reports for
reports of death. CDC physicians reviewed VAERS reports and available
death certificates for each death to form an impression about cause of
death. Impressions were assigned to one of the following categories: one
of the 15 most common diagnostic categories from the International
Classification of Disease, Tenth Revision, reported on US death
certificates,
COVID-19 related, other (ie, impression was not included in
prespecified categories), or unknown or unclear if not enough
information were available to determine a cause of death.
V-safe
V-safe
is a voluntary smartphone-based system that uses text messaging and
secure web-based surveys to actively monitor COVID-19 vaccine safety for
common local injection-site and systemic reactions.
V-safe participants receive text messages that link to web-based health
check-in surveys following vaccination, initially daily (days 0–7),
then at longer intervals after vaccination. The system resets to the
initial survey frequency after entry of another dose. We analysed survey
reports from days 0–7 for reactogenicity, severity (mild, moderate, or
severe),
and health impacts (ie, unable to perform normal daily activities,
unable to work, or received care from a medical professional) that were
submitted to v-safe between Dec 14, 2020, and June 14, 2021.
Participants who reported receiving medical care were contacted and
VAERS reports were completed, if clinically indicated.
Data analysis
We
conducted descriptive analyses of available VAERS and v-safe data
following dose one and dose two of BNT162b2 and mRNA-1273 vaccines among
individuals aged at least 16 years. We stratified analyses by sex, age
group, race and ethnicity, serious versus non-serious reports, and
vaccine manufacturer; and for death reports, by time from vaccination to
death (ie, onset interval) and cause of death. Reporting rates to VAERS
were calculated for adverse events using the number of doses of mRNA
vaccines administered during the 6-month period as the denominator.
COVID-19 vaccine administration data were provided through CDC's
COVID-19 Data Tracker.
V-safe
participants who responded to at least one health check-in survey
during days 0–7 after vaccination were included in analyses. Descriptive
statistics were calculated for participants' characteristics (sex, age,
and race and ethnicity), reaction (type and severity) and health impact
by manufacturer, dose number, and number of days following vaccination.
Analyses
were done using SAS (version 9.4). Both VAERS and v-safe conduct
surveillance as a public health function and are exempt from
institutional review board review. Activities were reviewed by the CDC
and done in accordance with applicable federal law and CDC policy.
Role of the funding source
Authors
from the CDC, the funder, were responsible for study design, data
analysis, data interpretation, and writing of the report.
Results
From
Dec 14, 2020, to June 14, 2021, 298 792 852 doses of mRNA COVID-19
vaccines were administered in the USA: 167 177 332 were BNT162b2 and
131 639 515 were mRNA-1273 (appendix p 2).
A greater proportion of vaccines was administered to females
(155 969 573 [53·2%]) than to males (134 373 958 [45·8%]). The median
age at vaccination was 50 years (IQR 33–65) for BNT162b2 and 56 years
(39–68) for mRNA-1273. 112 698 875 (38·4%) recipients were non-Hispanic
White. Race and ethnicity was unknown for 102 227 532 (34·9%) of all
vaccine recipients.
During the study
period, VAERS received and processed 340 522 reports: 164 669 following
BNT162b2 and 175 816 following mRNA-1273 vaccination (table 1).
Of these reports, 313 499 (92·1%) were classified as non-serious;
22 527 (6·6%) were serious, not resulting in death; and 4496 (1·3%) were
deaths (table 1).
246 085 (72·3%) reports were among female participants and 154 171
(45·3%) reports were among those aged 18–49 years; median age was 50
years (IQR 36–64; table 1).
169 877 (49·9%) of those reporting race or ethnicity identified as
non-Hispanic White, and for 75 334 (22·1%) race and ethnicity were
unknown (table 1).
The most common MedDRA preferred terms assigned to non-serious reports
were headache (64 064 [20·4%] of 313 499), fatigue (52 048 [16·6%]),
pyrexia (51 023 [16·3%]), chills (49 234 [15·7%]), and pain (47 745
[15·2%]; table 1).
The most common MedDRA preferred terms assigned to serious reports were
dyspnoea (4175 [15·4%] of 27 023), death (3802 [14·1%]), pyrexia (2986
[11·0%]), fatigue (2608 [9·7%]), and headache (2567 [9·5%]; table 1).
Table 1Characteristics of reports received and processed by VAERS for mRNA COVID-19 vaccines
Data
are n or n (%). Includes vaccines administered from Dec 14, 2020, to
June 14, 2021. VAERS=Vaccine Adverse Event Reporting System.
MedDRA=Medical Dictionary for Regulatory Activities.
* Total includes reports without a vaccine manufacturer listed.
† Race
is not reported for individuals who identify as Hispanic or Latino, but
it is reported for individuals with unknown ethnicity or non-Hispanic
ethnicity.
‡ Signs
or symptoms refer to MedDRA preferred terms and are ordered by most
frequently reported for both vaccines; MedDRA preferred terms are not
mutually exclusive.
§ Not all reports of death were coded with the MedDRA preferred term of death.
The
reporting rate to VAERS was 1049·2 non-serious reports per million
vaccine doses, and 90·4 serious reports per million doses (table 2).
Among the prespecified adverse events of special interest, reporting
rates ranged from 0·1 narcolepsy reports per million doses administered
to 31·3 reports of COVID-19 disease per million doses administered (table 2). 4496 reports of death were made to VAERS following receipt of an mRNA COVID-19 vaccine (table 3).
After review by clinical staff, 25 reports were excluded because of
miscoding of death or duplicate reporting. Of the 4471 reports of deaths
analysed, 2086 (46·7%) were reported following BNT162b2 and 2385
(53·3%) following mRNA-1273. 1906 (42·6%) deaths were in female vaccine
recipients and 2485 (55·6%) were in male recipients; the median age of
participants who died was 76 years (IQR 66–86; table 3). 3647 (81·6%) deaths were reported among individuals aged 60 years or older (table 3).
821 (18·4%) deaths were identified as being in long-term care-facility
residents. Time to death following vaccination was available for 4118
(92·1%) reports; median time was 10·0 days (IQR 3–25). The greatest
number of death reports occurred on day 1 (470 [11·4%] of 4118) and day 2
(312 [7·6%] 4118) following vaccination (appendix p 10).
Table 2Frequency and rates of adverse events of special interest reported to VAERS by recipients of mRNA COVID-19 vaccines
Includes vaccines administered from Dec 14, 2020, to June 14, 2021. VAERS=Vaccine Adverse Event Reporting System.
* Represents reports, not confirmed by case definition. Events are not mutually exclusive.
† Reported death is an adverse event of special interest but counts appear in Table 1, Table 3.
‡ Coagulopathy
is an aggregate term capturing three specific adverse events:
thrombocytopenia, deep venous thrombosis or pulmonary embolism, and
disseminated intravascular coagulopathy.
§ No vaccine manufacturer was provided for one report of stroke.
Includes
reports made and vaccines administered from Dec 14, 2020, to June 14,
2021. VAERS=Vaccine Adverse Event Reporting System.
* Of 4496 deaths, 25 were excluded as they could not be confirmed or were duplicate reports upon review.
† Doses
of vaccine administered in the study period were used for denominators
in each age group; does not include doses administered in Texas because
data for Texas were reported to the US Centers for Disease Control and
Prevention in aggregate.
‡ Reporting rates not shown for unknown categories because of unreliable dose denominators.
Death
certificates or autopsy reports were available for clinical review for
808 (18·1%) of 4471 reports of deaths. Among these, causes of death were
most commonly diseases of the heart (376 [46·5%]) and COVID-19 (102
[12·6%]; appendix pp 3–4).
Among the 3663 reports of death without a death certificate or autopsy,
causes of death were most commonly unknown or unclear (1984 [54·2%]),
diseases of the heart (621 [17·0%]), and COVID-19 (317 [8·7%]; appendix pp 3–4). Causes of death among reports with death certificate or autopsy reports available are shown by age in appendix p 5.
During
the study period, 7 914 583 mRNA COVID-19 vaccine recipients enrolled
in v-safe after dose one or dose two and completed at least one
post-vaccination health survey during days 0–7 (table 4).
The median age of v-safe participants was 50 years (IQR 36–63),
4 975 209 (62·9%) were female, 2 860 738 (36·1%) were male, and
4 701 715 (59·4%) identified as non-Hispanic White (table 4). 6 775 515 participants completed at least one survey during days 0–7 after dose one (table 5).
Of these participants, 4 644 989 (68·6%) reported a local
injection-site reaction and 3 573 429 (52·7%) reported a systemic
reaction (table 5).
Of the 5 674 420 participants who completed surveys after dose two,
4 068 447 (71·7%) reported an injection-site reaction and 4 018 920
(70·8%) a systemic reaction (table 5). Local injection-site reactions were reported more frequently after mRNA-1273 than after BNT162b2 (table 5). A similar pattern was found for systemic reactions after mRNA-1273 versus BNT162b2 (table 5).
The most frequently reported events after dose one of either mRNA
vaccine included injection-site pain, fatigue, and headache, which were
also more frequent after dose two than after dose one (table 5). Differences in proportions of reactogenicity by dose number were similar after stratifying by age (<65 vs ≥65 years) and sex (appendix p 6).
More reactogenicity was reported among participants younger than 65
years than older participants and by female participants than male
participants (appendix p 6).
Table 4Demographic
characteristics of v-safe participants reporting receipt of an mRNA
COVID-19 vaccine and completing at least one health survey 0–7 days
after vaccination
Data are n (%). Includes vaccines administered from Dec 14, 2020, to June 14, 2021.
* Race
is not reported for individuals who identify as Hispanic or Latino, but
it is reported for individuals with unknown ethnicity or non-Hispanic
ethnicity.
† Unknown indicates that v-safe participants selected unknown or preferred not to say.
‡ Unavailable refers to information that was not collected or was missing in v-safe.
Table 5Local
and systemic reactions and health impacts following mRNA COVID-19
vaccines reported during days 0–7 after vaccination to v-safe, by
manufacturer and dose
Local and systemic reactions stratified by manufacturer, dose, days after vaccination, and severity are shown in the figure. Most reported symptoms were mild (figure). Participants reported moderate and severe reactogenicity most commonly on day 1 after dose two of either mRNA vaccine (figure). The proportion of participants who reported symptoms was greatest on day 1 and then decreased subsequently (figure). The highest proportions of participants reporting severe symptoms occurred on day 1 following dose two of mRNA-1273 (appendix p 8). On all other days, proportions of participants reporting severe symptoms did not exceed 3·0% for any individual symptom (appendix pp 7–8).
FigureLocal
and systemic reactions to mRNA COVID-19 vaccines reported to v-safe, by
manufacturer, dose, days after vaccination, and severity
Reported
health impacts were greater following dose two of either vaccine than
dose one, and after mRNA-1273 than after BNT162b2 (table 5).
After dose two of BNT162b2, 598 584 (20·5%) of 2 920 526 participants
were unable to do normal activities, and 360 411 (12·3%) were unable to
work (table 5).
After dose two of mRNA-1273, 903 095 (32·8%) of 2 753 894 participants
were unable to do normal activities, and 550 955 (20·0%) were unable to
work (table 5). Less than 1·0% reported receiving medical care after receiving either dose of either vaccine (table 5). A very small proportion reported an emergency room visit or hospitalisation (table 5).
When
stratified by sex, female participants reported a health impact more
frequently than did male participants, peaking on day 1 after
vaccination (appendix p 11).
Following dose two of mRNA-1273 vaccine, 522 192 (41·4%) of 1 262 711
female participants reported an inability to do normal activities in the
day 1 survey, and 296 178 (23·5%) reported an inability to work (appendix pp 9, 11).
Among male recipients of dose two of mRNA-1273, on the day 1 survey
167 957 (25·6%) of 655 688 were unable to do normal activity and 110 868
(16·9%) were unable to work (appendix pp 9, 11).
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