COVID-19 Vaccines To Prevent SARS-CoV-2 Infection - UpToDate

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COVID-19: Vaccines to prevent SARS-CoV-2 infection

Authors: Kathryn M Edwards, MD, Walter A Orenstein, MD
Section Editor: Martin S Hirsch, MD
Deputy Editor: Allyson Bloom, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2021. | This topic last updated: Sep 08, 2021.
INTRODUCTION
At the end of 2019, a novel coronavirus now known as severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) was identified as the cause of a cluster of pneumonia cases in
Wuhan, a city in the Hubei Province of China. It rapidly spread, resulting in a global
pandemic. In February 2020, the World Health Organization named the disease COVID-19,
which stands for coronavirus disease 2019 [1].
Vaccines to prevent SARS-CoV-2 infection are considered the most promising approach for
curbing the pandemic and are being vigorously pursued. By the end of 2020, several vaccines
had become available for use in different parts of the world, over 40 candidate vaccines were
in human trials, and over 150 were in preclinical trials. The World Health Organization
maintains an updated list of vaccine candidates under evaluation [2].
This topic will cover vaccines for SARS-CoV-2, with a focus on vaccines available in the United
States, vaccines in the later stages of development, and anticipated issues related to
licensure, allocation, uptake, and post-licensure monitoring. Other aspects related to
prevention of COVID-19 are discussed in detail elsewhere. (See "COVID-19: Epidemiology,
virology, and prevention", section on 'Prevention'.)
GENERAL PRINCIPLES
Overview of vaccine development — As with the development of pharmaceuticals, vaccine
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development progresses through preclinical evaluation and three distinct clinical stages [3]:
● Phase I trials – These are designed to test vaccine safety, although immunogenicity is
also measured; dose-ranging studies are also often included.
● Phase II trials – These expand the safety profile and immune response assessment in
larger numbers of participants.
● Phase III trials – These are designed to determine efficacy in preventing a predefined
endpoint, usually laboratory-confirmed disease. Vaccine efficacy in percent is the
reduction in disease incidence among those who received vaccine versus those who
received the control product and is calculated with the following formula: ((attack rate in
the unvaccinated – attack rate in the vaccinated)/attack rate in the unvaccinated) x 100.
Efficacy criteria for SARS-CoV-2 trials are discussed elsewhere. (See 'Steps to vaccine
availability and delivery' below.)
Traditionally, these steps occur sequentially, and each usually takes several years for
completion. COVID-19 vaccine development has accelerated to an unprecedented pace, with
each step occurring over several months. Additionally, in the COVID-19 vaccine initiative,
phase I and II and phase II and III studies have frequently been combined with a seamless
transition from one phase into the next. Nevertheless, safety criteria remain stringent; data
safety and monitoring committees (DSMCs) composed of independent vaccine experts and
study sponsors assess adverse events that are reported in each phase of clinical study and
approve advancement to the next phase. In the United States, the Food and Drug
Administration (FDA) must also approve progression to each next step in human trials, from
initiation of phase I trials through progression to phase III trials, based on data generated in
the prior step.
Lessons from SARS-CoV-1 and MERS-CoV vaccines — Vaccine development for SARS-CoV-1

and Middle East respiratory syndrome coronavirus (MERS-CoV) paved the way for rapid
development of COVID-19 vaccines. Pre-clinical studies were completed with SARS-CoV-1
vaccines, and two vaccines were evaluated in small human trials; however, further work was
halted once the virus was eliminated from circulation [4,5]. After MERS-CoV emerged,
preclinical vaccine studies and phase I human studies were conducted against this agent
[6,7].
Antigenic target — The major antigenic target for both SARS-CoV-1 and MERS vaccines
was the large surface spike protein [8-10]. An analogous protein is also present in SARS-
CoV-2 ( figure 1); it binds to the angiotensin-converting enzyme 2 (ACE2) receptor on host
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cells and induces membrane fusion ( figure 2) [11]. Based on data from SARS-CoV-1 and
MERS-CoV vaccine studies, as well as observations that antibodies binding to the receptor-
binding domain of the SARS-CoV-2 spike protein can prevent attachment to the host cell and
neutralize the virus, the spike protein became the predominant antigenic target for
COVID-19 vaccine development [12].
Vaccine-enhanced disease — Animal studies of vaccines for SARS-CoV-1 and MERS-CoV

had raised concerns for enhanced disease with vaccination; after challenge with wild-type
virus, some previously vaccinated animals developed non-neutralizing antibody and Th2 cell
responses that were associated with eosinophilic lung inflammation [13-15]. No enhanced
disease was seen in any human studies. Nevertheless, specific immunologic parameters had
been proposed for animal and human studies to reduce the risk of enhanced disease with
COVID-19 vaccines [16]. These include criteria for neutralizing antibody and Th1-polarized
cellular immune responses.
Immunologic basis for SARS-CoV-2 vaccination — Several observations support the

concept that vaccination has the potential to prevent SARS-CoV-2 infection. In nonhuman
primate studies, experimental infection with wild-type SARS-CoV-2 virus protected against
subsequent reinfection, indicating that infection can result in protective immunity [17,18].
Vaccination of primates also protected against viral challenge; development of functional
neutralizing antibodies correlated with protection [19-21]. Epidemiologic studies in humans
have also suggested that neutralizing antibodies are associated with protection from
infection, as illustrated in an outbreak on a fishing vessel [22]. Thus, vaccines that elicit a
sufficient neutralizing response should be able to offer protection against COVID-19. (See
"COVID-19: Epidemiology, virology, and prevention", section on 'Immune responses following
infection'.)
The site of vaccine delivery may impact the character of the immune response [12]. Natural
respiratory infections elicit both mucosal and systemic immune responses. Most vaccines,
however, are administered intramuscularly (or intradermally) and elicit primarily a systemic
immune response, with less robust protection in the upper respiratory mucosa than after
natural infection. Some vaccines can be administered intranasally, approximating natural
infection, and these may elicit a mucosal immune response, although they typically do not
induce as high of a systemic antibody response as inactivated vaccines do [23,24]. Live
attenuated COVID-19 vaccines administered to the respiratory tract are undergoing
preclinical studies. (See 'Vaccine platforms' below.)
Vaccine platforms — COVID-19 vaccines are being developed using several different
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platforms ( figure 3) [12]. Some of these are traditional approaches, such as inactivated
virus or live attenuated viruses, which have been used for inactivated influenza vaccines and
measles vaccine, respectively. Other approaches employ newer platforms, such as
recombinant proteins (used for human papillomavirus vaccines) and vectors (used for Ebola
vaccines). Some platforms, such as RNA and DNA vaccines, have never been employed in a
licensed vaccine. General descriptions of the different platforms used for COVID-19 vaccines
are presented here. Examples of specific COVID-19 vaccines developed using these different
platforms are discussed in detail elsewhere. (See 'Immunogenicity, efficacy, and safety of
select vaccines' below.)
● Inactivated vaccines – Inactivated vaccines are produced by growing SARS-CoV-2 in cell

culture then chemically inactivating the virus [25,26]. The inactivated virus is often
combined with alum or another adjuvant in the vaccine to stimulate an immune
response. Inactivated vaccines are typically administered intramuscularly. They require a
biosafety level 3 facility for production. Immune responses to a SARS-CoV-2 inactivated
vaccine would target not only the spike protein but also other components of the virus.
Prototype inactivated COVID-19 vaccines are being developed in China, India, and
Kazakhstan; several are in late-stage clinical trials. (See 'Immunogenicity, efficacy, and
safety of select vaccines' below.)
● Live attenuated vaccines – Live attenuated vaccines are produced by developing

genetically weakened versions of the wild-type virus; these weakened viruses replicate in
the recipient to generate an immune response but do not cause disease [25,26].
Attenuation can be achieved by modifying the virus genetically or by growing it in
adverse conditions so that virulence is lost but immunogenicity is maintained. A live
attenuated COVID-19 vaccine would hopefully stimulate both humoral and cellular
immunity to multiple components of the whole attenuated virus. Another advantage of
live vaccines is that they can be administered intranasally, as with the live attenuated
influenza vaccine, which might induce mucosal immune responses at the site of viral
entry in the upper respiratory tract. However, safety concerns with live attenuated
vaccines include reversion to or recombination with the wild-type virus. Several live
attenuated COVID-19 vaccines are in pre-clinical development, but none have reached
human trials [2].
● Recombinant protein vaccines – Recombinant protein vaccines are composed of viral

proteins that have been expressed in one of various systems, including insect and
mammalian cells, yeast cells, and plants. These vaccines are typically administered
intramuscularly. They do not require replication of the live virus, which facilitates
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production, although production yields depend on the ability to express the spike
protein, which is variable. Recombinant COVID-19 vaccines in development include
recombinant spike protein vaccines, recombinant receptor-binding domain vaccines, and
virus-like particle (VLP) vaccines [2]. A recombinant spike protein vaccine in late-phase
clinical trials is discussed elsewhere. (See 'Immunogenicity, efficacy, and safety of select
vaccines' below.)
● Vector vaccines
• Replication-incompetent vector vaccines – Replication-incompetent vector

vaccines use a different vector virus that has been engineered to not replicate in vivo
and to express the viral protein that is the intended immune target. Many
replication-incompetent vector vaccine candidates use adenovirus vectors, but other
vectors include modified vaccinia Ankara (MVA), human parainfluenza virus,
influenza virus, adeno-associated virus (AAV), and Sendai virus [2]. One drawback to
vector vaccines is that pre-existing immunity to the vector can attenuate
immunogenicity of the vaccine [27]. This can be avoided by using viral vectors that
are uncommon in humans, vectors derived from animal viruses, such as a
chimpanzee adenovirus, or vectors that do not induce self-immunity, such as AAV.
Most SARS-CoV-2 replication-incompetent vector vaccines in development are
administered intramuscularly and are engineered to express the spike protein, with
a resultant host immune response to that protein. Several are in late phase clinical
trials. (See 'Immunogenicity, efficacy, and safety of select vaccines' below.)
• Replication-competent vector vaccines – Replication-competent vectors are

derived from attenuated or vaccine strains of viruses. Using replication-competent
vectors often results in a more robust immune response than with replication-
incompetent vectors, since they replicate within the vaccinated individual and
trigger an innate immune response. Among COVID-19 vaccine candidates,
replication-competent vectors have been engineered to express the spike protein in
measles vaccine strain vectors, influenza virus-based vectors, vesicular stomatitis
virus (VSV) [2], and Newcastle disease virus (NDV) [2,28,29]. NDV-based vectors
propagate to high titers in eggs and could be produced using the global influenza
vaccine production pipeline; they could also be given intranasally to stimulate
mucosal immunity at the site of viral entry. Several replication-competent vector
vaccines are in early-phase clinical trials.
• Inactivated virus vector vaccines – Inactivated virus vectors are engineered to
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express the target protein but have been inactivated and are thus safer since they
cannot replicate, even in the immunocompromised host. Inactivated virus vector
COVID-19 vaccines that display spike protein on the surface are still in the preclinical
stage of development.
● DNA vaccines – DNA vaccines consist of plasmid DNA that contain mammalian
expression promotors and the target gene, so that the target protein is expressed in the
vaccine recipient. Large quantities of stable plasmid DNA can be generated in Escherichia
coli, which is a major production advantage. However, DNA vaccines are often of low
immunogenicity and need special delivery devices, such as electroporators, which limit
their use. Further, DNA vaccines must reach the nucleus to be transcribed to messenger
RNA (mRNA) so proteins can be generated to stimulate an immune response. SARS-
CoV-2 DNA vaccines in development contain the spike protein gene as the target [20].
● RNA vaccines – RNA vaccines were the first vaccines for SARS-CoV-2 to be produced and
represent an entirely new vaccine approach. Once administered, the RNA is translated
into the target protein, which is intended to elicit an immune response. The mRNA
remains in the cell cytoplasm and does not enter into the nucleus; mRNA vaccines do not
interact with or integrate into the recipient's DNA. These vaccines are produced
completely in vitro, which facilitates production. However, since the technology is new,
the ability to produce large quantities of RNA vaccines has not been previously tested,
and some of the vaccines must be maintained at very low temperatures, complicating
storage. Some SARS-CoV-2 RNA vaccines are now available. (See 'Immunogenicity,
efficacy, and safety of select vaccines' below and 'Approach to vaccination' below.)
APPROACH TO VACCINATION
United States
Indications and vaccine selection — In the United States, the COVID-19 mRNA vaccine
BNT162b2 (Pfizer-BioNTech COVID-19 vaccine) has been approved by the Food and Drug
Administration, and the COVID-19 mRNA vaccine mRNA-1273 (Moderna COVID-19 vaccine)
and the adenoviral vector vaccine Ad26.COV2.S (Janssen COVID-19 vaccine, also referred to
as the Johnson & Johnson vaccine) have been granted emergency use authorization (EUA) for
prevention of COVID-19 [30-32]. We recommend vaccination with one of these vaccines.
● BNT162b2 (Pfizer-BioNTech COVID-19 vaccine) is indicated for individuals aged 12 years

or older.
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● mRNA-1273 (Moderna COVID-19 vaccine) is indicated for individuals aged 18 years or

older.
● Ad26.COV2.S (Janssen COVID-19 vaccine) is indicated for individuals aged 18 years or

older.
The choice between these COVID-19 vaccines is based on availability. They have not been
compared directly, so comparative efficacy is unknown. However, they are all highly effective
and substantially reduce the risk of COVID-19, especially severe/critical disease. Differences
in the magnitudes of effect reported from efficacy trials might be related to factors other
than effectiveness, including differences in the trial populations and locations, timing of the
trials during the pandemic, and study design. The differences in age ranges included in the
indications reflect the different age ranges included in the efficacy trials.
The possibility of rare adverse events should also inform the selection among vaccines.
Ad26.COV2.S has been associated with thrombosis with thrombocytopenia and possibly
Guillain-Barre syndrome, and the mRNA vaccines have been associated with myocarditis. The
risks of these events are extremely small, and the benefits of the vaccine outweigh them.
Nevertheless, potential recipients should be aware of the risks. (See 'Specific safety concerns'
below.)
Individuals who have a contraindication to a vaccine in one class (eg, an mRNA vaccine)
should not receive other vaccines in that class but can receive a vaccine in the other class
with precautions. (See 'Contraindications and precautions (including allergies)' below.)
Details on the efficacy and safety of these vaccines are discussed elsewhere. (See
'Immunogenicity, efficacy, and safety of select vaccines' below.)
Administration
Dose and interval
● BNT162b2 (Pfizer-BioNTech COVID-19 vaccine) is administered in two intramuscular

doses of 0.3 mL each, given three weeks (21 days) apart.
Each vial of BNT162b2 contains at least five doses after dilution. With low dead-space
syringes, the volume in each vial may be sufficient to supply six full doses; in such cases,
all six doses can be administered [33]. However, any residual volume less than a full dose
(ie, <0.3 mL) should be discarded and should not be pooled with residuals from other
vials.
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● mRNA-1273 (Moderna COVID-19 vaccine) is administered in two intramuscular doses of

0.5 mL each, given one month (28 days) apart.
● Ad26.COV2.S (Janssen COVID-19 vaccine, also referred to as the Johnson & Johnson
vaccine) is administered in one intramuscular dose of 0.5 mL.
For individuals with certain immunocompromising conditions ( table 1), the mRNA
vaccines are given as a three-dose series [30,31]. (See 'Immunocompromised individuals'
below.)
In adults and adolescents, intramuscular vaccines are typically injected into the deltoid.
Proper injection technique to reduce the risk of shoulder injury involves injection at a 90°
angle into the central, thickest part of the deltoid ( figure 4). (See "Standard immunizations
for nonpregnant adults", section on 'Technique'.)
Additional details on administration can be found on the CDC website. The following table
details CDC recommendations on the management of vaccine administration errors (
table 2).
Deviations from recommended dosing intervals — For the mRNA vaccines, which are
given as two-dose series, the second dose should be given as close to the recommended
interval as possible but not earlier than recommended [34]. If necessary, the second dose
can be scheduled for up to six weeks (42 days) after the first dose. If the second dose is not
given within this time frame, it should be given as soon as feasible. The United States
Centers for Disease Control and Prevention (CDC) notes that the series does not need to be
repeated if the second dose is given too early or given more than six weeks after the first
dose ( table 2). The efficacy of administering vaccines outside of the recommended time
frames is uncertain, although with some vaccines, using longer intervals has been associated
with higher titer antibody responses.
Completion of two-dose series — Each vaccine series should be completed with the

same vaccine initially used [34]; there are insufficient data to inform the efficacy and safety of
using one of the vaccines for the first dose and another for the second. If extenuating
circumstances result in needing to complete the series with a different mRNA vaccine, the
CDC recommends that the second dose be given at least 28 days after the first. If the mRNA
vaccine that was used for the first dose is temporarily unavailable at the time that the second
dose is due, the CDC prefers delaying the second dose so that the same vaccine product can
be used. If two different vaccine products are used to complete the series, no additional
doses of either mRNA vaccine are recommended ( table 2).
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For individuals who received a first dose of an mRNA vaccine but cannot receive either mRNA
vaccine for the second dose (eg, because of contraindications), Ad26.COV2.S can be given as
long as there is not also a contraindication to Ad26.COV2.S (see 'Contraindications and
precautions (including allergies)' below). The CDC suggests giving Ad26.COV2.S at least 28
days after the mRNA vaccine dose [34]. Such individuals should be considered to have
received a complete AD26.COV2.S vaccine regimen.
Use of Ad26.COV2.S to complete an mRNA vaccine series has not been directly studied.
However, some evidence on use of two different vaccines to complete a series suggests
robust immunogenicity but a higher rate of systemic reactions (fever, fatigue, headaches,
myalgias) compared with using the same vaccine for both doses [35-37].
Timing with relation to non-COVID-19 vaccines — Although there are no data

regarding safety and efficacy when COVID-19 vaccines are coadministered with other
vaccines, the CDC has stated that COVID-19 vaccines can be administered at any time in
relation to other non-COVID-19 vaccines, and if needed, can be administered on the same
day as other vaccines [34]. It is unknown if local and systemic side effects are more frequent
or more intense with coadministration on the same day, but this will be monitored. The
Advisory Committee on Immunization Practices (ACIP) had previously suggested that non-
COVID-19 vaccines not be administered within 14 days of COVID-19 vaccination, but the
recommendation was revised because of concerns of resulting delays in vaccination. The
updated approach was also influenced by experience with other vaccines that suggests that
coadministration does not compromise safety or immunogenicity.
Limited role for post-vaccination testing — Unless indicated to evaluate for

suspected infection, there is no role for routine post-vaccination testing for COVID-19.
Specifically, serologic testing following vaccination to confirm an antibody response is not
warranted. Many serologic tests will not detect the type of antibodies elicited by vaccination.
This is discussed elsewhere. (See "COVID-19: Diagnosis", section on 'Testing following
COVID-19 vaccination'.)
Some side effects of vaccination overlap with symptoms of COVID-19. Systemic reactions (eg,
fever, chills, fatigue, headache) that occur within the first day or two after vaccination and
resolve within a day or two are consistent with a reaction to the vaccine. However, respiratory
symptoms or systemic symptoms that occur after the first couple days following vaccination
or that last several days could be indicative of COVID-19 and warrant testing. (See "COVID-19:
Diagnosis", section on 'Preferred initial test and specimen collection'.)
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Special populations
History of SARS-CoV-2 infection — We suggest eligible individuals with a history of

SARS-CoV-2 infection receive a COVID-19 vaccine; pre-vaccination serologic screening to
identify prior infection is not recommended [34]. For two-dose vaccine series (ie, with the
mRNA COVID-19 vaccines), if SARS-CoV-2 infection is diagnosed following the first vaccine
dose, the second dose should still be given.
Individuals with recent, documented SARS-CoV-2 infection (including those who are
diagnosed following the first vaccine dose) should have recovered from acute infection and
met criteria for discontinuation of isolation precautions before receiving the vaccine (either
the initial dose or the second dose of a two-dose series) (see 'Administration' above). It is also
reasonable for such individuals to delay any vaccine receipt for a few months after infection
to allow others to get vaccinated sooner, as the risk of reinfection appears extremely low in
this period. The CDC also suggests that individuals who received monoclonal antibodies or
convalescent plasma for COVID-19 should delay vaccination for at least 90 days from the
time of treatment [34]. This delay also applies to receipt of the second vaccine dose of a two-
dose series if antibody-based COVID-19 therapy was administered after the initial vaccine
dose.
For individuals who had SARS-CoV-2 infection complicated by multisystem inflammatory

syndrome (MIS), the decision to vaccinate should weigh the risk of exposure, reinfection, and
severe disease with infection against the uncertain safety of vaccination in such individuals.
Given the hypothesis that MIS is associated with immune dysregulation precipitated by SARS-
CoV-2 infection, it is unknown if a SARS-CoV-2 vaccine could trigger a similar dysregulated
response.
Vaccination is likely still beneficial in many patients with a history of SARS-CoV-2 infection.
Although reinfection appears uncommon in individuals who develop detectable antibodies
after SARS-CoV-2 infection, ascertainment of prior infection can be unreliable or impractical
in some cases, and the duration of protection from prior infection is unknown. Vaccination
appears to further boost antibody levels in those with past infection and might improve the
durability and breadth of protection. Vaccination following SARS-CoV-2 infection has been
associated with a lower risk of subsequent reinfection [38]. Several small studies have
suggested that after a single mRNA vaccine dose, individuals with evidence of prior SARS-
CoV-2 infection mount substantially higher binding and neutralizing antibody responses
compared with SARS-CoV-2-naïve individuals [39-44]. Furthermore, studies suggest that in
individuals with prior infection, a single mRNA vaccine dose augments neutralizing antibody
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levels as well as cell-mediated responses against other SARS-CoV-2 variants (Alpha [B.1.1.7]
and Beta [B.1.351]) [45,46].
Despite the promising data, until there is longer follow-up of single-dose mRNA vaccination
in a broader population of individuals with prior infection, the full two-dose series is
recommended when mRNA vaccines are used.
Individuals with a history of SARS-CoV-2 may be more likely to experience local and systemic
adverse effects (eg, fevers, chills, myalgias, fatigue) after a first vaccine dose than SARS-
CoV-2-naïve individuals [34,42,47]. This is not a contraindication or precaution to a second
dose (if receiving a vaccine given as two doses). In published reports of individuals with
persistent symptoms following acute COVID-19, vaccination has not been associated with
exacerbation of these symptoms [48].
Immunocompromised individuals — We suggest that eligible individuals who have

an immunocompromising condition or are taking immunosuppressive agents undergo
COVID-19 vaccination. Immunogenicity and effectiveness of COVID-19 vaccines appear lower
in such individuals compared with the general population; nevertheless, the potential for
severe COVID-19 in this population outweighs the uncertainties. Considerations for
immunocompromised patients given the potential for reduced vaccine response include the
following:
● Additional vaccine dose – We agree with recommendations from the ACIP that
individuals with certain immunocompromising conditions who received a two-dose
mRNA vaccine series receive a third dose (if possible, the same vaccine formulation
should be used) [49]; authorization for the mRNA vaccines was updated to include a third
dose, to be given at least 28 days after the second dose, for such individuals [30,31].
Immunocompromising conditions that would warrant a third dose include active use of
chemotherapy for cancer, hematologic malignancies, hematopoietic stem cell or solid
organ transplant, advanced or untreated HIV infection with CD4 cell count <200
cells/microL, moderate or severe primary immunodeficiency disorder, and use of
immunosuppressive medications (eg, mycophenolate mofetil, rituximab, prednisone >20
mg/day for >14 days) ( table 1) [50]. Several other countries, including France,
Germany, and Israel, have made similar recommendations [51]. Patients with
immunocompromising conditions should be advised to continue other protective
measures regardless of the number of vaccine doses received, as immune response may
not be optimal even with three doses.
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In studies of transplant recipients who received a third dose of mRNA vaccines,

seroconversion rates were higher after the additional dose, although approximately 50
to 70 percent who were seronegative after two doses remained seronegative; adverse
effects were similar to those reported after prior doses [52-56]. Longitudinal follow-up
and evaluation of cellular immune responses are needed to more completely
characterize the impact of additional vaccine doses.
● Timing immunosuppressive agents and vaccination – Some expert groups

recommend holding certain immunosuppressive agents around the time of vaccination
or adjusting the timing of vaccination to account for receipt of such agents to try to
optimize the vaccine response. As an example, for patients receiving rituximab, the
American College of Rheumatology suggests scheduling vaccination so that the series is
initiated approximately four weeks prior to the next scheduled rituximab dose and
delaying administration of rituximab until two to four weeks after completion of
vaccination, if disease activity allows [57]. (See "COVID-19: Care of adult patients with
systemic rheumatic disease", section on 'COVID-19 vaccination while on
immunosuppressive therapy'.)
● Continued use of protective measures – We advise immunocompromised patients to

maintain personal measures to try to minimize exposure to SARS-CoV-2 (eg, masking,
distancing, avoiding crowds when possible) even after they are fully vaccinated because
of the potential for reduced vaccine effectiveness. Household and other close contacts of
immunocompromised patients should be vaccinated.
● Limited role for post-vaccination serology – At this time, antibody testing is not
recommended to determine response to vaccination; precise immune correlates of
protection remain uncertain [34]. Furthermore, heterogeneity in the accuracy of
available serologic tests complicates interpretation of results. (See 'Limited role for post-
vaccination testing' above.)
Emerging data suggest that vaccine effectiveness in immunocompromised patients is lower

than that in the general population. In a cohort study of over 1 million individuals who had
received at least one mRNA vaccine in Israel, vaccine effectiveness for symptomatic COVID-19
was 75 percent (95% CI 44-88) among immunocompromised patients compared with 94
percent (95% CI 87-97) overall [58]. Lower vaccine effectiveness regarding hospitalization for
COVID-19 in immunocompromised patients was also suggested by a smaller, unpublished
case-control study [59]. In studies of individuals hospitalized with COVID-19 despite
vaccination, a high proportion (eg, 40 percent) have been immunocompromised [60].
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These and other findings suggest that certain immunocompromised patients, including
transplant recipients and patients with hematologic malignancies, have suboptimal
immunogenicity with COVID-19 vaccination [61-69]. As an example, in a study of 658 solid
organ transplant recipients who received two doses of an mRNA COVID-19 vaccine, 46
percent had no detectable anti-spike or anti-receptor-binding domain antibodies at a median
of 29 days following the second vaccine dose [62]. Use of antimetabolites (eg,
mycophenolate mofetil, azathioprine) and a shorter time since transplantation were
associated with a higher rate of nonresponse.
Issues related to vaccination of specific immunocompromised populations are discussed in

detail elsewhere:
● (See "COVID-19: Cancer screening, diagnosis, post-treatment surveillance in uninfected

patients during the pandemic, and issues related to COVID-19 vaccination in cancer
patients", section on 'Vaccination to prevent SARS-CoV-2 infection'.)
● (See "COVID-19: Care of adult patients with systemic rheumatic disease", section on
'COVID-19 vaccination while on immunosuppressive therapy'.)
● (See "COVID-19: Issues related to solid organ transplantation", section on 'Vaccination'.)
● (See "Immunizations in patients with primary immunodeficiency", section on 'Issues
related to SARS-CoV-2 vaccination'.)
Pregnant individuals — Data on the safety of COVID-19 vaccines in pregnant

individuals are limited but emerging [70]. These data and considerations for COVID-19
vaccination in individuals who are pregnant or breastfeeding are discussed in detail
elsewhere. (See "COVID-19: Pregnancy issues and antenatal care", section on 'Vaccines'.)
Children — We suggest that eligible children undergo COVID-19 vaccination.

Specifically, in the United States, BNT162b2 (Pfizer COVID-19 vaccine) is authorized for
adolescents aged 12 through 15 years based on evidence that efficacy, immunogenicity, and
the adverse effect profile in that population are comparable to those in older individuals [71].
Studies with other vaccines and in younger children are underway. (See 'BNT162b2 (Pfizer-
BioNTech COVID-19 vaccine)' below.)
COVID-19 is generally less severe in children than adults; nevertheless, the risk of the
multisystem inflammatory syndrome in children (MIS-C) following acute infection, the risk of
severe disease in children with underlying medical conditions, and the general desire to
prevent COVID-19 in children remain compelling reasons for vaccination of children [72].
Given the hypothesis that MIS-C is associated with immune dysregulation precipitated by
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SARS-CoV-2 infection, immune-related side effects following vaccination in children must be

closely monitored. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C)
clinical features, evaluation, and diagnosis".)
Most vaccines for children are delivered by private health care providers, although many are
purchased using federal or other government funds. The Vaccines for Children (VFC)
program is an entitlement program for all ACIP-approved vaccines for eligible children
through 18 years of age [73,74]. Eligible children include those on Medicaid, those who are
completely uninsured, and American Indian/Alaskan Natives. Approximately 50 percent of
children are covered by the VFC. In addition, federal grants to states can be used to purchase
vaccines to cover other children. Since COVID-19 vaccines are free to all persons for whom
the vaccines are recommended, these funding mechanisms may be used with the COVID-19
vaccines that are licensed in children in addition to other funding sources.
Patient counseling
Expected adverse effects and their management
● Common local and systemic reactions – Vaccine recipients should be advised that side
effects are common and include local and systemic reactions, including pain at the
injection site, ipsilateral axillary lymph node enlargement, fever, fatigue, and headache.
Among mRNA vaccines, BNT162b2 may be associated with slightly lower rates of local
and systemic reactions compared with mRNA-1273 [75]. Rates of reactions for the
distinct vaccines are discussed in detail elsewhere. (See 'BNT162b2 (Pfizer-BioNTech
COVID-19 vaccine)' below and 'mRNA-1273 (Moderna COVID-19 vaccine)' below and
'Ad26.COV2.S (Janssen/Johnson & Johnson COVID-19 vaccine)' below.)
Although analgesics or antipyretics (eg, nonsteroidal anti-inflammatory drugs [NSAIDs]

or acetaminophen) can be taken if these reactions develop, prophylactic use of such
agents before vaccine receipt is not recommended because of the uncertain impact on
the host immune response to vaccination [34]. Although some data with other vaccines
suggested a lower antibody response with prophylactic acetaminophen, the antibody
responses to these vaccines remained in the protective range [76,77].
Because of the risk of axillary lymph node enlargement following vaccination, some
expert societies suggest postponing breast cancer screening mammography for several
weeks post-vaccination if it cannot be performed beforehand. (See "COVID-19: Cancer
screening, diagnosis, post-treatment surveillance in uninfected patients during the
pandemic, and issues related to COVID-19 vaccination in cancer patients", section on
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'COVID-19 vaccine-related adenopathy and implications for radiologic imaging'.)
● Syncope – Syncope has been reported following receipt of other injectable vaccines,
particularly among adolescents and young adults [78]. Monitoring is recommended for
15 to 30 minutes following COVID-19 vaccine receipt, and this may help reduce the risk
of syncope-related injury. (See 'Monitoring for immediate reactions to vaccine' below.)
● Rare adverse events – Very rare vaccine-associated adverse events include anaphylaxis
with the mRNA vaccines (BNT162b2 and mRNA-1273) and unusual types of thrombotic
events with thrombocytopenia with Ad26.COV2.S. These issues are discussed in detail
elsewhere. (See 'BNT162b2 (Pfizer-BioNTech COVID-19 vaccine)' below and 'mRNA-1273
(Moderna COVID-19 vaccine)' below and 'Thrombosis with thrombocytopenia' below.)
Other complications (including more common venous thromboembolic events without

thrombocytopenia such as deep vein thrombosis or pulmonary embolism, Bell’s palsy,
tinnitus) have been reported in vaccine recipients but have not been identified as causally
related vaccine-associated adverse events. (See 'Immunogenicity, efficacy, and safety of
select vaccines' below.)
Post-vaccine public health precautions — Although SARS-CoV-2 infection might still

occur despite vaccination, the risk is substantially lower, and certain public health
precautions may be relaxed for individuals who have been fully vaccinated. However,
recommendations have evolved with new developments in the pandemic (eg, emergence of
the highly transmissible Delta variant), and the approach should be tailored to the overall
rate of transmission in the community. Individuals are considered fully vaccinated once two
weeks have elapsed following receipt of a complete vaccination series.
In the United States, mask mandates are state dependent. The CDC suggests that fully
vaccinated individuals wear masks in indoor public settings in areas where community
transmission is substantial (ie, ≥50 cases/100,000 people over the prior seven days or >8
percent positive nucleic acid amplification test [NAAT] rate) [79]. In areas of lower community
transmission, masks in indoor spaces are optional for fully vaccinated individuals unless
otherwise mandated by government, employer, or business regulations; such individuals
who are or have household members at risk for severe COVID-19 should be encouraged to
wear masks indoors. Masks are also recommended on all forms of public transportation,
regardless of vaccination status. These updated recommendations revised previous ones
stating that vaccinated individuals could forgo masks in public settings. New evidence
suggesting that vaccinated individuals with breakthrough infection with the Delta variant
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may have a similar potential to transmit infection as unvaccinated individuals was one of the
primary reasons for this change [80]. These data are discussed elsewhere. (See 'Impact on
transmission risk' below.)
The CDC suggests waiving post-travel quarantine and testing requirements for fully
vaccinated individuals in the community who remain asymptomatic. Vaccinated individuals
do not have to quarantine following exposure to SARS-CoV-2 but should undergo testing
three to five days after exposure and wear a mask in public spaces for 14 days or until
receiving a negative SARS-CoV-2 test. Symptoms consistent with COVID-19 should prompt
testing, regardless of vaccination history.
Because individuals with immunocompromising conditions may have suboptimal responses

to COVID-19 vaccination, we counsel such individuals to maintain personal preventive
measures even if they have been vaccinated, particularly when contact with unvaccinated
individuals is possible, to minimize exposure to SARS-CoV-2. (See 'Immunocompromised
individuals' above.)
Recommendations on masking, distancing, and post-exposure management for individuals

who have not been fully vaccinated are discussed in detail elsewhere. (See "COVID-19:
Epidemiology, virology, and prevention", section on 'Prevention' and "COVID-19:
Epidemiology, virology, and prevention", section on 'Post-exposure management'.)
EUA status of certain vaccines — In addition to standard counseling around vaccine

information, vaccine providers are required to inform potential recipients of the COVID-19
mRNA vaccine mRNA-1273 (Moderna COVID-19 vaccine) or the adenoviral vector vaccine
Ad26.COV2.S (Janssen COVID-19 vaccine, also referred to as the Johnson & Johnson vaccine)
that those vaccines are available under emergency use authorization (EUA) and are not
licensed vaccines. It is not necessary, however, for recipients to sign informed consent
documents. (See 'Steps to vaccine availability and delivery' below.)
Contraindications and precautions (including allergies)
● Contraindications – The only contraindications to COVID-19 vaccination are allergic

reactions to the COVID-19 vaccines or their components. Specifically, they are [34]:
• Severe allergic reaction (eg, anaphylaxis) to a previous COVID-19 vaccine dose or to a

component of the vaccine.
• Immediate allergic reaction of any severity (including hives) developing within four
hours of a previous COVID-19 vaccine dose or known (diagnosed) allergy to a
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component of the vaccine. Symptoms of immediate reactions are listed on the CDC
website. Isolated hives that develop more than four hours after vaccine receipt are
unlikely to represent an allergic reaction to the vaccine. (See "COVID-19: Allergic
reactions to SARS-CoV-2 vaccines", section on 'Delayed urticarial reactions'.)
The mRNA vaccines, BNT162b2 (Pfizer-BioNTech COVID-19 vaccine) and mRNA-1273

(Moderna COVID-19 vaccine), each contain polyethylene glycol, and Ad26.COV2.S
(Janssen COVID-19 vaccine, also known as the Johnson & Johnson vaccine) contains
polysorbate. Allergic reaction to polysorbate is not a contraindication to mRNA vaccines,
but it is a contraindication to Ad26.COV2.S. Other components of COVID-19 vaccines are
listed on the CDC website.
● Precautions – Precautions to vaccination also consist of allergic reactions. These

precautions warrant longer post-vaccination monitoring than usual (see 'Monitoring for
immediate reactions to vaccine' below):
• Immediate allergic reaction to any other (non-COVID-19) vaccine or injectable

therapy.
• Contraindication to an mRNA COVID-19 vaccine is a precaution to Ad26.COV2.S

because of potential cross-reactive hypersensitivity.
• Contraindication to AD26.COV2.S is a precaution to an mRNA vaccine because of

potential cross-reactive hypersensitivity.
Allergy consultation can be helpful to evaluate suspected allergic reactions to a COVID-19

vaccine or its components and assess the risk of future COVID-19 vaccination. This is
discussed in detail elsewhere. (See "COVID-19: Allergic reactions to SARS-CoV-2 vaccines",
section on 'Possible anaphylaxis'.)
Caution may be warranted prior to administering any vaccine in certain rare but life-
threatening conditions, such as acquired thrombotic thrombocytopenia purpura and
capillary leak syndrome, exacerbations of which have been reported following COVID-19
vaccination [81,82]. (See "Acquired TTP: Management following recovery from an acute
episode and during remission", section on 'Vaccinations' and "Idiopathic systemic capillary
leak syndrome", section on 'Prodromal symptoms and triggers'.)
History of thromboembolic disease is not a contraindication to vaccination. However, very

rare cases of unusual types of thrombosis associated with thrombocytopenia have been
reported following vaccination with both ChadOx1 nCoV-19/AZD1222 (AstraZeneca COVID-19
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vaccine) and Ad26.COV2.S (Janssen COVID-19 vaccine, also referred to as the Johnson &
Johnson vaccine). Because of similarities between these events and immune-mediated,
heparin-induced thrombocytopenia (HIT), the CDC suggests that individuals with a syndrome
of thrombosis and thrombocytopenia (such as HIT) within the prior 90 days receive an mRNA
vaccine rather than Ad26.COV2.S [34]. There has not been a concerning signal for this type of
thrombotic complication with mRNA COVID-19 vaccines. Furthermore, there is no evidence
that classic risk factors for thrombosis (eg, thrombophilic disorders or prior history of venous
thromboembolism not associated with thrombocytopenia) increase the risk for this rare
adverse event [83], and individuals with these can receive any authorized COVID-19 vaccine.
(See 'Thrombosis with thrombocytopenia' below.)
Other reactions or conditions that are neither precautions nor contraindications include:
● Late local reactions characterized by a well-demarcated area of erythema appearing at

the injection site approximately a week after mRNA COVID-19 vaccination have been
reported, with recurrence occurring in some individuals after repeat vaccination [84].
This may occur more frequently with mRNA-1273 than with BNT162b2 [85]. This type of
reaction is not a contraindication to vaccination, and individuals who experience this
after the initial mRNA vaccine dose can proceed with the second dose as scheduled [34].
(See "COVID-19: Allergic reactions to SARS-CoV-2 vaccines", section on 'Late local
reactions'.)
● Facial swelling in areas previously injected with cosmetic dermal fillers has also been
rarely reported following vaccination with the mRNA COVID-19 vaccines. Dermal fillers
are not a contraindication to COVID-19 vaccination, and no specific precautions are
recommended [34]. However, it is reasonable to advise individuals with dermal fillers of
the possibility of post-vaccination swelling. This is discussed elsewhere. (See "COVID-19:
Cutaneous manifestations and issues related to dermatologic care", section on 'Soft
tissue fillers'.)
● Anticoagulation is not a contraindication to vaccination; excess bleeding is unlikely with

intramuscular vaccines in patients taking anticoagulants [86]. Such patients can be
instructed to hold pressure over the injection site to reduce the risk of hematoma. (See
"Standard immunizations for nonpregnant adults", section on 'Patients on
anticoagulation'.)
Monitoring for immediate reactions to vaccine — All individuals should be monitored

for immediate vaccine reactions following receipt of any COVID-19 vaccine.
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The following warrant monitoring for 30 minutes:
● Precautions to the administered vaccine (immediate reaction to any vaccine or injectable

therapy; contraindication to the other vaccine type) (see 'Contraindications and
precautions (including allergies)' above)
● History of anaphylaxis due to any cause
All other individuals are monitored for 15 minutes.
Vaccines should be administered in settings where immediate allergic reactions, should they
occur, can be appropriately managed. Recognition and management of anaphylaxis are
discussed in detail elsewhere ( table 3). (See "Anaphylaxis: Acute diagnosis" and
"Anaphylaxis: Emergency treatment".)
Anaphylaxis has been reported following administration of both authorized mRNA COVID-19
vaccines [87]. Following the first several million doses of mRNA COVID-19 vaccines
administered in the United States, anaphylaxis was reported at approximate rates of 4.5
events per million doses [88-90]. The vast majority of these events occurred in individuals
with a history of allergic reactions and occurred within 30 minutes. The mechanism for the
anaphylaxis is under investigation and has not been determined. Some suggest that it is IgE
mediated, with polyethylene glycol as the inciting antigen. However, other complement-
mediated mechanisms have been suggested in individuals without a previous history of
allergy. Evaluation of patients with possible anaphylaxis following COVID-19 vaccination is
discussed elsewhere. (See "COVID-19: Allergic reactions to SARS-CoV-2 vaccines", section on
'Possible anaphylaxis'.)
Reporting of adverse events — To facilitate ongoing safety evaluation, vaccine providers

are responsible for reporting vaccine administration errors, serious adverse events
associated with vaccination, cases of multisystem inflammatory syndrome (MIS), and cases
of COVID-19 that result in hospitalization or death through the Vaccine Adverse Event
Reporting System (VAERS). (See 'Ongoing safety assessment' below.)
Details on the efficacy and safety of available COVID-19 vaccines are discussed elsewhere.
(See 'Immunogenicity, efficacy, and safety of select vaccines' below.)
Other countries — Various vaccines are available in different countries. A list of vaccines

that have been authorized in at least one country can be found at
covid19.trackvaccines.org/vaccines. Data on some of these vaccines can be found elsewhere.
(See 'Immunogenicity, efficacy, and safety of select vaccines' below.)
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Dosing schedules vary by vaccine. Additionally, different countries may have specific
recommendations for vaccine use. As an example, Canadian national guidelines allow
administration of an mRNA vaccine to complete a two-dose series following receipt of the
adenovirus vector vaccine, ChAdOx1 nCoV-19/AZD1222 (University of Oxford/AstraZeneca
COVID-19 vaccine), as studies suggest the combination results in a more robust immune
response than a two-dose ChAdOx1 nCOV-19/AZD1222 series without major safety concerns
[37,91-93]. (See 'Completion of two-dose series' above.)
Different countries may also have specific allocation priorities for distributing the initial
vaccine supplies. As an example, the Joint Committee on Vaccination and Immunisation in
the United Kingdom recommends prioritizing a first vaccine dose for all eligible individuals
prior to securing a second vaccine dose for recipients [94]. However, both mRNA vaccines
were studied with two-dose schedules, and the efficacy estimates from those schedules are
difficult, if not impossible, to extrapolate to a single-dose schedule. Clinicians should refer to
local guidelines for vaccine recommendations in their location. (See 'Society guideline links'
below.)
Several countries had paused use of ChAdOx1 nCoV-19/AZD1222 to investigate scattered

reports of thromboembolic events; many have since resumed use, in some cases with age
restrictions. This is discussed in detail elsewhere. (See 'Thrombosis with thrombocytopenia'
below.)
IMMUNOGENICITY, EFFICACY, AND SAFETY OF SELECT VACCINES
The first human clinical trials of COVID-19 vaccines began in March 2020, several phase III
trials have been completed, and several more are nearing completion. Select vaccine
candidates that have completed, entered, or are nearing entry into phase III trials are
described here; some of these vaccines are available for use in different countries ( table 4
). They represent different vaccine approaches, including RNA vaccines, replication-
incompetent vector vaccines, recombinant protein vaccines, and inactivated vaccines; the
general features of these different platforms are described elsewhere. (See 'Vaccine
platforms' above.)
None of the vaccines have been studied against one another, and thus, comparative efficacy
is uncertain. Differences in the magnitudes of effect reported from phase III trials might be
related to factors other than effectiveness, including differences in the trial populations and
locations, timing of the trials during the pandemic, and study design.
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Immunogenicity, efficacy, and safety of specific vaccines are discussed below. General issues
related to breakthrough infections, impact on transmission, effectiveness against variants of
concern, and duration of effect are discussed elsewhere. (See 'Ongoing safety assessment'
below.)
BNT162b2 (Pfizer-BioNTech COVID-19 vaccine) — This mRNA vaccine is delivered in a lipid

nanoparticle to express a full-length spike protein ( table 4). It is given intramuscularly in
two doses three weeks apart. BNT162b2 has been authorized for use in several locations,
including the United States, the United Kingdom (UK), the European Union, and Canada
[30,95-97]. Clinical use of the vaccine is discussed elsewhere. (See 'Approach to vaccination'
above.)
● Immunogenicity – In a phase I/II randomized, placebo-controlled, observer-blind dose

escalation study in healthy adults 18 to 85 years of age, binding and neutralizing
antibody responses were demonstrated that were comparable to those in convalescent
plasma from patients who had asymptomatic or moderate SARS-CoV-2 infection [98].
Responses in participants ≥65 years old were generally lower than in younger subjects,
but still comparable to titers in convalescent plasma. Neutralizing antibody titers in
recipients aged 12 through 15 years were significantly higher than those induced in
individuals aged 16 to 25 years [99].
Studies suggest that plasma from individuals vaccinated with BNT162b2 retains
neutralizing activity against variants of concern, although the levels of neutralizing
antibodies generated are lower against Beta (B.1.351) [100-103] and to a lesser extent
against Delta (B.1.617.2) [101,102,104] compared with levels against previously
circulating strains. (See "COVID-19: Epidemiology, virology, and prevention", section on
'Variants of concern'.)
● Efficacy – In a large placebo-controlled phase III trial, this vaccine had 95 percent
efficacy (95% CI 90.3-97.6) in preventing symptomatic COVID-19 at or after day 7
following the second dose [105,106]. This effect was assessed after an analysis of 170
confirmed COVID-19 cases (8 in the vaccine group and 162 in the placebo group) among
over 36,000 participants aged 16 years and older with a median of two months follow-up
after vaccination. Nine of the 10 severe cases that occurred during the study were in the
placebo group. Among adults ≥65 years who had other medical comorbidities or obesity,
vaccine efficacy was 91.7 percent (95% CI 44.2-99.8). Among the entire trial population,
the rate of COVID-19 in the vaccine group started to decrease relative to the rate in the
placebo group approximately two weeks after the first dose. Vaccine efficacy after two
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doses was also high among 1983 adolescent trial participants aged 12 through 15 years
without evidence of prior infection, with 0 and 16 symptomatic cases among vaccine and
placebo recipients, respectively (efficacy 100 percent, 95% CI 75.3-100) [99].
Observational data from various countries following their national roll-outs of BNT162b2
support the trial findings [107-118]. In a study from Israel using national surveillance
data from more than 6.5 million individuals, of whom 72 percent had received
BNT162b2, estimated vaccine effectiveness seven days or more following the second
dose was 92 percent for documented SARS-CoV-2 infection, 97 percent for symptomatic
COVID-19, 97 percent for COVID-19-related hospitalization, and 97 percent for COVID-19-
related death [107]. Vaccine effectiveness for these outcomes was similarly high across
all age groups. The vaccine also appears effective against SARS-CoV-2 variants that have
become prevalent since the initial trial. In a study of over 23,000 health care workers in
the United Kingdom, covering a time frame when the Alpha variant (B.1.1.7) was
prevalent, vaccine effectiveness against SARS-CoV-2 infection (both asymptomatic and
symptomatic) was estimated at 85 percent 7 days or more after the second dose [110].
Additionally, in a study of the national COVID-19 database in Qatar, where over 265,000
individuals had received two doses of BNT162b2 and both the Alpha and Beta (B.1.351)
variants were predominant, vaccine effectiveness was estimated at 90 percent (95% CI
86-92) for any Alpha infection, 75 percent (95% CI 71-79) for any Beta infection, and 100
percent for severe, critical, or fatal infection with either variant [119]. Similarly, in a study
from the United Kingdom, estimated effectiveness against symptomatic infection caused
by Delta (B.1.617.2) was 88 percent (95% CI 85-90) compared with 94 percent (95% CI
92-95) for Alpha [120]. However, unpublished data from Israel have suggested that the
emergence of Delta as the predominant variant in the country was temporally associated
with lower effectiveness rates (64 percent) against symptomatic infection; effectiveness
against hospitalization remained very high [121].
Vaccine efficacy may wane over time. According to an unpublished follow-up report of
the phase III trial participants, vaccine efficacy against symptomatic disease remained
high over six months but slightly decreased from 96 percent up to two months, to 90
percent between two and four months, to 84 percent from four to six months [122]. Of
30 severe infections, only one occurred in a vaccinated individual. (See 'Role of booster
vaccinations' below.)
● Safety and side effects – Local and systemic adverse effects are relatively common,
particularly after the second dose; most are of mild or moderate severity (ie, do not
prevent daily activities) and are limited to the first two days after vaccination [75,90,105].
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Among 1.6 million vaccine recipients (16 years or older) in the United States who
responded to post-vaccination surveys, an injection site reaction (mainly pain, but also
redness, swelling, and pruritus) was reported in approximately 65 percent after each
dose; fatigue, headache, and myalgias were reported in 29, 25, and 17 percent after the
first dose and in 48, 40, and 37 percent after the second, respectively [75]. After the
second dose, fevers, chills, and joint pain each occurred in approximately 20 percent.
Reactions were most frequently reported on the day following vaccination. These
reactions were also commonly reported among adolescents aged 12 through 15 years
following the second dose (fatigue, headache, chills, and myalgia in 66, 65, 42, and 32
percent, respectively) [99]. Local and systemic reactions occur less frequently among
recipients 65 years or older but are still relatively common.
Myocarditis and pericarditis, mainly in male adolescents and young adults, have been
reported more frequently than expected following receipt of BNT162b2. This is discussed
in detail elsewhere. (See 'Myocarditis' below.)
Anaphylaxis following vaccination has been reported at an approximate rate of 5 events

per 1 million doses; 80 percent of anaphylaxis cases have occurred in individuals with a
history of allergic reactions and 90 percent occurred within 30 minutes [88]. Other
reported allergic reactions included pruritus, rash, scratchy sensations in the throat, and
mild respiratory symptoms [123].
Other major adverse events have not been consistently associated with BNT162b2
receipt [124]. Rare cases of Bell's palsy were noted in the phase III trial (four in vaccine
and zero in placebo recipients) [105]; however, the rate did not exceed background rates
found in the general population (15 to 30 cases per 100,000 people per year), and post-
vaccine monitoring has not identified an association between vaccination and Bell’s palsy
[88]. As of April 12, 2021, there had been no reports in the United States of central
venous sinus thrombosis with thrombocytopenia following nearly 98 million doses of
BNT162b2 administered [125]. In a large cohort study from Israel, BNT162b2 receipt was
most strongly associated with myocarditis, lymphadenopathy, appendicitis, and herpes
zoster [126].
mRNA-1273 (Moderna COVID-19 vaccine) — This messenger RNA (mRNA) vaccine was one
of the first vaccines for SARS-CoV-2 to be produced; it was developed and administered to
humans within two months of publication of the SARS-CoV-2 genomic sequence. The vaccine
utilizes mRNA delivered in a lipid nanoparticle to express a full-length spike protein (
table 4). It is given intramuscularly in two doses 28 days apart. mRNA-1273 has been
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authorized for use in the United States and the European Union [31,127]. Clinical use of the
vaccine is discussed elsewhere. (See 'Approach to vaccination' above.)
● Immunogenicity – A phase I open-label trial demonstrated binding and neutralizing

antibody responses comparable to those seen in convalescent plasma with vaccination
in healthy individuals 18 to 55 years of age [128]. CD4 cell responses with a Th1 bias
were also detected. Vaccination in adults older than 55 years also elicited immune
responses that were comparable to those seen in the younger populations [129].
Binding and neutralizing antibody responses declined slightly over six months in
participants from all age groups but antibody titers remained high and neutralizing
activity persisted over this time [130]. Immunogenicity in adolescents aged 12 to 17
years is comparable to or higher than that seen in young adults [131]. Vaccination with
mRNA-1273 is associated with higher antibody titers (measured 6 to 10 weeks after the
second dose) compared with BNT162b2 [132].
Studies suggest that plasma from individuals vaccinated with mRNA-1273 retains
neutralizing activity against variants of concern, although the levels of neutralizing
antibodies generated are lower against Beta (B.1.351) [133,134] and Delta (B.1.617.2)
[104] compared with levels against previously circulating strains. (See "COVID-19:
Epidemiology, virology, and prevention", section on 'Variants of concern'.)
● Efficacy – In a large placebo-controlled phase III results, mRNA-1273 had 94.1 percent
vaccine efficacy (95% CI 89.3-96.8) in preventing symptomatic COVID-19 at or after 14
days following the second dose [135]. This effect was assessed after an analysis of 196
confirmed COVID-19 cases (11 in the vaccine group and 185 in the placebo group)
among nearly 30,000 study participants aged 18 years and older with a median follow-up
of two months after vaccination. Among adults ≥65 years of age, vaccine efficacy was
86.4 percent (95% CI 61.4-95.5). Thirty cases were severe, and all of these occurred in the
placebo group.
Observational data evaluating vaccine effectiveness also support the trial findings
[115,116,118,136,137]. In a study of 489 individuals 65 years or older who were
hospitalized in the United States with a clinical syndrome compatible with COVID-19,
only 1 individual with confirmed COVID-19 by SARS-CoV-2 testing (0.5 percent) had
received the recommended two doses of an mRNA vaccine (either mRNA-1273 or
BNT162b2) compared with 18 individuals with negative SARS-CoV-2 testing (8 percent);
the estimated vaccine effectiveness for preventing COVID-19 hospitalization was 94
percent, although confidence intervals were wide because of the small sample size [115].
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A case-control study of over 100,000 veterans in the United States who were tested for
SARS-CoV-2 estimated vaccine effectiveness of mRNA-1273 of 98 percent (95% CI 98-99)
[116].
● Safety and side effects – Local and systemic adverse effects are relatively common,
particularly after the second dose; most are of mild or moderate severity (ie, do not
prevent daily activities or require pain relievers) and are limited to the first two days after
vaccination [75,90,138]. Among nearly 2 million vaccine recipients in the United States
who responded to post-vaccination surveys, an injection site reaction (mainly pain, but
also redness, swelling, and pruritus) was reported in 74 and 82 percent after each dose;
fatigue, headache, and myalgias were reported in 33, 27, and 21 percent after the first
dose and in 60, 53, and 51 percent after the second, respectively [75]. After the second
dose, fever and chills each occurred in approximately 40 percent and joint pain in 32
percent. Reactions were most frequently reported on the day following vaccination. Local
and systemic reactions occurred less frequently among recipients 65 years or older but
were still relatively common.
Myocarditis and pericarditis, mainly in male adolescents and young adults, have been
reported more frequently than expected following receipt of mRNA-1273. This is
discussed in detail elsewhere. (See 'Myocarditis' below.)
Anaphylaxis following vaccination has been reported at an approximate rate of 2.8

events per one million doses; 86 percent of anaphylaxis cases have occurred in
individuals with a history of allergic reactions, and 90 percent occurred within 30
minutes [88,123]. There were rare cases of Bell's palsy that were considered potentially
related to vaccination (three in the vaccine and one in the placebo group). However, the
rate did not exceed the background rate in the general population (15 to 30 cases per
100,000 people per year), and post-vaccine monitoring has not identified an association
between vaccination and Bell's palsy [88].
No other major vaccine-associated adverse events have been identified in post-vaccine

surveillance [124]. As of June 29, 2021, a single case of central venous sinus thrombosis
with thrombocytopenia following mRNA-1273 receipt had been reported in the United
States. Given only one case, it is difficult to determine whether the relation is causal or
coincidental; regardless, it is extremely rare [139].
Ad26.COV2.S (Janssen/Johnson & Johnson COVID-19 vaccine) — This vaccine is based on a

replication-incompetent adenovirus 26 vector that expresses a stabilized spike protein (
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table 4). It is given intramuscularly as a single dose but is also being evaluated as two
doses 56 days apart. Ad26.COVS.2 has been authorized for use in the United States [32].
● Immunogenicity – Double-blind, placebo-controlled phase I and II trials described high

rates of neutralizing and binding antibodies after a single vaccine dose in healthy
individuals 18 up to 85 years old; these responses overlapped with but were slightly
lower than those in convalescent plasma [140,141]. A second vaccine dose was evaluated
in a subset of participants, and this resulted in an increase in neutralizing titers. CD4 cell
responses with a Th1 bias were also detected after the first dose. Longitudinal evaluation
of recipients of Ad26.CoV2.S suggests that binding and neutralizing antibody responses
are largely stable over eight months with both one- and two-dose regimens [142].
Neutralizing activity was also retained against the Beta (B.1.351) and Delta (B.1.617.2)
variants at only a slightly lower level than against previously circulating strains.
Baseline seroprevalence to adenovirus 26 is low in North America and Europe; it is

moderately high in sub-Saharan Africa and Southeast Asia, although most seropositive
individuals have low neutralizing titers [143]. Nonhuman primate studies suggest that
these low titers do not suppress responses to adenovirus 26 vector vaccines.
● Efficacy – In a phase III efficacy trial, Ad26.COV2.S, given as a single dose, had 66.9
percent efficacy (95% CI 59.0-73.4) in preventing moderate to severe/critical COVID-19
(which included patients with pneumonia, dyspnea, tachypnea, or at least two symptoms
of COVID-19) starting at or after 14 days following vaccination [144]. This effect was
assessed after an analysis of 464 confirmed moderate to severe/critical COVID-19 cases
(116 in the vaccine group and 348 in the placebo group) among nearly 40,000 study
participants aged 18 years and older with a median follow-up of two months after
vaccination. There were only four mild COVID-19 cases. Vaccine efficacy starting at 28
days after vaccination was similar to that after 14 days. Vaccine efficacy against
severe/critical disease trended higher at 78 and 85 percent after 14 and 28 days post-
vaccination, respectively.
Reported overall efficacy varied by region: 74 percent in the United States, 66 percent in
Brazil, where the Gamma (P.2) variant was prevalent, and 52 percent in South Africa,
where most infections were caused by the variant Beta (B.1.351). Nevertheless, vaccine
efficacy against severe/critical disease was similar across regions (and in South Africa
was 73 and 82 percent after 14 and 28 days post-vaccination).
● Safety and side effects – Local and systemic adverse effects are relatively common;
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most are of mild or moderate severity (ie, do not prevent undertaking daily activities or
require pain relievers) and most commonly occur the first day after vaccination [145].
Among over 330,000 vaccine recipients in the United States who responded to post-
vaccination surveys, 76 percent reported at least one systemic reaction and 61 percent at
least one injection site reaction in the first week. The most common systemic reactions
were fatigue, pain, and headache. Anxiety-related events, including tachycardia,
hyperventilation, light-headedness, and syncope, have also been reported following
Ad26.COV2.S administration [146]. In the phase III efficacy trial, serious adverse event
rates in the vaccine and placebo group were similar [144]. There were more cases of
thromboembolic events (11 versus 3), tinnitus (6 versus 0), and seizures (4 versus 1)
among vaccine compared with placebo recipients, but the numbers of events were too
few to determine whether there is a causal association with vaccination. In a report of
over 200,000 health care workers who received Ad26.COV2.S in South Africa, there were
only five arterial or venous thromboembolic events (1.7 per 100,000) reported post-
vaccination, and all occurred in individuals with pre-existing risk factors [147]. However,
the vaccine has been associated with a specific syndrome of thrombosis with
thrombocytopenia and it is possibly associated with Guillain-Barre syndrome; these are
discussed in detail elsewhere. (See 'Thrombosis with thrombocytopenia' below and
'Guillain-Barre syndrome' below.)
ChAdOx1 nCoV-19/AZD1222 (University of Oxford, AstraZeneca, and the Serum Institute

of India) — This vaccine is based on a replication-incompetent chimpanzee adenovirus
vector that expresses the spike protein ( table 4). It is given intramuscularly and is being
evaluated as two doses 4 to 12 weeks apart. The World Health Organization (WHO)
recommends that the two doses be given 8 to 12 weeks apart [148]. ChAdOx1
nCoV-19/AZD1222 has been authorized for use in the European Union and several other
countries, including the United Kingdom, Canada, and India. Although there is some concern
about vaccine efficacy against certain SARS-CoV-2 variants, as discussed below, WHO
recommends use of this vaccine even if those variants are circulating in a country [148].
Because of an extremely rare side effect, several countries have suspended use of the
vaccine pending additional data, and some are limiting the vaccine to individuals over a
certain age; this is discussed in detail elsewhere. (See 'Thrombosis with thrombocytopenia'
below.)
● Immunogenicity – In a single-blind, randomized controlled phase I/II trial in healthy

individuals 18 to 55 years old, in which most of the vaccine recipients received a single
dose and a small cohort received an additional booster dose, neutralizing antibody titers
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28 days after the last dose were comparable to those detected in convalescent plasma
[149]. The levels of antibody titers achieved were higher following two doses, and a third
dose is associated with even higher antibody titers [150]. Cellular immune responses
were also detected. In a study that included older vaccine recipients (>70 years), the
vaccine resulted in similar antibody responses after the second dose as in younger
adults [151]. However, the Beta (B.1.351) and Delta (B.1.617.2) variants may evade
immune responses in some vaccinated individuals [102,152]; in one study of 63 ChAdOx1
nCoV-19/AZD1222 recipients, approximately 60 percent had detectable neutralizing
activity against those variants [152].
● Efficacy – In a report of interim results from a multinational phase III randomized trial,
this vaccine had 70.4 percent efficacy (95% CI 54.8-80.6) in preventing symptomatic
COVID-19 at or after 14 days following the second dose [153]. This effect was assessed
after an analysis of 131 confirmed COVID-19 cases (30 in the vaccine group and 101 in
the control group) among over 11,000 participants with a median follow-up of two
months after vaccination. Ten participants were hospitalized for COVID-19, including two
who were categorized as having severe disease; all of them were in the control group. A
subgroup of participants inadvertently received a lower vaccine dose for the first of the
two vaccine doses, and the overall vaccine efficacy in this subgroup differed from the
rest. Vaccine efficacy was 90.0 percent (95% CI 67.4-97.0) among the 2741 participants
who received the lower dose and 62.1 percent (95% CI 41-75.7) among those who
received full-dose vaccine. Reasons for this difference are uncertain, although the
overlapping confidence intervals indicate that the difference is not statistically
significant. Differences in the control administered (meningococcal vaccine for both
doses at some study sites versus meningococcal vaccine for one dose with saline for
another dose at other sites) and in the interval between administration of the two
vaccine doses further contribute to uncertainty about the findings.
In a subsequent analysis of this trial, vaccine efficacy for symptomatic COVID-19 was 76
percent from 21 days after receipt of the first dose until receipt of the second dose or
day 90, whichever came first, suggesting protection with a single dose [154].
Additionally, receipt of the second dose at 12 weeks or later was associated with higher
vaccine efficacy than receipt at <6 weeks (81 versus 55 percent). These findings lend
support to extending the time interval for the second dose to 12 weeks.
Largely similar findings were reported in a press release of preliminary results of a

placebo-controlled trial conducted in the United States, Chile, and Peru [155]. ChAdOx1
nCoV-19/AZD1222 given as two full doses four weeks apart had 76 percent efficacy at
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preventing symptomatic COVID-19 starting 15 days after the second dose. Publication of
full trial details is necessary to critically assess these results. Nevertheless, observational
data from various countries following their national roll-outs of ChAdOx1
nCoV-19/AZD1222 support the trial findings [108,156]. As an example, in a nationwide
study from Scotland that included over 600,000 individuals who received at least one
dose of ChAdOx1 nCoV-19/AZD1222, vaccine receipt was associated with an 88 percent
reduction in hospitalization for COVID-19 in the fourth week after vaccination [108].
Efficacy against variants of concern may be attenuated. In an analysis of one of the

randomized trials, vaccine efficacy against symptomatic COVID-19 caused by Alpha
(B.1.1.7), a viral variant that has emerged as the dominant variant in the United Kingdom
and has been identified in other countries, was not statistically different compared with
other variants (70 versus 82 percent), despite induction of lower neutralizing activity
against the Alpha variant [157]. However, according to preliminary results of a phase I/II
trial in South Africa, ChAdOx1 nCoV-19/AZD1222 did not reduce the rate of mild to
moderate COVID-19 (at least one symptom but no tachypnea, hypoxia, or organ failure)
over a time frame when Beta (B.1.351) was the dominant variant circulating [158].
Because the trial was small and the number of cases was low, the estimate of vaccine
efficacy had very wide confidence intervals (21.9 percent, 95% CI -49.9 to 59.8). Impact
on severe disease, which was rare in the young, healthy trial population, could not be
assessed. In an unpublished study from the United Kingdom, estimated effectiveness
against symptomatic infection caused by Delta (B.1.617.2) was 67 percent (95% CI 61-72)
compared with 75 percent (95% CI 68-79) for Alpha [120].
● Safety and side effects – In earlier-phase trials, fatigue, headache, and fever were
relatively common after vaccine receipt and were severe in up to 8 percent of recipients
[149]. In the phase III trial, there were two cases of transverse myelitis in ChAdOx1
nCoV-19 vaccine recipients [153]. One was thought to be possibly related to vaccination
and was described as an idiopathic, short-segment spinal cord demyelination; the other
was in a participant with previously unrecognized multiple sclerosis and thought to be
unrelated to the vaccine. The vaccine also may be associated with an extremely small risk
of thrombotic events associated with thrombocytopenia, which is discussed in detail
elsewhere. (See 'Thrombosis with thrombocytopenia' below.)
NVX-CoV2373 (Novavax) — This is a recombinant protein nanoparticle vaccine composed of

trimeric spike glycoproteins and a potent Matrix-M1 adjuvant ( table 4). The vaccine is
given intramuscularly in two doses 21 days apart. In a phase I/II randomized, placebo-
controlled trial of healthy individuals <60 years old, the adjuvanted vaccine induced high
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binding and neutralizing responses, comparable to those in convalescent plasma from

patients who had been hospitalized with COVID-19 [159]. CD4 cell responses with a Th1 bias
were also detected. Approximately 6 percent of participants experienced severe systemic
effects (mainly fatigue, headache, myalgias, and/or malaise) following the second dose.
In a press release concerning a phase III efficacy trial in the United States and Mexico, NVX-
CoV2373 had 90.4 percent (95% CI 82.9-94.6) efficacy in preventing symptomatic COVID-19
starting at or after seven days following the second dose in seronegative individuals [160].
This effect was assessed after interim analysis of 77 confirmed COVID-19 cases (14 in the
vaccine group and 63 in the placebo group) among over 29,000 individuals aged 18 to 84
years. Only four of those cases were severe and occurred in the placebo group. Similar
vaccine efficacy (89.7 percent, 95% CI 802-94.6) was reported in a phase III trial in the United
Kingdom with approximately 14,000 participants [161]. The vaccine appeared to be highly
effective against the variant B.1.1.7 (Alpha). However, in a smaller trial in South Africa, where
most COVID-19 cases were caused by the B.1.351 (Beta) variant, vaccine efficacy appeared
lower, at 49.4 percent (95% CI 6.1-72.8) [162].
Local and systemic adverse effects (mainly injection site pain, fatigue, headache, myalgias)
were relatively common, particularly after the second dose; most were of mild or moderate
severity with a mean duration of two or fewer days [161].
Other vaccines — Details on select vaccines that are available internationally are presented
below. A list of vaccines that have been authorized in at least one country can be found at
covid19.trackvaccines.org/vaccines.
● Ad5-based COVID-19 vaccine (CanSino Biologics) – This vaccine is based on a

replication-incompetent adenovirus 5 vector that expresses the spike protein. It is given
as a single intramuscular dose. In early clinical trials, it was immunogenic in healthy
adults at 28 days with only mild to moderate local and systemic reactions [163].
However, both pre-existing immunity to adenovirus 5 and older age were associated
with lower titers of binding and neutralizing antibodies following vaccination; this may
limit its utility in locations where pre-existing immunity is prevalent. Prior studies of
adenovirus 5 vector HIV vaccine candidates identified an increased risk of HIV acquisition
among male vaccine recipients who were uncircumcised and seropositive for adenovirus
5 at baseline [164]. It is uncertain whether these observations are relevant for
adenovirus 5 COVID-19 vaccines. Data from efficacy trials have not been published; a
press release reported an efficacy rate of 75 percent, but trial details essential for critical
review of these results are not yet public [165]. This vaccine is available in China and
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some other countries, including Mexico and Pakistan.
● Gam-COVID-Vac/Sputnik V (Gamaleya Institute) – This is a vaccine developed in Russia

that uses two replication-incompetent adenovirus vectors that express a full-length spike
glycoprotein ( table 4). The vaccine is given intramuscularly as an initial adenovirus 26
vector dose followed by an adenovirus 5 vector boosting dose 21 days to 3 months later
[166]. This vaccine is available in Russia and several other countries, including Mexico.
In an open-label, nonrandomized phase I/II trial, SARS-CoV-2 humoral and cellular

immune responses were detected in the participants [167].
According to interim analysis of a phase III trial that included over 20,000 participants
without serologic evidence of prior SARS-CoV-2 infection, this vaccine had 91.6 percent
(95% CI 85.6-95.2) efficacy in preventing symptomatic COVID-19 starting at 21 days
following the first dose (at the time of the second dose) [167]. This effect was assessed
after 78 cases of COVID-19 (16 of 14,964 participants who received vaccine and 62 of
4902 participants who received placebo). All 20 cases of severe COVID-19 that occurred
21 days after the first dose were in the placebo group. Median follow-up time was 48
days after the first dose. Local and systemic flu-like reactions were more common in the
vaccine group, at rates of 15 and 5 percent, respectively. No serious adverse events were
deemed related to vaccine.
● WIV04 and HB02 (Sinopharm) – These are inactivated, whole-virus vaccines based on
two different SARS-CoV-2 isolates from patients in China; they each have an aluminum
hydroxide adjuvant. HB02 is also known as BBIBP-CorV. They are each given
intramuscularly in two doses 28 days apart. Each of these vaccines elicited neutralizing
and binding antibody responses in healthy individuals 18 to 80 years old participating in
several phase I/II placebo-controlled randomized trials; no severe reactions were
reported [168,169]. Neutralizing activity elicited by HB02 is reduced against the variant
B.1.351 (Beta) [170]. In a phase III efficacy trial that included nearly 40,000 participants
without evidence of prior SARS-CoV-2 infection, vaccine efficacy starting 14 days after full
vaccination was estimated as 73 percent (95% CI 58-82) for WIV04 and 78 percent (95%
CI 65-86) for HB02, each compared with an alum-only placebo [171]. This effect was
assessed after 26, 21, and 95 cases following WIV04, HB02, and placebo, respectively.
Only two severe cases occurred, both in the placebo group. Systemic and injection site
reactions occurred at similar frequencies in all three groups (eg, pain in 20 to 27 percent,
headache in 13 percent, fatigue in 11 percent). These vaccines are available in China and
some other countries, including the United Arab Emirates and Hungary.
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● CoronaVac (Sinovac) – This inactivated COVID-19 vaccine was developed in China; it has
an aluminum hydroxide adjuvant. The vaccine is given intramuscularly in two doses 28
days apart. In phase I/II randomized, placebo-controlled trials, the vaccine appeared safe
and immunogenic in healthy individuals aged 18 to 59 years [172] as well as those 60
years or older [173]. Neutralizing activity against the variant B.1.351 (Beta) is reduced
[170]. According to interim results of a phase III trial of 10,000 participants in Turkey
without evidence of prior SARS-CoV-2 infection, vaccine efficacy starting 14 days after full
vaccination was 83.5 percent (95% CI 65.4–92.1) [174]; however, lower efficacy rates have
been reported in press releases of trials in different countries [165]. In an observational
study that included over 10 million individuals in Chile, estimated vaccine effectiveness
was 70 percent for preventing COVID-19 and 86 to 88 percent for preventing hospital
admission or death [175]; a subsequent study in Brazil reported lower vaccine
effectiveness among adults older than 70 years in the context of prevalent Gamma
variant (47, 56, and 61 percent against COVID-19, hospitalization, and death,
respectively) [176]. This vaccine is available in China and some other countries, including
Brazil, Chile, Indonesia, Mexico, and Turkey.
● Covaxin (Bharat Biotech/Indian Council of Medical Research) – This inactivated

COVID-19 vaccine was developed and is being used in India; it has an aluminum
hydroxide and a toll-like receptor agonist adjuvant. It is given intramuscularly in two
doses 29 days apart. In a phase I randomized controlled trial, the vaccine appeared safe
and immunogenic in healthy individuals aged 18 to 55 years [177]. Serum from vaccine
recipients also neutralizes the B.1.617 variants prevalent in India, but at lower titers than
observed with wild-type virus [178].Data from efficacy trials have not been published; a
press release reported an efficacy rate of 81 percent against symptomatic COVID-19 in
those without prior infection after an interim analysis of 43 cases among 25,800
participants (36 with placebo and 7 with vaccine); trial details essential for critical review
of these results are not yet public [179].
SPECIFIC SAFETY CONCERNS
Thrombosis with thrombocytopenia — ChadOx1 nCoV-19/AZD1222 (AstraZeneca COVID-19

vaccine) and Ad26.COV2.S (Janssen COVID-19 vaccine, also referred to as the Johnson &
Johnson vaccine) have each been associated with an extremely small risk of unusual types of
thrombotic events associated with thrombocytopenia. A similar risk has not been identified
with the mRNA vaccines. Many of these cases have been associated with autoantibodies
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directed against the platelet factor 4 (PF4) antigen, similar to those found in patients with
autoimmune heparin-induced thrombocytopenia (HIT) [180-183]. Some experts are referring
to this syndrome as vaccine-associated immune thrombotic thrombocytopenia (VITT); others
have used the term thrombosis with thrombocytopenia syndrome (TTS).
In reported cases, thrombosis often occurred at unusual sites, including the cerebral venous
sinuses and mesenteric vessels, and at more than one site [184-186]. Most of the initially
reported events occurred within two weeks of receipt of the initial vaccine dose and in
females under 60 years of age, although subsequent cases have been reported following a
longer post-vaccine interval and in males and older females. In the United States, the risk of
this syndrome following Ad26.COV2.S receipt was assessed as 3.0 cases per million overall
and 8.8 cases per million for females 30 to 49 years old [187]. Regulatory bodies in the
United States and Europe have concluded that the population and individual benefits of
these vaccines, including reductions in death and critical illness outweigh the risk of these
rare events [188-190]. Nevertheless, recipients of these vaccines should be aware of the
possible association and seek immediate care for signs and symptoms suggestive of
thrombocytopenia (eg, new petechiae or bruising) or thrombotic complications (including
shortness of breath, chest pain, lower extremity edema, persistent severe abdominal pain,
unabating severe headache, severe backache, new focal neurologic symptoms, and seizures)
[190].
The incidence, risk factors, clinical features, evaluation, and management of VITT/TTS are
discussed in detail elsewhere. (See "COVID-19: Vaccine-induced immune thrombotic
thrombocytopenia (VITT)".)
A clear, causal relation between either of these vaccines and thromboembolic disorders
overall (eg, pulmonary embolism and deep vein thrombosis) has not been identified
[125,191]. For ChadOx1 nCoV-19/AZD1222, one analysis suggested that the total rate of
thromboembolic events following vaccination is lower than that expected based on the
background rate in the general population [191]. However, a separate analysis from
Denmark suggested a slightly higher total rate of thromboembolic events following ChadOx1
nCoV-19/AZD1222 than expected [192].
Myocarditis — Myocarditis and pericarditis, mainly in male adolescents and young adults,

have been reported more frequently than expected following receipt of the mRNA vaccines,
BNT162b2 (Pfizer vaccine) and mRNA-1273 (Moderna vaccine) [193,194]. A similar pattern of
cases has not been reported following receipt of Ad26.COV2.S (Janssen/Johnson & Johnson
vaccine). Nevertheless, given the infrequency and the mild nature of the myocarditis and
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pericarditis cases, the benefits of mRNA vaccination greatly exceed the small increased risk
[194]. For those who develop myocarditis or pericarditis following a first dose of an mRNA
vaccine, we suggest that the second dose be deferred in most cases; it is reasonable for such
individuals to choose to receive a second dose once the episode has completely resolved if
the risk of severe COVID-19 is high [34]. Individuals with a history of resolved myocarditis or
pericarditis unrelated to COVID-19 vaccination can receive an mRNA vaccine.
In a review of the Vaccine Adverse Event Reporting System (VAERS), a passive surveillance
system in the United States to which patients and providers can submit reports of events,
there were 267 reported cases of myocarditis/pericarditis following one dose of an mRNA
vaccine, 827 following two doses, and 132 without the number of doses specified as of June
11, 2021 [194]. The median ages for events after one and two doses were 30 and 24 years,
respectively. Approximately three-quarters of the cases occurred in males. Among individuals
aged 12 to 39 years, the number of events observed within a 21-day post-vaccine window
exceeded the expected number. The estimated rate of myocarditis/pericarditis among males
12 to 29 years of age was 41 cases per million following a second dose of an mRNA. The
estimated rates among females of the same age range was 4.2 cases per million and among
males ≥30 years was 2.4 cases per million.
Among the cases that have been reported, most were mild. Onset was generally within the
first week after vaccine receipt, more commonly after the second dose. Most patients who
presented for care responded well to medical treatment and had rapid symptom
improvement. There have been very rare reports of fulminant myocarditis in individuals who
had received an mRNA vaccine within the preceding weeks, although a causal relationship is
difficult to establish [195].
The clinical presentation has been illustrated in several case series [196-198]. In one series,
seven males aged 14 to 19 years developed chest pain within four days of their second dose
of BNT162b2 and had ST elevations on electrocardiogram and elevated troponin levels [196].
None had evidence of acute SARS-CoV-2 infection or met criteria for multisystem
inflammatory syndrome (MIS). Cardiac magnetic resonance imaging was consistent with
myocarditis in all, and echocardiogram was normal in all but one. Three received
nonsteroidal anti-inflammatory agents only, and four received intravenous immune globulin
and glucocorticoids; all had symptom resolution within a week. Patients will be followed to
assess whether there are any long-term implications.
The possibility of myocarditis should be considered in adolescents and young adults who
develop new chest pain, shortness of breath, or palpitations after receiving an mRNA vaccine.
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The possibility of other causes of myocarditis (including SARS-CoV-2 infection) should also be
considered. The diagnosis and management of myocarditis are discussed in detail elsewhere.
(See "Clinical manifestations and diagnosis of myocarditis in children" and "Clinical
manifestations and diagnosis of myocarditis in adults" and "Treatment and prognosis of
myocarditis in children" and "Treatment and prognosis of myocarditis in adults".)
Guillain-Barre syndrome — A potential association between the adenovirus vector vaccines

(Ad26.COV2.S [Janssen/Johnson & Johnson COVID-19 vaccine] and ChAdOx1
nCoV-19/AZD1222 [AstraZeneca COVID-19 vaccine]) and Guillain-Barre syndrome (GBS) is
being investigated. A similar signal has not been observed with the mRNA COVID-19
vaccines. The US FDA and CDC and European regulators affirm that the benefits of these
vaccines outweigh their risks [199,200]. Cases of GBS, including recurrent cases, have also
been reported in the setting of SARS-CoV-2 infection [201,202]. Pending additional data, for
individuals with a documented history of GBS, we suggest using COVID-19 vaccines other
than adenovirus vector vaccines; if only an adenovirus vector vaccine is available, we
individualize the decision to administer it based on that person’s risk for severe COVID-19
and GBS history. The general approach to vaccination in individuals with a history of GBS is
discussed elsewhere. (See "Guillain-Barré syndrome in adults: Treatment and prognosis",
section on 'Subsequent immunizations'.)
● In the United States, there had been 100 preliminary reports of GBS among Ad26.COV2.S
recipients after approximately 12.6 million doses [187]. The estimated rate was 7.8 cases
per million doses, a rate that is approximately five times the background rate; the rate
was highest among males aged 50 to 64 years, at 15.6 cases per million. The mean age
was 57 years (ranging from 24 to 76), the mean time to onset was 13 days following
vaccination, 10 required mechanical ventilation, and 1 patient died. A quarter of the
patients reported bilateral facial weakness.
● In Europe, a total of 227 cases of GBS in ChAdOx1 nCoV-19/AZD1222 recipients had been
reported to regulators as of June 27, 2021, at which point approximately 51 million doses
had been administered [200]. Other scattered reports have also described GBS, including
variant GBS with bilateral facial weakness, following ChAdOx1 nCoV-19/AZD1222
vaccination [203,204].
STEPS TO VACCINE AVAILABILITY AND DELIVERY
● Establishing efficacy and licensing a vaccine – Initial estimates of vaccine efficacy are
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established by phase III trials. In the United States, the minimum criteria for licensure
defined by the US Food and Drug Administration (FDA) were at least 50 percent efficacy
in preventing microbiologically confirmed symptomatic SARS-CoV-2 infection, with a
lower bound of a 95% confidence interval of 30 percent, and at least six months of
follow-up for safety assessment [205]. The World Health Organization (WHO) has
proposed the same minimal efficacy targets [206].
Once safety and efficacy meeting the criteria have been demonstrated, the FDA makes
decisions on vaccine licensure, relying on guidance from the Vaccines and Related
Biologic Products Advisory Committee (VRBPAC), a standing advisory group of
experienced clinicians, vaccine experts, epidemiologists, and other subject matter
experts. Similar approaches are taken by regulatory bodies in Canada and European
countries for the licensure of their vaccines.
In addition to the traditional process to issue a license for a vaccine, the FDA can issue an
emergency use authorization (EUA), which is designed to make products available during
public health emergencies [207]. For a COVID-19 vaccine to receive EUA, it must meet the
prespecified efficacy criteria defined for the primary endpoint with a median of two
months of follow-up for half of the trial participants [208].
● Allocation priorities – When vaccine supplies are limited, it is essential that vaccine
deployment be equitable and efficient. Several expert organizations have released
guidance documents for vaccine allocation approaches that maximize the individual and
societal benefits of vaccination [209-211]. These prioritize vaccination according to risks
of acquiring infection, severe morbidity and mortality, negative societal impact (eg, if
essential critical societal functions depend on an individual or groups of individuals), and
transmission to others; they also emphasize equitable vaccine allocation to populations
disproportionately impacted by the pandemic because of structural inequities and social
determinants of health, including Black, Latin American, and Indigenous populations.
The framework proposed by the WHO also takes into account global equity concerns,
including assurance of vaccine access to low- and middle-income countries [211].
● Strategies for maximizing vaccine supply – Most currently available vaccines were
evaluated and authorized for a two-dose series. However, some have argued for
delaying the second vaccine dose or decreasing the vaccine dose in order to maximize
the number of individuals who can be rapidly vaccinated. We do not support diverging
from the vaccine schedule as authorized. Although alternate dosing strategies may be
able to improve vaccination rates with the given supply, more data are needed to assess
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the safety and efficacy of these strategies before adopting them. This stance is
consistent with a statement from the US FDA [212]. The WHO suggests that in
extenuating circumstances (eg, locations with very high burden of infection and limited
vaccine supplies), countries can decide to defer the second dose of the mRNA vaccines
up to six weeks after the first, although it notes that this approach is based on very
limited data [213,214].
Some modeling studies have suggested that offering a single vaccine dose to more
people could result in similar population outcomes as a two-vaccine series, even if a
single dose results in lower efficacy rates [215,216]. However, these studies make
assumptions about vaccine outcomes (such as duration of protection) that are unknown.
Although data from phase III trials of the mRNA COVID-19 vaccines suggested some
early protection following a single dose, follow-up of individuals who received only one
dose was too short to inform potential single-dose vaccine efficacy beyond one month
[106,135]. Furthermore, these models do not take into account operational challenges of
distribution, which remain major challenges to vaccination in the United States and
elsewhere.
Additionally, immunogenicity studies of mRNA COVID-19 vaccines suggested that

neutralizing titers following the first dose were substantively lower than those following
the second dose. However, the immunologic correlates of protection are uncertain, and
the lower titers may still be protective. Limited data from trials and subsequent
observational studies suggest potential protection following a single dose of vaccines
that are given as a two-dose series; however, the magnitude and duration of protection
from the single doses are uncertain because most participants received the second dose
in the series within several weeks. These data are discussed elsewhere. (See
'Immunogenicity, efficacy, and safety of select vaccines' above.)
● Vaccine reimbursement – In the United States, COVID-19 vaccines will be free of charge
for any individual for whom the ACIP recommends vaccination [217]. Vaccine providers
can get administration costs reimbursed by public or private insurers, or for uninsured
patients, by the Health Resources and Services Administration's Provider Relief Fund
[218].
POST-LICENSURE ISSUES
Combating vaccine hesitancy — Vaccine hesitancy presents a major obstacle to achieving
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vaccination coverage that is broad enough to result in herd immunity and slow community
transmission. In general, vaccine hesitancy has become more common worldwide and was
cited by the WHO as a top 10 global health threat in 2019 [219]. With COVID-19 vaccines, the
accelerated nature of development, which has led to perceptions that corners are being cut
with regard to safety assessments, and misinformation about SARS-CoV-2 infection and the
vaccines may contribute further to concerns or skepticism about safety and utility among
vaccine-hesitant individuals. Efforts to optimize COVID-19 vaccine uptake should identify
reasons for and characteristics associated with vaccine refusal and use that information to
tailor approaches to individuals and populations.
Based on evidence from other vaccines, health care providers can improve vaccine
acceptance in individual patients by making direct recommendations for vaccination,
identifying concerns, educating patients on vaccine risks and benefits, and dispelling
misconceptions about the disease and the vaccine. (See "Standard childhood vaccines:
Parental hesitancy or refusal", section on 'Target education'.)
Communication points that may be helpful when speaking with patients who are uncertain
about whether to receive a COVID-19 vaccine can be found here or on the Centers for
Disease Control and Prevention (CDC) website [220,221].
Willingness to accept a COVID-19 vaccine varies by country. In an online survey of 13,426

participants from 19 countries who were asked if they would accept a "proven, safe and
effective vaccine," 72 percent overall said they completely or somewhat agreed [222]. The
highest proportion of positive responses were from China, South Korea, and Singapore (over
80 percent), whereas the lowest were from Russia (55 percent).
In the United States, rates of vaccine hesitancy appear to have decreased since the
availability of COVID-19 vaccines but remain substantial. In an internet survey of
approximately 3500 adults conducted by the CDC in September and December 2020, the
proportion who reported that they were very likely or absolutely certain to receive a
COVID-19 vaccine increased from 39 to 49 percent, and the proportion who were unlikely to
receive one decreased from 38 to 32 percent [223]. In another survey of approximately 7200
adults, rates of vaccine hesitancy also decreased from 46 percent in October 2020 to 35
percent in March 2021 [224-227].
COVID-19 vaccine hesitancy has been associated with younger age (eg, <60 years old), lower
levels of education, lower household income, rural residence, and lack of health insurance
[223,224,228]. In the CDC survey, the main reasons for reporting non-intent to receive
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vaccine were concerns about vaccine side effects and safety and lack of trust in the process
[223].
Ongoing efficacy assessment — Phase III clinical trials may not answer several efficacy
questions related to SARS-CoV-2 vaccination. These include:
● Duration of protection from disease

● Potential need for and timing of additional booster doses
● Effectiveness in subpopulations not evaluated in the clinical trials
● Impact on community transmission (ie, herd immunity)
Ongoing follow-up of trial participants and additional observational studies are necessary to
address these issues.
Breakthrough infections after vaccination — Since no COVID-19 vaccine is 100 percent

effective, some infections in fully vaccinated individuals are expected. However,
breakthrough infection after vaccination occurs much less frequently than infection in
unvaccinated individuals and a high proportion may be asymptomatic [229,230]. Although
some reports suggest a higher rate of breakthrough infections with Delta, the dominant
variant in many countries, the risk of severe breakthrough infection with the Delta variant
remains very low [121,231]. (See 'Efficacy against variants of concern' below.)
Studies performed prior to the emergence of the prevalent Delta variant had highlighted the
low rate of breakthrough infections. Additionally, breakthrough infection, even with the Delta
variant, is unlikely to cause severe disease. In the United States as of April 30, 2021, 10,262
breakthrough infections had been reported to the CDC among 101 million fully vaccinated
individuals [229]. Of those with breakthrough infection, only 10 percent were hospitalized
and 2 percent died, although not all hospitalizations or deaths were related to COVID-19.
Twenty-seven percent of infections were asymptomatic. In a study from an Israeli medical
center with over 11,000 fully vaccinated health care workers, nearly 1500 underwent SARS-
CoV-2 testing (eg, for any symptoms or exposure) among whom 39 breakthrough infections
were identified (2.6 percent test positive rate, and 0.4 percent population infection rate)
[232]. Among those with infection, 33 percent were asymptomatic for the duration of the
infection, and none were hospitalized. However, 19 percent had persistent symptoms
(anosmia, cough, fatigue, myalgias, or dyspnea) for six weeks or longer following infection.
In a report of 274 individuals with breakthrough infection with the Delta variant, 21 percent
were asymptomatic [80]. Other observational data suggest that breakthrough infection is
associated with a lower number of symptoms, shorter duration of symptoms, and a higher
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likelihood of asymptomatic infection compared with infection in unvaccinated individuals

[233].
Impact on transmission risk — Widespread vaccination reduces the overall transmission

risk, since vaccinated individuals are less likely to get infection. Previous data had also
suggested that individuals who developed infection despite vaccination may be less likely to
transmit to others, thereby further decreasing transmission risk. However, with the
emergence of the Delta variant, which appears more transmissible than other variants and
for which vaccines have slightly lower effectiveness, the extent to which vaccination reduces
transmission is uncertain.
In particular, several studies, some unpublished, suggest that levels of upper respiratory
tract SARS-CoV-2 RNA in fully vaccinated individuals with breakthrough Delta infection are
similar to those in unvaccinated individuals with Delta infection [80,234-236]. As an example,
in one study of a Delta variant outbreak, the median cycle threshold was 22.8 in vaccinated
individuals compared with 21.5 in those who were unvaccinated, not fully vaccinated, or of
unknown vaccination status [80]. Higher viral RNA levels have been associated with a higher
likelihood of detectable infectious virus in the upper respiratory tract, so these data raise the
possibility that vaccinated individuals with breakthrough Delta infection could be as
infectious as unvaccinated individuals, although direct data on secondary attack rates with a
vaccinated index case are lacking. Furthermore, one unpublished study from Singapore
suggested that although viral RNA levels in vaccine-breakthrough infections were similar to
those in unvaccinated individuals at the time of diagnosis, they declined more rapidly in
vaccinated individuals, suggesting a shorter period of infectiousness [237]. Additional data
are needed to confirm these findings and better understand their clinical implications.
Studies performed when the Delta variant was not circulating had suggested a lower
transmission risk with breakthrough infection [238,239]. In an unpublished study from Public
Health England that included over 550,000 households with at least one member with SARS-
CoV-2 infection, the secondary household attack rate was 10 percent for unvaccinated index
cases versus 5.7 or 6.3 percent for index cases who had received their first vaccine dose
(ChAdOx1 nCoV-19/AZD1222 or BNT162b2, respectively) at least 21 days prior to testing
positive [239]. Although interpretation of these results is limited by several potential
confounders (including the unknown rate of vaccination among household contacts), they
raised the possibility of a direct effect of vaccination on transmission risk. Other studies had
suggested that if infection occurs after vaccination, it is associated with lower viral RNA levels
than in unvaccinated individuals [104,238].
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Earlier studies had also highlighted potential for vaccines to reduce asymptomatic infection
and thus transmission. In an unpublished analysis of the mRNA-1273 (Moderna COVID-19
vaccine) trial, in which participants underwent nasopharyngeal swab testing for SARS-CoV-2
RNA prior to each dose, asymptomatic infection following the first dose was detected in 14
vaccine versus 38 placebo recipients (0.1 versus 0.3 percent) [240]. Several observational
studies have also suggested that COVID-19 mRNA vaccination can reduce asymptomatic
infection [109,241-244]. As an example, in a study of nearly 4000 essential workers in the
United States who underwent weekly SARS-CoV-2 polymerase chain reaction (PCR) testing
and of whom nearly 3000 received at least one mRNA vaccine dose, the rate of infection per
1000 person-days was 0.04 for fully vaccinated (at least 14 days after the second dose), 0.19
for partially vaccinated (at least 14 days after the first dose but before receipt of the second),
and 1.38 for unvaccinated participants. Estimated vaccine effectiveness for PCR-confirmed
infection was 90 percent for full and 80 percent for partial vaccination.
Reductions in asymptomatic infection have also been suggested with other vaccines. A
subset of participants in the ChAdOx1 nCoV-19/AZD1222 (AstraZeneca COVID-19 vaccine)
trial underwent weekly screening for SARS-CoV-2 infection; there was a nonstatistically
significant trend toward fewer asymptomatic infections in vaccine recipients (20 percent
overall), although the effect differed by vaccine dose (49 and 2 percent in the low- and
standard-dose groups, respectively) [153,154]. In a subset of the Ad26.COV2.S (Janssen
COVID-19 vaccine) trial that underwent repeat serologic testing 29 days or later following
vaccination, the rate of asymptomatic seroconversion was lower in the vaccine compared
with placebo group (estimated vaccine efficacy 74 percent), but follow-up time was limited
[144]. Despite the variable apparent effect on asymptomatic cases among these trials, the
lack of increase in asymptomatic cases in the vaccine groups suggests that vaccination
reduces SARS-CoV-2 infection overall and does not just convert symptomatic infections to
asymptomatic ones.
Efficacy against variants of concern — Several SARS-CoV-2 variants that are concerning

for their potential for immune escape have been identified worldwide ( table 5) (see
"COVID-19: Epidemiology, virology, and prevention", section on 'Variants of concern'). Data
on whether vaccine-induced immunity can protect against these variants are limited. Based
on data from efficacy trials and immunogenicity studies, some of which are unpublished,
COVID-19 vaccines likely remain effective against the variants, but efficacy may be variably
attenuated against Delta (B.1.617.2) and Beta (B.1.351).
● Delta – Observational evidence suggests that vaccine effectiveness against symptomatic

infection with the Delta variant is lower than that with Alpha [120,245-248]. However,
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data from the United States, England, Canada, and Israel suggest that vaccine
effectiveness against severe disease and/or hospitalization remains high with Delta and
is comparable to that with Alpha [121,236,245,249,250]. As an example, in an analysis of
SARS-CoV-2 infections in Los Angeles, California from May to July 2021, over which time
Delta became the dominant variant, the age-adjusted rate of hospitalization among
unvaccinated individuals was 29 times that among fully vaccinated individuals [236]. (See
'BNT162b2 (Pfizer-BioNTech COVID-19 vaccine)' above and 'ChAdOx1 nCoV-19/AZD1222
(University of Oxford, AstraZeneca, and the Serum Institute of India)' above.)
● Beta – Vaccine efficacy against the Beta variant may be less when compared with the
original wild-type virus. Overall efficacies of Ad26.COV2.S (Janssen vaccine), NVX-
CoV2373 (Novavax vaccine), and ChAdOx1 nCoV-19/AZD1222 (University of
Oxford/AstraZeneca vaccine) were lower in South Africa, where the Beta variant was
circulating, compared with other locations where Beta was not prevalent. For
Ad26.COV2.S, efficacy against severe/critical disease remained high in all locations;
impact on severe disease in South Africa was not assessed for the other two vaccines.
Whether the difference in overall efficacy in South Africa compared with other sites could
be related to local factors other than Beta is uncertain. Observational evidence suggests
that BNT162b2 effectiveness against any infection with Beta is slightly lower than with
Alpha, but remains high against severe infection. These studies are discussed for the
individual vaccines elsewhere. (See 'Immunogenicity, efficacy, and safety of select
vaccines' above.)
There have also been reports of breakthrough infections in fully vaccinated individuals
caused by other SARS-CoV-2 variants that share some mutations with variants of concern
(such as E484K, which is associated with reduced neutralization by convalescent plasma from
individuals with wild-type infection) [251,252]; however, in at least one report, the risk of
infection with a variant that contained E484K was still lower among vaccinated compared
with unvaccinated individuals [251].
Role of booster vaccinations — Because of the possibility of waning immunity and

decreased efficacy against variants that might escape the immune response directed against
spike proteins targeted by the original vaccines, the role of booster vaccinations to prolong
and broaden immunity is being investigated. Several countries, including the United States,
have initiated or announced plans to administer a booster vaccine for individuals who have
been fully vaccinated [253]; this is in addition to recommending three mRNA vaccine doses
for certain immunocompromised patients (see 'Immunocompromised individuals' above).
The WHO, however, notes that evidence on the need for and potential benefit of widespread
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use of booster vaccinations remains inconclusive [254].
Data from observational studies have suggested that vaccine protection against SARS-CoV-2
infection wanes over time [122,250,255]. However, protection against hospitalization and
severe COVID-19 appears to be preserved. As an example, a review of data on nursing home
residents reported to a national database in the United States suggested that vaccine
effectiveness against laboratory-confirmed SARS-CoV-2 infection among this population
declined from 75 percent in March to May 2021 to 53 percent during June to July 2021 [255].
Similarly, in a study of state-wide data in New York that included approximately 10 million
vaccinated adults, age-adjusted vaccine effectiveness against SARS-CoV-2 infection declined
from 92 to 80 percent from May to July 2021; however, effectiveness against hospitalization
remained stable over that time at 92 to 95 percent [250]. Another study of 3000 hospitalized
patients estimated vaccine effectiveness against COVID-19-related hospitalization as 86
percent 2 to 14 weeks after vaccination and 84 percent 13 to 24 weeks after vaccination
[256].
Evidence that a booster vaccine may improve vaccine effectiveness is limited to data on
immunogenicity. According to a press release report of a small study of individuals who had
received mRNA-1273 (Moderna COVID-19 vaccine) six to eight months prior, a boosting dose
of mRNA-1273 or mRNA-1273.351, a modified vaccine that targets the spike protein of the
Beta (B.1.351) variant, resulted in neutralizing antibody levels against wild-type virus and the
Beta and Gamma (P1) variants that were as high as or higher than those elicited against wild-
type virus following the initial vaccine series [257]. The rate and severity of adverse reactions
following the booster dose were similar to those following the second dose in prior trials.
Ongoing safety assessment — Adequately assessing vaccine safety is critical to the success

of immunization programs. Although existing comprehensive systems to monitor vaccine
safety are in place, they are being enhanced for the rollout of the COVID-19 vaccine program.
It is particularly important to identify rare adverse events that are causally related to vaccine
administration and assess their incidence and risk factors to inform potential vaccine
contraindications.
In the United States, there are several systems in place to assess safety in the post-licensure
setting; some are passive (ie, rely on others reporting the event) and others are active (ie,
review databases or conduct studies to identify events) [258]. These include the Vaccine
Adverse Event Reporting System (VAERS), a passive surveillance system in which providers,
parents, and patients report adverse events. VAERS is intended to raise hypotheses about
whether receipt of a vaccine could cause the adverse event rather than evaluate causation.
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The Vaccine Safety Datalink (VSD) is a collaborative project between the United States
Centers for Disease Control and Prevention's (CDC's) Immunization Safety Office and eight
health care organizations to actively monitor the safety of vaccines and conduct studies
about rare and serious post-vaccination adverse events. The Clinical Immunization Safety
Assessment project (CISA) is a national network of vaccine safety experts from the CDC's
Immunization Safety Office, seven academic medical research centers, and subject matter
experts, and it provides a comprehensive vaccine safety public health service to the nation.
In addition, specific post-licensure vaccine safety systems have been implemented for the
introduction of COVID-19 vaccines, similar to those established during the 2009 H1N1
influenza pandemic [259,260]. These systems will be coordinated through the CDC and will
enlist multiple other health care groups to provide ongoing data on vaccine safety. These
systems and information sources add an additional layer of safety monitoring [261,262].
● V-SAFE is a new smartphone-based health checker for people who have received a
COVID-19 vaccine. The CDC will send text messages and web-based surveys to vaccine
recipients through V-SAFE to check in regarding health problems following vaccination.
The system will also provide telephone follow-up to anyone who reports clinically
significant adverse events.
● Enhanced reporting through National Healthcare Safety Network (NHSN) sites – A

monitoring system for health care workers and long-term care facility residents that
reports to the VAERS.
● Monitoring of larger insurer/payer databases through the US Food and Drug

Administration – A system of administrative and claims-based data for surveillance and
research.
Since most vaccine-preventable diseases are transmitted person-to-person, effective

vaccination not only protects the recipient but also indirectly protects others who cannot be
vaccinated or do not respond adequately by preventing another source for transmission
("herd immunity") [263]. Therefore, if someone is injured by vaccine, society owes that
person compensation. This is the basis for the National Vaccine Injury Compensation
Program (NVICP) [264]. This program also reduces liability for the vaccine provider and the
manufacturer, since it is a no-fault alternative to the traditional legal system for resolving
vaccine injury claims. With COVID-19 vaccines, another compensation system called the
Countermeasures Injury Compensation Program (CICP) may be used [265].
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SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: COVID-19 – Index of
guideline topics".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th
grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles on
a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topics (see "Patient education: COVID-19 vaccines (The Basics)" and "Patient
education: COVID-19 overview (The Basics)" and "Patient education: COVID-19 and
pregnancy (The Basics)" and "Patient education: COVID-19 and children (The Basics)")
SUMMARY AND RECOMMENDATIONS
● Vaccines to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

infection are considered the most promising approach for controlling the pandemic.
COVID-19 vaccine development is occurring at an unprecedented pace. (See 'Overview of
vaccine development' above.)
● The primary antigenic target for COVID-19 vaccines is the large surface spike protein (
figure 1), which binds to the angiotensin-converting enzyme 2 (ACE2) receptor on host
cells and induces membrane fusion ( figure 2). (See 'Antigenic target' above.)
● Several vaccine candidates using several different platforms ( figure 3) have
45 de 86 09/09/2021 07:56 p. m.
demonstrated efficacy in preventing laboratory-confirmed symptomatic COVID-19 and

are available in various countries ( table 4). (See 'Immunogenicity, efficacy, and safety
of select vaccines' above.)
● For individuals who are eligible for vaccination according to local allocation priorities, we
recommend COVID-19 vaccination (Grade 1B). Selection of vaccine depends on local
availability. The different vaccines have not been studied head-to-head, and thus,
comparative efficacy is uncertain. (See 'Approach to vaccination' above and
'Immunogenicity, efficacy, and safety of select vaccines' above.)
● In the United States, the following COVID-19 vaccines are available (see 'Indications and
vaccine selection' above and 'Dose and interval' above):
• The COVID-19 mRNA vaccine BNT162b2 (Pfizer COVID-19 vaccine): Two

intramuscular injections given three weeks apart in individuals 12 years or older.
This is associated with a rare risk of myocarditis.
• The COVID-19 mRNA vaccine mRNA-1273 (Moderna COVID-19 vaccine): Two

intramuscular injections given one month apart in individuals 18 years or older. This
is associated with a rare risk of myocarditis.
• The COVID-19 adenovirus-vector vaccine Ad26.COV2.S (Janssen COVID-19 vaccine,

also referred to as the Johnson & Johnson vaccine): A single intramuscular injection
in individuals 18 years or older. This is associated with a rare risk of thrombosis with
thrombocytopenia and possibly Guillain-Barre syndrome.
For individuals with certain immunocompromising conditions ( table 1), we suggest

administering a three-dose mRNA vaccine series rather than a two-dose series (Grade
2C). (See 'Immunocompromised individuals' above.)
The benefits of vaccination greatly outweigh the rare risks of specific adverse events.
(See 'Specific safety concerns' above.)
● The second dose of either mRNA vaccine should be given as close to the recommended
interval as possible, although, if necessary, the second dose can be scheduled for up to
six weeks after the first dose. If the vaccine is administered in a manner different from
the recommended approach, the dose or series generally does not have to be repeated.
CDC recommendations on how to manage vaccination errors or deviations are
presented in the table ( table 2). (See 'Deviations from recommended dosing intervals'
above.)
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● Vaccine recipients should be advised that side effects are common and include local and
systemic reactions, including pain at the injection site, fever, fatigue, and headache.
Analgesics or antipyretics (eg, nonsteroidal anti-inflammatory drugs [NSAIDs] or
acetaminophen) can be taken if these reactions develop, although prophylactic use of
these agents before vaccine receipt is generally discouraged because of the uncertain
impact on the host immune response to vaccination. (See 'Patient counseling' above.)
● The only contraindications to COVID-19 vaccination are severe or immediate allergic

reactions to the vaccine or any of its components. All individuals should be monitored for
an immediate reaction for at least 15 minutes following vaccination. Individuals without
a contraindication who have a history of anaphylaxis of any kind, an immediate allergic
reaction to other vaccines or injectable therapies, or a contraindication to a COVID-19
vaccine class other than the one they are receiving should be monitored for 30 minutes.
(See 'Contraindications and precautions (including allergies)' above and 'Monitoring for
immediate reactions to vaccine' above.)
● Although SARS-CoV-2 infection might still occur despite vaccination, the risk is
substantially lower. Certain public health precautions such as quarantine may be relaxed
for individuals who have been fully vaccinated (ie, two weeks have elapsed following
receipt of a complete series). However, in regions with substantial SARS-CoV-2
transmission (ie, ≥50 cases/100,000 people over the prior seven days or >8 percent
positive nucleic acid amplification test [NAAT] rate), vaccinated individuals should wear
masks in indoor public spaces given the potential for transmission following
breakthrough infection with the Delta variant. Because individuals with
immunocompromising conditions may have suboptimal responses to COVID-19
vaccination, we counsel them to maintain personal preventive measures, even in regions
without substantial transmission, particularly when contact with unvaccinated
individuals is possible. (See 'Post-vaccine public health precautions' above.)
● Several SARS-CoV-2 variants with potential for immune escape have been identified
worldwide. COVID-19 vaccines likely retain efficacy against Alpha (B.1.1.7). Vaccine
efficacy appears reduced against overall infection with the Beta (B.1.351) variant and to a
lesser extent against Delta (B.1.617.2), although reported efficacy against severe disease
with Beta and Delta is still high. Booster vaccination to prolong and broaden immunity
against these variants is being investigated, but the future need for a booster remains
uncertain. (See 'Efficacy against variants of concern' above and 'Role of booster
vaccinations' above.)
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Topic 129849 Version 105.0
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GRAPHICS
Structure of SARS-CoV-2 spike protein in the prefusion conformation
(A) Schematic of SARS-CoV-2 spike (S) protein primary structure colored by domain. Domains that were excluded from the ectodomain expr
be visualized in the final map are colored white. SS: signal sequence; S2': S2' protease cleavage site; FP: fusion peptide; HR1: heptad repeat
connector domain; HR2: heptad repeat 2; TM: transmembrane domain; CT: cytoplasmic tail. Arrows denote protease cleavage sites.
(B) Side and top views of the prefusion structure of the SARS-CoV-2 spike (S) protein with a single receptor binding domain (RBD) in the up
down protomers are shown as cryo-electron-microscopy density in either white or gray and the RBD up protomer is shown in ribbons colo
schematic in (A).
From: Wrapp D, Wang N, Corbett KS, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020; 367:1260. Available at:
/content/367/6483/1260.long. Copyright © 2020 The Authors. Reproduced under the terms of the Creative Commons Attribution License 4.0.
Graphic 130132 Version 1.0
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Structure and function of the SARS-CoV-2 spike protein
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(A) The schematic structure of the spike (S) protein.

(B) The spike (S) protein binds to the receptor ACE2.
(C) The binding and virus-cell fusion process mediated by the spike (S) protein.
(D) The life cycle of SARS-CoV-2 in host cells.
SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.
Reprinted by permission from Macmillan Publishers Ltd: Acta Pharmacologica Sinica. Huang Y, Yang C, Xu XF, et al. Structural and functional properties of SA
drug development for COVID-19. Acta Pharmacol Sin 2020; 41:1141. Copyright © 2020. https://www.nature.com/aps/.
72 de 86 09/09/2021 07:56 p. m.
Platforms for SARS-CoV-2 vaccines in development
This reflects vaccines under development as of mid-2020. The World Health Organization maintains an
updated list of COVID-19 vaccine candidates on their website.
SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.

* Other efforts include testing whether existing vaccines against poliovirus or tuberculosis could help to fight SARS-
CoV-2 by eliciting a general immune response (rather than specific adaptive immunity) or whether certain immune
cells could be genetically modified to target the virus.
Reprinted by permission from Macmillan Publishers Ltd: Nature. Callaway E. The race for coronavirus vaccines: a graphical
guide. Nature 2020; 580:576. Copyright © 2020. https://www.nature.com/.
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Moderate to severe immunocompromising conditions that warrant a 3-dose series for the
COVID-19 mRNA vaccines in the United States [1]
Active treatment for solid tumor and hematologic malignancies
Receipt of solid-organ transplant and taking immunosuppressive therapy
Receipt of CAR-T-cell or hematopoietic stem cell transplant (within 2 years of transplantation or taking immunosuppressive
therapy)
Moderate or severe primary immunodeficiency (eg, DiGeorge, Wiskott-Aldrich syndromes)
Advanced or untreated HIV infection
Active treatment with:

▪ High-dose corticosteroids (ie, ≥20 mg prednisone or equivalent per day)
▪ Alkylating agents
▪ Antimetabolites
▪ Transplant-related immunosuppressive drugs
▪ Cancer chemotherapeutic agents classified as severely immunosuppressive
▪ TNF blockers
▪ Other biologic agents that are immunosuppressive or immunomodulatory
In the United States, the emergency use authorizations for BNT162b2 (Pfizer-BioNTech COVID-19 vaccine) and mRNA-1273
(Moderna COVID-19 vaccine) allow for the use of 3 doses in certain immunocompromised individuals, specifically solid
organ transplant recipients or those who are diagnosed with conditions considered to have an equivalent level of
immunocompromise. The ACIP lists the above conditions as examples of moderate to severe immunocompromising
conditions that warrant 3 mRNA vaccine doses. It recommends that the same mRNA vaccine be used for all 3 doses and that
the third dose be administered at least 28 days after the second.
CAR: chimeric antigen receptor; TNF: tumor necrosis factor; ACIP: Advisory Committee on Immunization Practices.
Reference:
1. Centers for Disease Control and Prevention. Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Authorized in the
United States. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html (Accessed on August 20,
2021).
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Deltoid injection site
The arm should be completely exposed and lifted slightly out to the side (which causes the
subdeltoid bursa to slide under the acromion). Identify the shoulder tip (acromion) and the deltoid
tuberosity (ie, the site of insertion of the deltoid). Draw an imaginary inverted triangle between the
acromion and the deltoid tuberosity. The correct injection site is in the middle one-third of this
triangle (ie, in the center of the deltoid muscle, midway between the acromion and the deltoid
tuberosity).
Adapted from:
1. Administration of vaccines. In: The Australian Immunisation Handbook, 10 th ed. Available at:
https://immunisationhandbook.health.gov.au/vaccination-procedures/administration-of-
vaccines (Accessed on September 30, 2019).
2. Wadman M. Vaccines on trial. Science 2017; 356:370.
75 de 86 09/09/2021 07:56 p. m.
Interim CDC recommendations for COVID-19 vaccine administration errors and deviations
Vaccines Type Administration error/deviation Interim recommendation
All currently Site/route ▪ Incorrect site (ie, site other than the ▪ Do not repeat dose.* Inform the
authorized deltoid muscle [preferred site] or recipient of the potential for local and
vaccines anterolateral thigh [alternate site]) systemic adverse events.
(Pfizer-
▪ Incorrect route (eg, subcutaneous) ▪ Do not repeat dose.* Inform the
BioNTech,
recipient of the potential for local and
Moderna, and
systemic adverse events.
Janssen
COVID-19 Age ▪ Unauthorized age group ▪ If received dose at age less than 16
vaccines) years, do not give any additional dose
at this time. ¶
▪ If age 16 to 17 years and a vaccine
other than Pfizer-BioNTech was
inadvertently administered:
• If Moderna vaccine administered
as the first dose, may administer
Moderna vaccine as the second
dose (as off-label use, because
Moderna vaccine is not authorized
in this age group).
• If Janssen vaccine administered, do
not repeat dose with Pfizer-
BioNTech vaccine.
Dosage ▪ Higher-than-authorized dose volume ▪ Do not repeat dose.* Δ

administered
▪ Lower-than-authorized dose volume ▪ If more than half of the dose was

administered (eg, leaked out, administered, do not repeat dose.*
equipment failure, recipient pulled ▪ If less than half of the dose was
away) administered or the proportion of the
dose cannot be estimated, administer
the authorized dose immediately (no
minimum interval) in the opposite
arm. ◊
Storage and ▪ Dose administered after improper ▪ Contact the manufacturer for
handling storage and handling (eg, temperature guidance. If the manufacturer
excursion, more than allowed time provides information supporting that
after first vial puncture) the dose should be repeated, the
repeated dose may be given
immediately (no minimum interval) in
the opposite arm.
▪ Dose administered past the ▪ Contact the manufacturer for

expiration/beyond-use date guidance. If the manufacturer
provides information supporting that
the dose should be repeated, the
the opposite arm.
Coadministration ▪ Dose administered within 90 days of ▪ Do not repeat COVID-19 vaccine dose.
monoclonal antibodies or If person has already received one
convalescent plasma for COVID-19 mRNA COVID-19 vaccine dose, defer
76 de 86 09/09/2021 07:56 p. m.
treatment administration of second dose for 90

days following receipt of antibody
therapy. This deviation from CDC
guidance does not require VAERS
reporting.
mRNA vaccines Intervals ▪ Second dose administered fewer than ▪ Do not repeat dose.
only 17 days (Pfizer-BioNTech) or fewer
(Pfizer-BioNTech than 24 days (Moderna) after the first
and Moderna) dose (ie, administered earlier than the
4-day grace period)
▪ Second dose administered more than ▪ Do not repeat dose. This deviation
42 days after the first dose from CDC guidance does not require
VAERS reporting.
Mixed series ▪ Incorrect mRNA COVID-19 vaccine ▪ Do not repeat dose. §

product administered for second dose
in 2-dose series
Pfizer- Diluent ▪ ONLY diluent administered (ie, sterile ▪ Inform the recipient that no vaccine
BioNTech only 0.9% sodium chloride) was administered. Administer the
authorized dose immediately (no
minimum interval) in the opposite
arm. ◊
▪ No diluent, resulting in higher than ▪ Do not repeat dose.* Δ Inform the

authorized dose (ie, 0.3 mL of recipient of the potential for local and
undiluted vaccine administered) systemic adverse events.
▪ Incorrect diluent type (eg, sterile ▪ Contact the manufacturer for

water, bacteriostatic 0.9% NS) guidance. If the manufacturer
provides information supporting that
the dose should be repeated, the
the opposite arm.
▪ Incorrect diluent volume (ie, the vial ▪ For doses administered with diluent
contents were diluted with a diluent volume less than 1.8 mL, inform the
volume other than 1.8 mL, but a 0.3 recipient of the potential for local and
mL dose was still administered) systemic adverse events.* Δ
▪ For doses administered with diluent
volume greater than 1.8 mL, do not
repeat dose.* (NOTE: Dilution with a
volume up to 4.0 mL [which exceeds
vial capacity] results in more-than-half
of the authorized dose administered.)
COVID-19: coronavirus disease 2019; CDC: United States Centers for Disease Control and Prevention; VAERS: Vaccine Adverse Event
Reporting System.
Pfizer-BioNTech and Moderna vaccines only:
* If the dose given in error is the first dose, a second dose should be administered at the recommended interval (21 days [Pfizer-
BioNTech] or 28 days [Moderna]). If this dose is the second dose, the series is complete, and no additional doses are needed.
¶ Do not administer the second dose until the person becomes eligible to receive vaccination (either by reaching the authorized age
or if the authorization is extended to include additional age groups), even if this results in the second dose being administered after
the recommended interval between doses.
Δ If the administration error resulted in a higher-than-authorized vaccine dose, in general the second dose may still be administered
at the recommended interval. However, if local or systemic side effects following vaccination are clinically concerning (outside of the
expected side effect profile), lead to serious adverse reactions, or are ongoing at the time of the second dose, the decision to
administer the second dose may be assessed on a case-by-case basis.
77 de 86 09/09/2021 07:56 p. m.
◊ If the dose given in error is the first dose, the second dose should be administered at the recommended interval (21 days [Pfizer-
BioNTech] or 28 days [Moderna]) from the date of receipt of the valid dose (not the date of receipt of the erroneous dose).
§ Although CDC provides considerations for a mixed series in exceptional circumstances, this is still considered an administration
error that requires VAERS reporting (as a mixed series is not authorized under the vaccine Emergency Use Authorizations).
Reproduced from: Centers for Disease Control and Prevention. Interim Clinical Considerations for Use of COVID-19 Vaccines Currently
Authorized in the United States. Available at: https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-considerations.html (Accessed
on March 4, 2021).
78 de 86 09/09/2021 07:56 p. m.
Rapid overview: Emergency management of anaphylaxis in adults
Diagnosis is made clinically:

The most common signs and symptoms are cutaneous (eg, sudden onset of generalized urticaria, angioedema, flushing,
pruritus). However, 10 to 20% of patients have no skin findings.
Danger signs: Rapid progression of symptoms, respiratory distress (eg, stridor, wheezing, dyspnea, increased work of
breathing, persistent cough, cyanosis), vomiting, abdominal pain, hypotension, dysrhythmia, chest pain, collapse.
Acute management:
The first and most important treatment in anaphylaxis is epinephrine. There are NO absolute contraindications to
epinephrine in the setting of anaphylaxis.
Airway: Immediate intubation if evidence of impending airway obstruction from angioedema. Delay may lead to complete
obstruction. Intubation can be difficult and should be performed by the most experienced clinician available. Cricothyrotomy
may be necessary.
Promptly and simultaneously, give:
IM epinephrine (1 mg/mL preparation): Give epinephrine 0.3 to 0.5 mg intramuscularly, preferably in the mid-outer
thigh. Can repeat every 5 to 15 minutes (or more frequently), as needed. If epinephrine is injected promptly IM, most
patients respond to one, two, or at most, three doses. If symptoms are not responding to epinephrine injections, prepare
IV epinephrine for infusion.
Place patient in recumbent position, if tolerated, and elevate lower extremities.
Oxygen: Give 8 to 10 L/minute via facemask or up to 100% oxygen, as needed.
Normal saline rapid bolus: Treat hypotension with rapid infusion of 1 to 2 liters IV. Repeat, as needed. Massive fluid shifts
with severe loss of intravascular volume can occur.
Albuterol (salbutamol): For bronchospasm resistant to IM epinephrine, give 2.5 to 5 mg in 3 mL saline via nebulizer, or 2
to 3 puffs by metered dose inhaler. Repeat, as needed.
Adjunctive therapies:
H1 antihistamine*: Consider giving cetirizine 10 mg IV (given over 2 minutes) or diphenhydramine 25 to 50 mg IV (given

over 5 minutes) - for relief of urticaria and itching only.
H2 antihistamine*: Consider giving famotidine 20 mg IV (given over 2 minutes).
Glucocorticoid*: Consider giving methylprednisolone 125 mg IV.
Monitoring: Continuous noninvasive hemodynamic monitoring and pulse oximetry monitoring should be performed.
Urine output should be monitored in patients receiving IV fluid resuscitation for severe hypotension or shock.
Treatment of refractory symptoms:

Epinephrine infusion ¶: For patients with inadequate response to IM epinephrine and IV saline, give epinephrine continuous
infusion, beginning at 0.1 mcg/kg/minute by infusion pump Δ. Titrate the dose continuously according to blood
pressure, cardiac rate and function, and oxygenation.
Vasopressors ¶: Some patients may require a second vasopressor (in addition to epinephrine). All vasopressors should be
given by infusion pump, with the doses titrated continuously according to blood pressure and cardiac rate/function and
oxygenation monitored by pulse oximetry.
Glucagon: Patients on beta-blockers may not respond to epinephrine and can be given glucagon 1 to 5 mg IV over 5 minutes,
followed by infusion of 5 to 15 mcg/minute. Rapid administration of glucagon can cause vomiting.
Instructions on how to prepare and administer epinephrine for IV continuous infusions are available as separate tables in
UpToDate.
IM: intramuscular; IV: intravenous.

* These medications should not be used as initial or sole treatment.
¶ All patients receiving an infusion of epinephrine and another vasopressor require continuous noninvasive monitoring of blood
pressure, heart rate and function, and oxygen saturation.
79 de 86 09/09/2021 07:56 p. m.
Δ For example, the initial infusion rate for a 70 kg patient would be 7 mcg/minute. This is consistent with the recommended range
for non-weight-based dosing for adults, which is 2 to 10 mcg/minute. Non-weight-based dosing can be used if the patient's weight is
not known and cannot be estimated.
Adapted from: Simons FER. Anaphylaxis. J Allergy Clin Immunol 2010; 125:S161.
80 de 86 09/09/2021 07:56 p. m.
Characteristics of select COVID-19 vaccines [1]
Efficacy
Doses and Rate of
against Storage
Name Company/developer Platform intended severe
symptomatic requirements
interval COVID-19
COVID-19*
BNT162b2 ¶ Pfizer/BioNTech mRNA 2 doses 3 weeks 95% 1 in vaccine Ultracold freezer

apart group (–80 to –60°C)
(n≈18,000) then freezer (–25
9 in placebo to –15°C) for up
group to 2 weeks
(n≈18,000) cumulative time
then refrigerated
(2 to 8°C) for up
to 1 month
mRNA-1273 ¶ Moderna mRNA 2 doses 4 weeks 94% 0 in vaccine Freezer

apart group –15°C) then
(n≈14,000) refrigerated (2 to
30 in 8°C) for up to 30
placebo days
group
(n≈14,000)
Ad26.COV2.S ¶ Janssen/Johnson & Replication- 1 dose 66% efficacy 85% efficacy Refrigerated (2 to
Johnson incompetent against against 8°C)
adenovirus moderate to severe
26 vector severe COVID-19 Δ
COVID-19 Δ
ChAdOx1 AstraZeneca/University of Replication- 2 doses 70% 0 in vaccine Refrigerated (2 to

nCoV-19/AZD1222 Oxford/Serum Institute of incompetent group 8°C)
▪ 4 to 12 weeks
India chimpanzee (n≈6000)
apart
81 de 86 09/09/2021 07:56 p. m.
adenovirus (manufacturer 2 in placebo

vector recommendation) group
▪ 8 to 12 weeks (n≈6000)
apart (WHO
recommendation)
NVX-CoV2373 Novavax Recombinant 2 doses 3 weeks 89% Δ 0 in vaccine Refrigerated (2 to

protein apart group; 1 in 8°C)
placebo
group
(n≈15,000
total) Δ
COVID-19: coronavirus disease 2019; WHO: World Health Organization.

* None of the vaccines have been studied head-to-head, and thus comparative efficacy is uncertain. Differences in the magnitudes
of effect reported from phase III trials could be related to factors other than efficacy, including differences in the trial populations
and locations, timing of the trials during the pandemic, and study design. Most efficacy estimates were determined with a median
follow-up of two months after vaccination.
¶ These vaccines are available through emergency use authorization in the United States.
Δ These data have not yet been published.
◊ Efficacy was assessed with the liquid form.
Reference:
1. Connors M, Graham BS, Lane HC, Fauci AS. SARS-CoV-2 Vaccines: Much Accomplished, Much to Learn. Ann Intern Med 2021; M21.
82 de 86 09/09/2021 07:56 p. m.
SARS-CoV-2 Variants of Concern
Spike
protein
substitutions
Name
WHO Name (receptor- First
(Pango Known attributes
label [1] (Nextstrain*) binding detected
lineage*)
domain
substitutions
in bold)
Alpha B.1.1.7 ¶ 20I/501Y.V1 Δ69/70 United ▪ ~50% increased transmission [2]

Δ144Y Kingdom ▪ Potential increased severity based on
hospitalizations and case fatality
(E484K ◊)
rates [3]
(S494P ◊)
▪ Minimal impact on neutralization by
N501Y monoclonal antibody therapies §
A570D • Bamlanivimab-etesevimab: No
change in susceptibility [4]
D614G
• Casirivimab-imdevimab: No
P681H
• Sotrovimab: No change in
susceptibility [6]
▪ Minimal impact on neutralization by
convalescent and post-vaccination
sera [7-13]
Beta B.1.351 20H/501.V2 K417N South Africa ▪ ~50% increased transmission [14]
E484K ▪ Significant impact on neutralization
by some monoclonal antibody
N501Y
therapies §
D614G
• Bamlanivimab-etesevimab:
Unlikely to be active (>45-fold
decrease in susceptibility) [4]
susceptibility [6]
▪ Moderate reduction in neutralization
by convalescent and post-vaccination
sera
83 de 86 09/09/2021 07:56 p. m.
Gamma P.1 20J/501Y.V3 K417N/T Japan/Brazil ▪ Significant impact on neutralization

E484K by some monoclonal antibody
therapies §
N501Y
D614G Unlikely to be active (>511-fold
susceptibility [6]
▪ Reduced neutralization by
convalescent and post-vaccination
sera [15]
Delta B.1.617.2 ¥ 20A T19R India ▪ Increased transmissibility compared

(G142D ◊) with B.1.1.7 (Alpha) [16]
▪ Potential increased severity based on
Δ156
associated hospitalization rate [16,17]
Δ157
▪ Potential minimal reduction in
R158G neutralization by monoclonal
L452R antibody therapies ‡
▪ Potential modest/moderate
T478K
reduction in vaccine effectiveness
D614G against symptomatic COVID-19
P681R without significant impact on vaccine
D950N effectiveness against severe
disease [17-20]
Epsilon B.1.427 and 20C/S:452R L452R US- ▪ ~20% increased transmissibility [21]
B.1.429 † D614G California ▪ Significant impact on neutralization
by some monoclonal antibody
S13I (B.1.429
therapies §
only)
W152C (B.1.429
Unlikely to be active (7.4-fold
only)
susceptibility [6]
▪ Moderate reduction in neutralization
by convalescent and post-vaccination
sera [21]
"Variants of Concern" have evidence of an increase in transmissibility, greater risk of severe disease, a significant reduction
in neutralization by antibodies generated during previous infection or vaccination, or reduced effectiveness of treatments or
vaccines. These variants share one specific mutation called D614G. This mutation was one of the first documented in the
United States in the initial stages of the pandemic, after having initially circulated in Europe. There is evidence that variants
with this mutation spread more quickly than viruses without this mutation. In the United States, the proportion of
circulating variants in each state can be found on the CDC website.
EUA: emergency use authorization; BEI resources: Biodefense and Emerging Infections Research resources; NIAID: National Institute
of Allergy and Infectious Diseases; CDC: United States Centers for Disease Control and Prevention.
* Pango lineage (or Pangolin) and Nextstrain are resources that compile reported SARS-CoV-2 genome sequences and assign them
to a most likely phylogenetic lineage. Each tool uses its own nomenclature.
¶ As of April 2021, the B.1.1.7 variant is the most common lineage circulating in the United States.
◊ Detected in some sequences but not all.
§ These estimates were established by manufacturers' assessments of neutralizing activity against pseudoviruses bearing the key
spike protein mutations found in each variant. Key mutations in B.1.526/20C, a Variant of Interest (distinct from a Variant of
84 de 86 09/09/2021 07:56 p. m.
Concern) that was first identified in New York and contains the E484K mutation, was also assessed for susceptibility to monoclonal
antibody therapy and showed a 17-fold reduction in susceptibility to bamlanivimab-etesevimab and no change in susceptibility to
casirivimab-imdevimab and sotrovimab. [4-6]
¥ This lineage has been designated a Variant of Concern by the World Health Organization and a Variant of Interest by the CDC in
the United States.
‡ B.1.617.2 does not contain mutations associated with reduced susceptibility to bamlanivimab-etesevimab, casirivimab-imdevimab,
or sotrovimab. [5,6,17]
† These lineages have been designated Variants of Concern by the CDC in the United States and Variants of Interest by the World
Health Organization.
References:
1. World Health Organization. Tracking SARS-CoV-2 variants. Available at: https://www.who.int/en/activities/tracking-SARS-CoV-2-
variants/.
2. Davies NG, Abbott S, Barnard RC, et al. Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England. MedRXiv
2021.
3. Horby P, Huntley C, Davies N, et al. NERVTAG note on B.1.1.7 severity. New & Emerging Threats Advisory Group. Available at:
https://depts.washington.edu/pandemicalliance/2021/01/25/nervtag-note-on-b-1-1-7-severity/.
4. US Food and Drug Administration. Fact sheet for health care providers emergency use authorization (EUA) of bamlanivimab and
etesevimab. Available at: https://www.fda.gov/media/145802/download.
5. US Food and Drug Administration. Fact sheet for health care providers emergency use authorization (EUA) of REGEN-COV
(casirivimab with imdevimab). Available at: https://www.fda.gov/media/145611/download.
6. US Food and Drug Administration. Fact sheet for health care providers emergency use authorization (EUA) of sotrovimab. Available
at: https://www.fda.gov/media/149534/download.
7. Wang P, Nair MS, Liu L, et al. Antibody Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7. BioXRiv 2021.
8. Shen X, Tang H, McDanal C, et al. SARS-CoV-2 variant B.1.1.7 is susceptible to neutralizing antibodies elicited by ancestral Spike
vaccines. BioRxiv 2021.
9. Edara VV, Floyd K, Lai L, et al. Infection and mRNA-1273 vaccine antibodies neutralize SARS-CoV-2 UK variant. MedRxiv 2021.
10. Collier DA, DeMarco A, Ferreira I, et al. SARS-CoV-2 B.1.1.7 sensitivity to mRNA vaccine-elicited, convalescent and monoclonal
antibodies. MedRxiv 2021.
11. Wu K, Werner AP, Moliva JI, et al. mRNA-1273 vaccine induces neutralizing antibodies against spike mutants from global SARS-CoV-2
variants. BioRxiv 2021.
12. Emary KRW, Golubchik T, Aley PK, et al. Efficacy of ChAdOx1 nCoV-19 (AZD1222) Vaccine Against SARS-CoV-2 VOC 202012/01 (B.1.1.7).
The Lancet (preprint) 2021.
13. Novavax. Press release: Novavax COVID-19 Vaccine Demonstrates 89.3% Efficacy in UK Phase 3 Trial. Available at:
https://ir.novavax.com/news-releases/news-release-details/novavax-covid-19-vaccine-demonstrates-893-efficacy-uk-phase-3.
14. Pearson CAB, Russell TW, Davies NG, et al. Estimates of severity and transmissibility of novel South Africa SARS-CoV-2 variant 501Y.V2.
Available at: https://cmmid.github.io/topics/covid19/reports/sa-novel-variant
/2021_01_11_Transmissibility_and_severity_of_501Y_V2_in_SA.pdf.
15. Wang P, Wang M, Yu J, et al. Increased Resistance of SARS-CoV-2 Variant P.1 to Antibody Neutralization. BioRxiv 2021.
16. Public Health England. SARS-CoV-2 variants of concern and variants under investigation in England. Technical briefing 14. June 3,
2021. Available at: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/991343
/Variants_of_Concern_VOC_Technical_Briefing_14.pdf.
17. Sheikh A, McMenamin J, Taylor B, et al. SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine
effectiveness. Lancet 2021; 397:2461.
18. Lopez Bernal J, Andrews N, Gower C, et al. Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant. N Engl J Med 2021.
19. Public Health England. COVID-19 vaccine surveillance report: Week 29. Available at: https://assets.publishing.service.gov.uk
/government/uploads/system/uploads/attachment_data/file/1005085/Vaccine_surveillance_report_-_week_29.pdf
20. Nasreen S, He S, Chung H, et al. Effectiveness of COVID-19 vaccines against variants of concern, Canada. MedRxiv 2021.
21. Deng X, Garcia-Knight MA, Khalid MM, et al. Transmission, infectivity, and antibody neutralization of an emerging SARS-CoV-2
variant in California carrying a L452R spike protein mutation. MedRxiv 2021.
Adapted from: Centers for Disease Control and Prevention. SARS-CoV-2 Variant Classifications and Definitions. Available at:
https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/variant-info.html#Concern (Accessed on March 31, 2021).
85 de 86 09/09/2021 07:56 p. m.
Contributor Disclosures
Kathryn M Edwards, MD Grant/Research/Clinical Trial Support: CDC [vaccine safety assessments]; NIH
[mentoring young investigators in vaccine trials]. Consultant/Advisory Boards: Bionet [pertussis
vaccines]; IBM [vaccine safety]. Other Financial Interest: Member Data Safety and Monitoring Boards
for Sanofi [pneumococcal vaccines]; X-4 Pharma [immunomodulator to increase white cell counts];
Seqirus [influenza vaccines]; Moderna [RSV and parainfluenza vaccines]; Pfizer [COVID-19 and RSV
vaccines]; Merck [RSV vaccines]. Walter A Orenstein, MD Consultant/Advisory Boards: Moderna
[Scientific Advisory Board]. Martin S Hirsch, MD Nothing to disclose Allyson Bloom, MD Nothing to
disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conflict of interest policy
86 de 86 09/09/2021 07:56 p. m.

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COVID-19: Vaccines to prevent SARS-CoV-2 infection

Overview of vaccine development — As with the development of pharmaceuticals, vaccine

Lessons from SARS-CoV-1 and MERS-CoV vaccines — Vaccine development for SARS-CoV-1

Vaccine-enhanced disease — Animal studies of vaccines for SARS-CoV-1 and MERS-CoV

Immunologic basis for SARS-CoV-2 vaccination — Several observations support the

Vaccine platforms — COVID-19 vaccines are being developed using several different

● Inactivated vaccines – Inactivated vaccines are produced by growing SARS-CoV-2 in cell

● Live attenuated vaccines – Live attenuated vaccines are produced by developing

● Recombinant protein vaccines – Recombinant protein vaccines are composed of viral

• Replication-incompetent vector vaccines – Replication-incompetent vector

• Replication-competent vector vaccines – Replication-competent vectors are

• Inactivated virus vector vaccines – Inactivated virus vectors are engineered to

● BNT162b2 (Pfizer-BioNTech COVID-19 vaccine) is indicated for individuals aged 12 years

● mRNA-1273 (Moderna COVID-19 vaccine) is indicated for individuals aged 18 years or

● Ad26.COV2.S (Janssen COVID-19 vaccine) is indicated for individuals aged 18 years or

Dose and interval

● BNT162b2 (Pfizer-BioNTech COVID-19 vaccine) is administered in two intramuscular

● mRNA-1273 (Moderna COVID-19 vaccine) is administered in two intramuscular doses of

Completion of two-dose series — Each vaccine series should be completed with the

Timing with relation to non-COVID-19 vaccines — Although there are no data

Limited role for post-vaccination testing — Unless indicated to evaluate for

History of SARS-CoV-2 infection — We suggest eligible individuals with a history of

For individuals who had SARS-CoV-2 infection complicated by multisystem inflammatory

Immunocompromised individuals — We suggest that eligible individuals who have

In studies of transplant recipients who received a third dose of mRNA vaccines,

● Timing immunosuppressive agents and vaccination – Some expert groups

● Continued use of protective measures – We advise immunocompromised patients to

Emerging data suggest that vaccine effectiveness in immunocompromised patients is lower

Issues related to vaccination of specific immunocompromised populations are discussed in

● (See "COVID-19: Cancer screening, diagnosis, post-treatment surveillance in uninfected

Pregnant individuals — Data on the safety of COVID-19 vaccines in pregnant

Children — We suggest that eligible children undergo COVID-19 vaccination.

SARS-CoV-2 infection, immune-related side effects following vaccination in children must be

Expected adverse effects and their management

Although analgesics or antipyretics (eg, nonsteroidal anti-inflammatory drugs [NSAIDs]

'COVID-19 vaccine-related adenopathy and implications for radiologic imaging'.)

Other complications (including more common venous thromboembolic events without

Post-vaccine public health precautions — Although SARS-CoV-2 infection might still

Because individuals with immunocompromising conditions may have suboptimal responses

Recommendations on masking, distancing, and post-exposure management for individuals

EUA status of certain vaccines — In addition to standard counseling around vaccine

Contraindications and precautions (including allergies)

● Contraindications – The only contraindications to COVID-19 vaccination are allergic

• Severe allergic reaction (eg, anaphylaxis) to a previous COVID-19 vaccine dose or to a

The mRNA vaccines, BNT162b2 (Pfizer-BioNTech COVID-19 vaccine) and mRNA-1273

● Precautions – Precautions to vaccination also consist of allergic reactions. These

• Immediate allergic reaction to any other (non-COVID-19) vaccine or injectable

• Contraindication to an mRNA COVID-19 vaccine is a precaution to Ad26.COV2.S

• Contraindication to AD26.COV2.S is a precaution to an mRNA vaccine because of

Allergy consultation can be helpful to evaluate suspected allergic reactions to a COVID-19

History of thromboembolic disease is not a contraindication to vaccination. However, very

● Late local reactions characterized by a well-demarcated area of erythema appearing at

● Anticoagulation is not a contraindication to vaccination; excess bleeding is unlikely with

Monitoring for immediate reactions to vaccine — All individuals should be monitored

The following warrant monitoring for 30 minutes:

● Precautions to the administered vaccine (immediate reaction to any vaccine or injectable

● History of anaphylaxis due to any cause

All other individuals are monitored for 15 minutes.

Reporting of adverse events — To facilitate ongoing safety evaluation, vaccine providers

Other countries — Various vaccines are available in different countries. A list of vaccines

Several countries had paused use of ChAdOx1 nCoV-19/AZD1222 to investigate scattered