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

9/8/2021 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: Jul 2021. | This topic last updated: Jul 30, 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 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
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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 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 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 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 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 vaccines BNT162b2 (Pfizer-BioNTech COVID-
19 vaccine) and 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.
● 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, particularly individuals <50 years old, 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.
● 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.
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 1).
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 1). 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 1).
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'.)
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. 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 [38-43].
Furthermore, studies suggest that in individuals with prior infection, a single mRNA vaccine dose augments neutralizing
antibody levels as well as cell-mediated responses against other SARS-CoV-2 variants (Alpha [B.1.1.7] and Beta [B.1.351]) [44,45].
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 [34,41,46]. 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 [47].
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. Immunocompromising conditions that may adversely impact vaccine
response include active use of chemotherapy for cancer, hematologic malignancies, hematopoietic stem cell or solid organ
transplant, untreated HIV infection with CD4 cell count <200 cells/microL, combined primary immunodeficiency disorder, and
use of immunosuppressive medications (eg, mycophenolate mofetil, rituximab, prednisone >20 mg/day for >14 days) [48].
Considerations for immunocompromised patients given the potential for reduced vaccine response include the following:
● 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.
● 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 [49]. (See "COVID-19: Care of adult patients with systemic rheumatic disease", section on 'COVID-19
vaccination while on immunosuppressive therapy'.)
● Possible role for additional vaccines – Several countries, including France and Israel, have recommended that severely
immunocompromised patients (eg, transplant recipients, patients with hematologic malignancies, patients receiving highly
immunosuppressive agents) receive a third dose of COVID-19 vaccines typically given as a two-dose series [50]. In the
United States, the Food and Drug Administration (FDA) has not altered the EUA to include an additional dose for
immunocompromised patients. If an immunocompromised patient receives an additional vaccine dose, they should be
advised to continue other protective measures as immune response may still not be optimal. In reports 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 [51-54]. Longitudinal follow-up and evaluation of cellular immune
responses are needed to more completely characterize the impact of additional vaccine doses.
● 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 [55]. Lower vaccine effectiveness regarding hospitalization for COVID-19 in immunocompromised patients was
also suggested by a smaller, unpublished case-control study [56]. In studies of individuals hospitalized with COVID-19 despite
vaccination, a high proportion (eg, 40 percent) have been immunocompromised [57].
These and other findings suggest that certain immunocompromised patients, including transplant recipients and patients with
hematologic malignancies, have suboptimal immunogenicity with COVID-19 vaccination [58-65]. 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 [59]. 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'.)
Pregnant individuals — Data on the safety of COVID-19 vaccines in pregnant individuals are limited but emerging [66].
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, BNTb162b
(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 [67]. 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 [68]. Given the hypothesis
that MIS-C is associated with immune dysregulation precipitated by 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 [69,70]. 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 [71]. 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 [72,73].

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 '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 [74]. 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) [75]. 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 may have a similar potential
to transmit infection as unvaccinated individuals was one of the primary reasons for this change [76]. 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 vaccines — In addition to standard counseling around vaccine information, vaccine providers are required
to inform potential recipients that the COVID-19 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 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 "Allergic reactions to 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 "Allergic reactions to vaccines", section on
'Proposed evaluation'.)
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 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 [77], 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 [78]. This may occur more frequently with mRNA-1273 than with BNT162b2 [79]. 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 "Allergic reactions to 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 [80]. 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.
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 2). (See "Anaphylaxis: Acute
diagnosis" and "Anaphylaxis: Emergency treatment".)
Anaphylaxis has been reported following administration of both authorized mRNA COVID-19 vaccines [81]. 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 [82-84]. 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 "Allergic reactions to 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.)
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 robust immune response without major safety concerns [37,85]. (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 [86]. 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
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 3). 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.)
https://utd.taikhoanykhoa.com/contents/covid-19-vaccines-to-prevent-sars-cov-2-infection/print?search=covid 19&source=search_result&select… 10/49

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.
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 3). 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 [30,87-89].
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 [90]. 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 [91].
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) [92-95] and to a lesser
extent against Delta (B.1.617.2) [93,95,96] 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 [97,98]. 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 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) [91].
Observational data from various countries following their national roll-outs of BNT162b2 support the trial findings [99-109].
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 [99]. 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 [102]. 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 [110]. 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 [111]. 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 [112].
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 [113]. Of 30 severe
infections, only one occurred in a vaccinated individual.
Although some of these data suggest some efficacy of a single vaccine dose, the actual magnitude and duration of
protection from a single dose are unknown because most participants in the trial and the observational studies received
the second dose three weeks after the first. Additionally, studies suggest that a single dose of BNT162b2 is not associated
with high effectiveness against the Alpha, Beta, and Delta variants [110,111].
● 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 [71,84,97]. 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 [71]. 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) [91]. Local and systemic reactions occur
less frequently among recipients 65 years or older but are still relatively common.
Anaphylaxis following vaccination has been reported at an approximate rate of 5 events per one million doses [82].
Following the first 10 million doses of BNT162b2 administered in the United States, 50 episodes were reported to the
United States Centers for Disease Control and Prevention (CDC); this reflects a lower risk than had initially been estimated
[114,115]. Of the anaphylaxis cases, 80 percent occurred in individuals with a history of allergic reactions and 90 percent
occurred within 30 minutes. Other reported allergic reactions included pruritus, rash, scratchy sensations in the throat, and
mild respiratory symptoms [114]. Rare cases of Bell's palsy were also noted in the phase III trial (four in vaccine and zero in
placebo recipients) [97]; 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 [82]. No other major vaccine-associated adverse events were identified in post-vaccine surveillance [84]. 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 [116].
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 3). It is
given intramuscularly in two doses 28 days apart. mRNA-1273 has been authorized for use in the United States and the
European Union [31,117]. 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 [118]. 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 [119]. 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 [120]. 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)
[121,122] and Delta (B.1.617.2) [96] 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 [123]. 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. Among approximately 2000 participants who only received a single dose of vaccine or placebo, vaccine
efficacy following the dose was 80.2 percent (95% CI 55.2-92.5); however, these individuals only had a median follow-up
time of 28 days, so the duration of protection from a single dose remains uncertain. A preliminary analysis also suggested a
reduction in asymptomatic infections between dose 1 and 2 [124].

Observational data evaluating vaccine effectiveness also support the trial findings [109,125-127]. 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 [125]. 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) [109].
● 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 [71,84,128]. 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 [71]. 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.
Anaphylaxis following vaccination has been reported at an approximate rate of 2.8 events per one million doses [82,129].
Following the first 7,581,429 doses of mRNA-1273 administered in the United States, 21 cases of anaphylaxis were reported
to the CDC; 86 percent occurred among individuals with pre-existing allergies, and 90 percent occurred within 30 minutes.
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 [82]. No other major vaccine-associated adverse events have been identified in post-vaccine surveillance [84]. 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 [130].
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 ( table 3). 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 [131,132]. 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 [133]. 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 [134]. 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 [135]. 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; 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 [136]. 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 [137]. In
the phase III efficacy trial, serious adverse event rates in the vaccine and placebo group were similar [135]. 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 [138]. 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 3). 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 [139]. 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 [139]. 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 28 days after the last dose were comparable to those detected in convalescent plasma [140].
The levels of antibody titers achieved were higher following two doses; and subsequent studies are evaluating the two-dose
regimen. 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 [141]. However, the Beta (B.1.351)
and Delta (B.1.617.2) variants may evade immune responses in some vaccinated individuals [95,142]; in one study of 63
ChAdOx1 nCoV-19/AZD1222 recipients, approximately 60 percent had detectable neutralizing activity against those variants
[142].
● 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 [143]. 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
[144]. 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 [145]. ChAdOx1 nCoV-19/AZD1222 given as two full doses four weeks apart had 76 percent
efficacy at 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 [100,146]. 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
[100].
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 [147]. 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 [148]. 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 [111]
● 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 [140]. In the phase III trial, there were two cases of transverse myelitis in
ChAdOx1 nCoV-19 vaccine recipients [143]. 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
NVX-CoV2373 (Novavax) — This is a recombinant protein nanoparticle vaccine composed of trimeric spike glycoproteins and a
potent Matrix-M1 adjuvant ( table 3). 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 binding and
neutralizing responses, comparable to those in convalescent plasma from patients who had been hospitalized with COVID-19
[149]. 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 [150]. 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 [151]. 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) [152].
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 [151].
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 [153]. 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 [154]. 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 [155]. This vaccine is
available in China and 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 3). 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 [156]. 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 [157].
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) [157]. 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 [158,159]. Neutralizing activity elicited by HB02 is reduced against the variant B.1.351
(Beta) [160]. 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 [161]. 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.
● 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 [162] as well as those 60 years or older
[163]. Neutralizing activity against the variant B.1.351 (Beta) is reduced [160]. 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) [164]; however, lower efficacy rates have been reported in press releases of
trials in different countries [155]. 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. 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 [165]. Serum from vaccine recipients also neutralizes the B.1.617 variants prevalent in India,
but at lower titers than observed with wild-type virus [166].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 [167].
SPECIFIC SAFETY CONCERNS

Thrombosis with thrombocytopenia — Cases of thrombosis associated with thrombocytopenia have been reported following
vaccination with both ChadOx1 nCoV-19/AZD1222 (AstraZeneca COVID-19 vaccine) and Ad26.COV2.S (Janssen COVID-19 vaccine,
also referred to as the Johnson & Johnson vaccine). Many of these cases have been associated with autoantibodies directed
against the platelet factor 4 (PF4) antigen, similar to those found in patients with autoimmune heparin-induced
thrombocytopenia (HIT) [168-171]. Some experts are referring to this syndrome as vaccine-associated immune thrombotic
thrombocytopenia (VITT); others have used the term thrombosis with thrombocytopenia syndrome (TTS). (See "COVID-19:
Vaccine-induced immune thrombotic thrombocytopenia (VITT)".)
Case descriptions and suggested evaluation and management are as follows:
● ChAdOx1 nCoV-19/AZD1222 (AstraZeneca COVID-19 vaccine) – This vaccine is associated with an extremely small risk of
unusual types of thrombotic events associated with thrombocytopenia. Because of the rarity of these events and the
potential severity of COVID-19, the European Medicines Agency (EMA) concluded that the overall benefits of the vaccine
continue to outweigh the risk ( figure 5) [172]. The WHO has also stated that a causal relationship, while plausible, has
not been confirmed, and that the very rare incidence should be weighed against the risk of morbidity from COVID-19 [173].
Nevertheless, several countries have suspended use of the vaccine pending additional data, and some are limiting the
vaccine to individuals over a certain age (eg, over 60 years old in Germany) because of the possible risk of this syndrome
[174]. Among approximately 34 million vaccine recipients in the United Kingdom and European Economic Area, there were
169 cases of cerebral venous sinus thrombosis (CVST) and 53 cases of splanchnic vein thrombosis reported through safety
surveillance systems, which reflect rates that are higher than would be expected for these rare types of thromboses [172].
Severe thrombocytopenia was also observed in most cases. Most of these events occurred within 14 days of receipt of the
first dose and in females under 60 years of age, although some cases were reported up to 24 days after vaccination and in
males and older females. High levels of anti-PF4 antibodies (HIT antibodies) in patients with this syndrome have been
described [170,171,175]. Clear risk factors have not been identified. Another study suggested a small increased risk of
immune thrombocytopenia with ChadOx1 nCoV-19/AZD1222 [176], suggesting that isolated post-vaccination
thrombocytopenia is not necessarily indicative of TTS (also termed VITT).
● Ad26.COV2.S (Janssen COVID-19 vaccine, also referred to as the Johnson & Johnson vaccine) – This vaccine is also
associated with an extremely small risk of unusual types of thrombotic events associated with thrombocytopenia. In the
United States, the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention
concluded that the population and individual benefits of the vaccine, including reductions in death and critical illness as
well as the practical benefits of a single-dose vaccine, outweigh the risk of these rare events, and it reaffirmed the
recommendation for use of this vaccine under the emergency use authorization (EUA) [177]; the US Food and Drug
Administration (FDA) ended a pause on Ad26.COV2.S use that had been recommended when the risk first became apparent
[178]. The European Medicines Agency (EMA) has also investigated these events and made the same conclusion, although
the vaccine is not yet available in Europe [179].
As of May 7, 2021, after administration of 8.7 million doses of Ad26.COV2.S in the United States, 28 cases of thrombosis with
thrombocytopenia syndrome have been reported to the United States Centers for Disease Control and Prevention (CDC),
with 25 of those cases occurring at unusual sites (19 with cerebral venous sinus thrombosis with or without thromboses at
other sites, including mesenteric vessels); three cases were fatal [116,180-182]. Twenty-two cases occurred in females, and
the median age was 40 years (range 18 to 59). Another case, in a young male who was a vaccine recipient in one of the pre-
EUA efficacy trials, was previously reported. The risk was assessed as 12.4 per million for females 30 to 39 years old and 9.4
per million for females 40 to 49 years old; the risk in other age groups and males ranged from 1.3 to 4.7 per million.
Additional possible cases remain under investigation, and this risk assessment may change. Initial symptoms included
headache, chills, fever, nausea/vomiting, abdominal pain, and malaise, and these progressed to severe headache, severe
abdominal pain, and focal neurologic deficits. Intracerebral hemorrhage was also seen in some patients. Symptom onset
was usually one to two weeks after vaccination (range 3 to 15 days). Of the 26 patients tested for the anti-PF4 HIT antibody
by enzyme-linked immunosorbent assay (ELISA), 24 were positive. None of the 25 patients who underwent SARS-CoV-2 viral
testing at the time of presentation had evidence of acute infection. These cases appear similar to those reported following
ChAdOx1 nCoV-19/AZD1222, which is another adenovirus-vector vaccine, although the vectors and spike protein inserts in
the two vaccines are distinct [183].
● Evaluation and management of possible thrombotic complications – Recipients 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) [172].
Evaluation and management of suspected cases are discussed 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 [116,184]. 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 [184]. However, a separate analysis from Denmark suggested a slightly higher total rate of thromboembolic events
following ChadOx1 nCoV-19/AZD1222 than expected [185].
Myocarditis — Myocarditis and pericarditis, mainly in male adolescents and young adults, have been reported more frequently
than expected following receipt of the mRNA vaccines, BNTb162b (Pfizer vaccine) and mRNA-1273 (Moderna vaccine) [186,187].
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 pericarditis cases, the benefits of mRNA
vaccination greatly exceed the small increased risk [187]. 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 [187].
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.
The clinical presentation has been illustrated in several case series [188,189]. In one series, seven males aged 14 to 19 years
developed chest pain within four days of their second dose of BNTb162b and had ST elevations on electrocardiogram and
elevated troponin levels [188]. 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. 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 [190,191]. Cases of GBS, including recurrent
cases, have also been reported in the setting of SARS-CoV-2 infection [192,193]. 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
12.5 million doses, a rate that is approximately five times the background rate [190,194]. The mean age was 54 years
(ranging from 24 to 76), the mean time to onset was 14 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 [191]. Other scattered reports have also
described GBS, including variant GBS with bilateral facial weakness, following ChAdOx1 nCoV-19/AZD1222 vaccination
[195,196].
STEPS TO VACCINE AVAILABILITY AND DELIVERY
● Establishing efficacy and licensing a vaccine – Initial estimates of vaccine efficacy are 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 [197]. The World Health
Organization (WHO) has proposed the same minimal efficacy targets [198].
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 [199]. 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 [200].
● 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 [201-203]. 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 [203].
● 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 the safety and efficacy of these strategies before adopting them. This stance is consistent with a
statement from the US FDA [204]. 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 [205,206].
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 [207,208]. 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
[98,123]. 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 [209]. 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 [210].
POST-LICENSURE ISSUES
Although COVID-19 vaccines have received emergency use authorization based on trials conducted in tens of thousands of
participants, they are recommended for hundreds of millions of individuals. Thus, when used to this extent, efficacy questions
that were not addressed in clinical trials will need to be monitored, and safety issues that were not initially evident may emerge.
Combating vaccine hesitancy — Vaccine hesitancy presents a major obstacle to achieving 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 [211]. 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 [212,213].
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 [214]. 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 [215]. 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 [216-219].
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 [215,216,220]. In the CDC survey, the main reasons for
reporting non-intent to receive vaccine were concerns about vaccine side effects and safety and lack of trust in the process
[215].
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, these appear to be uncommon, and a high proportion may be asymptomatic

[221,222]. Although some largely unpublished reports suggest a somewhat 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
[112,223]. (See 'Efficacy against variants of concern' below.)
Studies performed prior to the emergence of the prevalent Delta variant highlighted the low rate of breakthrough infections. 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 [221]. 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) [224]. 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 [76].
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, in one study of a Delta variant outbreak, the levels of upper respiratory tract SARS-CoV-2 RNA in fully vaccinated
individuals with breakthrough infection were similar to those in individuals who were unvaccinated, not fully vaccinated, or of
unknown vaccination status (median cycle threshold 22.8 versus 21.5) [76]. 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.
These findings contrast with those of studies performed when the Delta variant was not circulating, which suggested a lower
transmission risk with breakthrough infection [225-227]. 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 [225]. 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 [96,226].
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) [124]. Several observational studies have also suggested that COVID-19
mRNA vaccination can reduce asymptomatic infection [101,228-231]. 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) [143,232]. 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 [135]. 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 4) (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 – Preliminary evidence suggests that vaccine effectiveness against symptomatic infection with the Delta variant is
largely preserved but is lower than that with Alpha [111,233,234]. Unpublished data from Public Health 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 [112,233,235]. (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) [236,237]; 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 [236].
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. The future need for routine booster vaccination remains
uncertain [238].
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 [239]. 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) [240]. 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. 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 [241,242]. 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 [243,244].
● 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") [245]. Therefore, if someone is injured by vaccine, society owes that person compensation. This
is the basis for the National Vaccine Injury Compensation Program (NVICP) [246]. 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 [247].
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 demonstrated efficacy in preventing
laboratory-confirmed symptomatic COVID-19 and are available in various countries ( table 3). (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 have been granted emergency use authorization (EUA) (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.
The benefits of vaccination greatly outweigh these 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 1). (See
'Deviations from recommended dosing intervals' above.)
● 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 93.0

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 expression construct or could not
be visualized in the final map are colored white. SS: signal sequence; S2': S2' protease cleavage site; FP: fusion peptide; HR1: heptad repeat 1; CH: central helix; CD:
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 conformation. The two RBD
down protomers are shown as cryo-electron-microscopy density in either white or gray and the RBD up protomer is shown in ribbons colored corresponding to the
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:
https://science.sciencemag.org/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

Structure and function of the SARS-CoV-2 spike protein
(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 SARS-CoV-2 spike protein: potential antivirus
drug development for COVID-19. Acta Pharmacol Sin 2020; 41:1141. Copyright © 2020. https://www.nature.com/aps/.

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/.

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.

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 deltoid muscle Do not repeat dose.* Inform the recipient of the
authorized vaccines [preferred site] or anterolateral thigh [alternate site]) potential for local and systemic adverse events.
(Pfizer-BioNTech,
Incorrect route (eg, subcutaneous) Do not repeat dose.* Inform the recipient of the
Moderna, and Janssen
potential for local and systemic adverse events.
COVID-19 vaccines)
Age Unauthorized age group If received dose at age less than 16 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 administered Do not repeat dose.* Δ
Lower-than-authorized dose volume administered (eg, If more than half of the dose was administered, do not
leaked out, equipment failure, recipient pulled away) repeat dose.*
If less than half of the dose was administered or the
proportion of the dose cannot be estimated, administer
the authorized dose immediately (no minimum interval)
in the opposite arm. ◊
Storage and handling Dose administered after improper storage and handling Contact the manufacturer for guidance. If the
(eg, temperature excursion, more than allowed time manufacturer provides information supporting that the
after first vial puncture) dose should be repeated, the repeated dose may be
given immediately (no minimum interval) in the opposite
arm.
Dose administered past the expiration/beyond-use date Contact the manufacturer for guidance. If the
manufacturer provides information supporting that the
dose should be repeated, the repeated dose may be
arm.
Coadministration Dose administered within 90 days of monoclonal Do not repeat COVID-19 vaccine dose. If person has
antibodies or convalescent plasma for COVID-19 already received one mRNA COVID-19 vaccine dose,
treatment defer administration of second dose for 90 days
following receipt of antibody therapy. This deviation
from CDC guidance does not require VAERS reporting.
mRNA vaccines only Intervals Second dose administered fewer than 17 days (Pfizer- Do not repeat dose.
(Pfizer-BioNTech and BioNTech) or fewer than 24 days (Moderna) after the first
Moderna) dose (ie, administered earlier than the 4-day grace
period)
Second dose administered more than 42 days after the Do not repeat dose. This deviation from CDC guidance
first dose does not require VAERS reporting.
Mixed series Incorrect mRNA COVID-19 vaccine product administered Do not repeat dose. §
for second dose in 2-dose series
Pfizer-BioNTech only Diluent ONLY diluent administered (ie, sterile 0.9% sodium Inform the recipient that no vaccine was administered.
chloride) Administer the authorized dose immediately (no
minimum interval) in the opposite arm. ◊
No diluent, resulting in higher than authorized dose (ie, Do not repeat dose.* Δ Inform the recipient of the
0.3 mL of undiluted vaccine administered) potential for local and systemic adverse events.
Incorrect diluent type (eg, sterile water, bacteriostatic Contact the manufacturer for guidance. If the
0.9% NS) manufacturer provides information supporting that the
dose should be repeated, the repeated dose may be
arm.
Incorrect diluent volume (ie, the vial contents were For doses administered with diluent volume less than 1.8
diluted with a diluent volume other than 1.8 mL, but a mL, inform the recipient of the potential for local and
0.3 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.
◊ 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).

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.
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.

Characteristics of select COVID-19 vaccines [1]
Efficacy Rate of
Doses and Common
against severe Storage
Name Company/developer Platform intended side Rare adverse effects
symptomatic COVID- requirements
interval effects
COVID-19* 19
BNT162b2 ¶ Pfizer/BioNTech mRNA 2 doses 3 weeks 95% 1 in Ultracold freezer Local Anaphylaxis
apart vaccine (–80 to –60°C) injection (approximately 5 per
group then freezer (–25 site million)
(n≈18,000) to –15°C) for up reactions Myocarditis/pericarditis
9 in to 2 weeks Systemic (approximately 16 per
placebo cumulative time symptoms million among 16-39
group then refrigerated (fevers, year olds)
(n≈18,000) (2 to 8°C) for up chills,
to 1 month fatigue,
myalgias,
headache)
mRNA-1273 ¶ Moderna mRNA 2 doses 4 weeks 94% 0 in Freezer (–25 to Local Anaphylaxis
apart vaccine –15°C) then injection (approximately 2.8 per
group refrigerated (2 to site million)
(n≈14,000) 8°C) for up to 30 reactions Myocarditis/pericarditis
30 in days Systemic (approximately 16 per
placebo symptoms million among 16-39
group (fevers, year olds)
(n≈14,000) chills,
fatigue,
myalgias,
headache)
Ad26.COV2.S ¶ Janssen/Johnson & Replication- 1 dose 66% efficacy 85% Refrigerated (2 to Local Thrombotic
Johnson incompetent against efficacy 8°C) injection complications
adenovirus moderate to against site associated with
26 vector severe COVID- severe reactions thrombocytopenia:
19 Δ COVID- Systemic For females 30-
19 Δ symptoms 39 years old:
(fevers, 12.4
chills, cases/million
fatigue, For females 40-
myalgias, 49 years old:
headache) 9.4
cases/million
For females in
other age
ranges and
males: 1.3 to
4.7
cases/million
Guillain-Barre
syndrome
(approximately 8
cases/million)
ChAdOx1 AstraZeneca/University of Replication- 2 doses 70% 0 in Refrigerated (2 to Local Very rare thrombotic
nCoV- Oxford/Serum Institute of incompetent vaccine 8°C) injection complications
4 to 12 weeks
19/AZD1222 India chimpanzee group site associated with
apart
adenovirus (n≈6000) reactions thrombocytopenia:
(manufacturer
vector 2 in Systemic Cerebral
recommendation)
placebo symptoms venous sinus
8 to 12 weeks
group (fevers, thrombosis
apart (WHO
(n≈6000) chills, (169 of ≈
recommendation)
fatigue, 34 million)
myalgias, Splanchnic vein
headache) thrombosis (54
of ≈ 34 million)
Guillain-Barre
syndrome (227
cases/51 million)
NVX-CoV2373 Novavax Recombinant 2 doses 3 weeks 89% Δ 0 in Refrigerated (2 to Local Unknown

protein apart vaccine 8°C) injection
group; 1 site
in placebo reactions
group Systemic
(n≈15,000 symptoms
total) Δ (fevers,
chills,
fatigue,
myalgias,
headache)
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.

Balancing the potential benefits and harms of AZD1222 (AstraZeneca COVID-19 vaccine)
COVID-19: coronavirus disease 2019; ICU: intensive care unit; UK: United Kingdom.
* Based on coronavirus incidence of 2 per 10,000 per day: roughly UK in March.

¶ Based on coronavirus incidence of 6 per 10,000 per day: roughly UK in February.
Δ Based on coronavirus incidence of 20 per 10,000 per day: roughly UK at peak of second wave.
Reproduced with permission. Copyright © 2021 Winton Centre for Risk and Evidence Communication, University of Cambridge.

SARS-CoV-2 Variants of Concern
Spike protein
substitutions
Name
(receptor-
Name
WHO label [1] (Pango binding First detected Known attributes

(Nextstrain*)
lineage*) domain
substitutions
in bold)
Alpha B.1.1.7 ¶ 20I/501Y.V1 Δ69/70 United Kingdom ~50% increased transmission [2]
Δ144Y Potential increased severity based on hospitalizations and case
fatality rates [3]
(E484K ◊)
Minimal impact on neutralization by monoclonal antibody
(S494P ◊)
therapies §
N501Y Bamlanivimab-etesevimab: No change in susceptibility [4]
A570D Casirivimab-imdevimab: No change in susceptibility [5]
D614G Sotrovimab: No change in susceptibility [6]
P681H 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 therapies §
N501Y
Bamlanivimab-etesevimab: Unlikely to be active (>45-fold
D614G
decrease in susceptibility) [4]
Casirivimab-imdevimab: No change in susceptibility [5]
Sotrovimab: No change in susceptibility [6]
Moderate reduction in neutralization by convalescent and post-
vaccination sera
Gamma P.1 20J/501Y.V3 K417N/T Japan/Brazil Significant impact on neutralization by some monoclonal
E484K antibody therapies §
Bamlanivimab-etesevimab: Unlikely to be active (>511-fold
N501Y
D614G
Reduced neutralization by convalescent and post-vaccination
sera [15]
Delta B.1.617.2 ¥ 20A T19R India Increased transmissibility compared with B.1.1.7 (Alpha) [16]
(G142D ◊) Potential increased severity based on associated hospitalization
rate [16,17]
Δ156
Potential minimal reduction in neutralization by monoclonal
Δ157
antibody therapies ‡
R158G Potential modest/moderate reduction in vaccine effectiveness
L452R against symptomatic COVID-19 without significant impact on
vaccine effectiveness against severe disease [17-20]
T478K
D614G
P681R
D950N
Epsilon B.1.427 and 20C/S:452R L452R US-California ~20% increased transmissibility [21]
B.1.429 † D614G Significant impact on neutralization by some monoclonal
antibody therapies §
S13I (B.1.429 only)
Bamlanivimab-etesevimab: Unlikely to be active (7.4-fold
W152C (B.1.429
only)
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 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).

Contributor Disclosures
Kathryn M Edwards, MD Grant/Research/Clinical Trial Support: CDC; NIH. Consultant/Advisory Boards: Bionet; IBM. Other Financial Interest:
Member Data Safety and Monitoring Boards for Sanofi; X-4 Pharma; Seqirus; Moderna; Pfizer; Merck. 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

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Official reprint from UpToDate®

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

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Dose and interval

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Expected adverse effects and their management

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Contraindications and precautions (including allergies)

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• 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

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

The following warrant monitoring for 30 minutes:

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● History of anaphylaxis due to any cause

All other individuals are monitored for 15 minutes.

IMMUNOGENICITY, EFFICACY, AND SAFETY OF SELECT VACCINES

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Ad26.COV2.S (Janssen/Johnson & Johnson COVID-19 vaccine) — This vaccine is based on a replication-incompetent

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SPECIFIC SAFETY CONCERNS

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Case descriptions and suggested evaluation and management are as follows:

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STEPS TO VACCINE AVAILABILITY AND DELIVERY

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● Duration of protection from disease

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SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

SUMMARY AND RECOMMENDATIONS

Use of UpToDate is subject to the Subscription and License Agreement.

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12. Krammer F. SARS-CoV-2 vaccines in development. Nature 2020; 586:516.

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50. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-07/07-COVID-Oliver-508.pdf (Accessed on July 23, 202

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75. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/fully-vaccinated-guidance.html#anchor_1619526673330 (Accessed o

88. Canada. Pfizer-BioNTech COVID-19 vaccine: Authorization information. https://www.canada.ca/en/health-canada/services/d

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s://www.biorxiv.org/content/10.1101/2021.02.05.430003v1 (Accessed on February 18, 2021).

112. https://www.gov.il/en/departments/news/06072021-04 (Accessed on July 29, 2021).

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essed on April 23, 2021).

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168. Updated GTH statement on vaccination with the AstraZeneca COVID-19

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182. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-05-12/07-COVID-Shimabukuro-508.pdf (Accessed on

184. European Medicines Agency. https://www.ema.europa.eu/en/news/covid-19-vaccine-astrazeneca-benefits-still-outweigh-ris