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COVID-19: Vaccines

COVID-19: Vaccines
Authors:
Kathryn M Edwards, MD
Walter A Orenstein, MD
Section Editor:
Martin S Hirsch, MD
Deputy Editor:
Allyson Bloom, MD
Literature review current through: Feb 2022. | This topic last updated: Feb 25, 2022.

INTRODUCTION — Vaccines to prevent SARS-CoV-2 infection are considered the most promising approach for curbing the COVID-19 pandemic. Several COVID-19 vaccines are available globally. The World Health Organization maintains an updated list of vaccine candidates under evaluation [1].

This topic will cover vaccines for SARS-CoV-2, with a focus on vaccines available in the United States. 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

Pace of COVID-19 vaccine development — Although COVID-19 vaccine development has been accelerated, each vaccine that has received emergency use listing by the World Health Organization (which includes those that have been authorized or approved in the United States) has gone through the standard preclinical and clinical stages of development. Safety criteria have remained 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.

Calculation of vaccine efficacy — 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, often abbreviated as ([ARU – ARV]/ARU) x 100

Antigenic target — The major antigenic target for COVID-19 vaccines is the surface spike protein (figure 1). It binds to the angiotensin-converting enzyme 2 (ACE2) receptor on host cells and induces membrane fusion (figure 2) [2]. 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 [3].

Vaccine platforms — COVID-19 vaccines have been and are being developed using several different platforms (figure 3) [3]. 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, had never been employed in a licensed vaccine. General descriptions of the different platforms used for COVID-19 vaccines are presented in the table (table 1).

Site of delivery and immune response — COVID-19 vaccines have been demonstrated to elicit a sufficient neutralizing response that protects against COVID-19. The site of vaccine delivery may impact the character of the immune response [3]. 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 [4,5]. Live attenuated COVID-19 vaccines administered to the respiratory tract are under development. (See 'Vaccine platforms' above.)

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 [6-8]. 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 [9]. These include criteria for neutralizing antibody and Th1-polarized cellular immune responses.

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) have been fully approved by the Food and Drug Administration (FDA) for persons aged 16 years and older and persons aged 18 years and older, respectively (table 2). In addition, BNT162b2 is available under emergency use authorization (EUA) for children 5 to 15 years of age. The adenoviral vector vaccine Ad26.COV2.S (Janssen COVID-19 vaccine, also referred to as the Johnson & Johnson vaccine) has been granted EUA for prevention of COVID-19 for persons age 18 years and older [10-12].

BNT162b2 (Pfizer-BioNTech COVID-19 vaccine) is indicated for individuals aged 5 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.

We recommend vaccination with one of these vaccines; if both mRNA and adenoviral vector vaccines are available, we suggest an mRNA vaccine (BNT162b2 or mRNA-1273) rather than Ad26.COV2.S, in agreement with the Centers for Disease Control and Prevention (CDC). However, if mRNA vaccines are not available or appropriate because of contraindications (see 'Contraindications and precautions (including allergies)' below), we recommend vaccination with Ad26.COV2.S rather than forgoing COVID-19 vaccination.

The preference for mRNA vaccines over Ad26.COV2.S is based on a more favorable risk-benefit profile with the mRNA 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 all the vaccines outweigh them. However, cases of vaccine-associated thrombosis with thrombocytopenia and Guillain-Barre syndrome have been more severe with greater morbidity compared with cases of vaccine-associated myocarditis. Potential recipients of any vaccine should be aware of the specific risks, which are discussed in detail elsewhere. (See 'Specific safety concerns' below.)

Additionally, although precise comparative efficacy is uncertain because the different vaccines have not been compared directly in trials, limited evidence suggests that mRNA vaccines may be more effective than Ad26.COV2.S, including against severe infection, and mRNA-1273 may be slightly more effective than BNT162b2 [13-18].

In several observational studies, vaccine effectiveness associated with two doses of the mRNA vaccines is higher than that with one dose of Ad26.COV2.S [13,19-21]. As an example, in a case control study of 3689 immunocompetent adults hospitalized for COVID-19, estimated effectiveness against COVID-19-related hospitalization was 93 and 88 percent for mRNA-1273 and BNT162b2, respectively, compared with 71 percent for Ad26.COV2.S. Although the analysis adjusted for age, sex, admission date, geographic region, and race, the contribution of these and other unmeasured confounders, such as variable exposure risk, to the apparent differences in effectiveness is uncertain.

Several observational studies also suggest that mRNA-1273 vaccine effectiveness is slightly higher than that of BNT162b2, although it is unclear whether there is a clinically significant difference [13-18]. In a study from the United States that compared over 400,000 veterans who received either mRNA-1273 or BNT162b2, mRNA-1273 was associated with lower rates of documented infection, symptomatic COVID-19, and associated hospitalization over 24 weeks, but the absolute differences were low (differences of 1.23, 0.44, and 0.55 cases per 1000 people, respectively) [15].

Nevertheless, all the available vaccines are highly effective, substantially reduce the risk of COVID-19, especially severe/critical disease, and have been associated with substantial reductions in COVID-19-associated hospitalizations and deaths [19,22-26], even in the context of variants that partially evade vaccine-induced immune responses (see 'Efficacy against variants of concern' below). In addition to direct reductions in COVID-19-associated morbidity and mortality, vaccination (with any of the three vaccines authorized or licensed in the United States) has been associated with lower non-COVID-19 mortality rates, supporting evidence that COVID-19 vaccination does not increase the risk of death [27]. Details on the efficacy and safety of the individual vaccines are discussed elsewhere. (See 'Immunogenicity, efficacy, and safety of select vaccines' below.)

Administration

Dose and interval — Vaccine dosing and intervals are listed in the table (table 2).

BNT162b2 (Pfizer-BioNTech COVID-19 vaccine, an mRNA vaccine)

For adults and adolescents ≥12 years of age:

Primary series – Two intramuscular doses of 0.3 mL (30 mcg; purple or gray cap formulation) each are given three weeks (21 days) apart. Healthy individuals <65 years old can extend the interval to eight weeks [28].

For individuals with certain immunocompromising conditions (table 3), a third dose is given at least 28 days after the second [10]. (See 'Immunocompromised individuals' below.)

Booster dose – One intramuscular dose of 0.3 mL (30 mcg; purple or gray cap formulation) is recommended for all individuals 12 years or older [10,28-30]. It is given at least five months after the last dose in the primary series for most people; for immunocompromised patients, the booster dose is recommended at least three months after the last dose [28]. (See 'Role of booster vaccinations/waning efficacy' below.)

For children 5 to 11 years of age:

Primary series – Two intramuscular doses of 0.2 mL (10 mcg; orange cap formulation) each are given three weeks (21 days) apart. Clinicians should be aware that this is a lower dose and a different formulation than those used for older individuals, and it should be used for all children in this age range regardless of their weight. Those who turn 12 after the first dose of the series should complete it with the dose recommended for adolescents ≥12 years of age; however, if they receive the lower dose after turning 12, it does not need to be repeated [28].

For individuals in this age group with certain immunocompromising conditions (table 3), the FDA has authorized and the CDC suggests a third primary series dose, given at least 28 days after the second [31,32]. (See 'Immunocompromised individuals' below.)

mRNA-1273 (Moderna COVID-19 vaccine, an mRNA vaccine)

Primary series – Two intramuscular doses of 0.5 mL (100 mcg) each are given one month (28 days) apart. Healthy individuals <65 years old can extend the interval to eight weeks [28].

For individuals with certain immunocompromising conditions (table 3), a third dose is given at least 28 days after the second [11]. (See 'Immunocompromised individuals' below.)

Booster dose – One intramuscular dose of 0.25 mL (50 mcg), is recommended for all adults 18 years or older [11,29]. It is given at least five months after the last dose in the primary series for most people; for immunocompromised patients, the booster dose is recommended at least three months after the last dose [28]. (See 'Role of booster vaccinations/waning efficacy' below.)

Ad26.COV2.S (Janssen COVID-19 vaccine, also referred to as the Johnson & Johnson vaccine, an adenoviral vector vaccine)

Primary series – One intramuscular dose of 0.5 mL (5x1010 viral particles) is given [12].

For individuals with certain immunocompromising conditions (table 3), an additional dose with an mRNA vaccine is recommended at least 28 days later [11]. (See 'Immunocompromised individuals' below.)

Booster dose – One intramuscular dose of 0.5 mL (5x1010 viral particles) is recommended for all adults 18 years or older at least two months after the primary series. (See 'Role of booster vaccinations/waning efficacy' below.)

The same vaccine, if available, is generally used to complete the primary series. A different vaccine can be used for the booster dose as long as that vaccine is approved or authorized for the age group; the interval and indications for the booster dose depend on the vaccine given for the primary series. As an example, an individual who received a primary series with one dose of Ad26.COV2.S can receive a booster dose at least two months later with another Ad26.COV2.S dose or with one of the two mRNA vaccines. This is discussed in detail elsewhere (see 'Mixing vaccine types' below). However, in general, we agree with recommendations from the CDC to use an mRNA vaccine rather than Ad26.COV2.S, if possible. (See 'Indications and vaccine selection' above.)

Although the mRNA vaccines were originally evaluated with a three- to four-week interval between the two primary series doses, extending that interval to eight weeks may be preferable for young, healthy adults who do not need to maximize protection within a shorter period of time. Specifically, an eight-week or longer interval has been associated with a lower risk of vaccine-associated myocarditis than a one month or shorter interval, which is most relevant for males 12 to 39 years old [33] (see 'Myocarditis' below). Additionally, some studies have suggested that increasing the interval between the two doses of the primary series (eg, separating them by 6 to 14 weeks rather than 3 to 4 weeks) is associated with higher titer antibody responses [34,35] and slightly greater vaccine effectiveness [36,37].

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 4).

Mixing vaccine types

Completing the primary series – For the mRNA vaccines, the CDC suggests that the primary series be completed with the same vaccine, if possible [28]; there are insufficient data to inform the efficacy and safety of mixing mRNA vaccines for the primary series. 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 4). Presumably, the same principles apply to patients with immunocompromising conditions that warrant a third mRNA vaccine dose.

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 [28]. Such individuals should be considered to have received a complete AD26.COV2.S vaccine regimen.

Providing booster doses – The FDA and CDC indicate that a booster dose can be a different vaccine than the one used for the primary series (ie, a heterologous boost), and we agree with the CDC suggestion to use an mRNA vaccine rather than Ad26.COV2.S, if possible [10-12,38]. The interval for the booster dose depends on the vaccine given for the primary series and is discussed elsewhere. (See 'Dose and interval' above.)

Support for use of a different vaccine for the booster dose comes from studies indicating robust immunogenicity with heterologous primary and booster doses [39,40] and at least comparable effectiveness as seen with homologous boosting [41,42]. As an example, in a study of nearly 5 million United States veterans, receipt of an mRNA vaccine boost after a primary Ad26.COV2.S dose was associated with a lower risk of infection than receipt of an Ad26.COV2.S boost (adjusted rate ratio 0.49); for mRNA vaccine recipients, there was not a substantial difference in infection rates in recipients of a homologous mRNA boost versus a heterologous mRNA boost [42]. Immunogenicity studies support these findings. In an open-label trial, participants who had received a primary series of one of the three vaccines approved or authorized in the United States were given a booster dose with the same vaccine or one of the other two [39]. In all groups, binding and neutralizing antibody titers (targeting wild-type virus and variants) following the booster dose rose at least fourfold compared with pre-boost levels, and heterologous boost resulted in similar or higher antibody responses as using the same vaccine to boost. Among those who received a primary Ad26.COV2.S vaccine, receipt of an mRNA vaccine boost rather than an Ad26.COV2.S boost was associated with a greater rise in antibody titers; a similar finding was reported in a randomized trial of individuals who had received a primary Ad26.COV2.S series, in which an mRNA-1273 (Moderna COVID-19 vaccine) boost resulted in higher binding and neutralizing antibody levels than a BNT162b2 (Pfizer COVID-19 vaccine) boost, and levels with both mRNA vaccine boosts were higher than with another Ad26.COV2.S dose [40]. No safety concerns were identified; the frequency and duration of systemic symptoms (eg, fever, chills, myalgias) may be slightly higher with mRNA-1273 booster doses.

Studies from other countries using different vaccines to complete a series (eg, ChAdOx1 nCoV-19/ADZ122 followed by BNT162b2 or mRNA-1273) suggests a more robust and broad immune response with certain heterologous vaccine combinations, although in some cases there is a higher rate of systemic reactions (fever, fatigue, headaches, myalgias) compared with using the same vaccine for both doses [43-46].

Timing with relation to non-COVID-19 vaccines — The CDC specifies that COVID-19 vaccines can be administered at any time in relation to other non-COVID-19 vaccines, and if needed, can be administered simultaneously with other vaccines [28]. When coadministered, each vaccine should be injected in different sites separated by at least one inch (and vaccines that are associated with local reactions should ideally be injected in a different limb than COVID-19 vaccines). Limited data suggest that coadministration of COVID-19 vaccines with certain other vaccines is likely safe. In a randomized trial, frequency of adverse effects and immunogenicity were largely similar when a COVID-19 vaccine (BNT162b2 or ChAdOx1) was given concomitantly with either an influenza vaccine or placebo [47].

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 or to determine whether to give additional doses of vaccine (eg, booster doses) is not indicated. 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 diagnostic 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 [28]. All recommended doses of a primary series and booster dose should be given, even if SARS-CoV-2 infection is diagnosed after vaccination has been initiated.

Individuals with recent, documented SARS-CoV-2 infection (including those who are diagnosed after initiating a vaccine series) should have recovered from acute infection and met criteria for discontinuation of isolation precautions before receiving a vaccine dose. This applies to receipt of any primary series or booster dose. (See 'Administration' above.)

For individuals who had SARS-CoV-2 infection complicated by multisystem inflammatory syndrome (MIS), the decision to vaccinate should be individualized and 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. Nevertheless, the benefits of vaccination may outweigh the risk among those with a history of MIS if they have recovered clinically, had MIS ≥90 days previously, and are at increased risk for SARS-CoV-2 exposure and if the MIS was not associated with COVID-19 vaccination [28].

Vaccination is likely still beneficial in many patients with a history of SARS-CoV-2 infection. Vaccination appears to further boost antibody levels and cell-mediated responses in those with past infection and might improve the durability and breadth of protection [48-50]. In observational studies of individuals with prior infection, vaccination has been associated with a lower risk of subsequent reinfection [51-55]; it has also been associated with a lower risk of breakthrough infection compared with vaccination in individuals without prior infection [56]. In some of these studies, a single mRNA vaccine dose was associated with similar risk reductions as two doses; however, pending additional data, dosing recommendations for individuals with prior infection remain the same as for the general population.

Vaccination has been associated with greater protection against hospitalization for COVID-19 compared with prior infection in some studies [57]. However, one study suggested that when Delta variant was prevalent, prior infection was associated with greater protection against COVID-19-related hospitalization than vaccination, although vaccination was still protective; estimates were age adjusted, but this study did not account for other potential confounders that may affect hospitalization risk (eg, comorbidities, exposure risk) [58].

Among individuals who have persistent symptoms following acute COVID-19, vaccination has been associated with a higher likelihood of symptom improvement compared with no vaccination, according to a systematic review by the United Kingdom Health Security Agency; however, for most individuals, symptoms remain unchanged regardless of vaccination [59].

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 [28,60,61]. This is not a contraindication or precaution for subsequent vaccine doses.

Recent SARS-CoV-2 exposure — Individuals with a known SARS-CoV-2 exposure should receive COVID-19 vaccination, as recommended for the general population. However, such individuals who are in the community should wait until they have completed their post-exposure quarantine period to avoid inadvertent exposures to others in the event of infection [28]. Individuals who are exposed to SARS-CoV-2 in a congregate residential setting can receive COVID-19 vaccination without delay.

Given that the time needed to generate a protective immune response following vaccination exceeds the mean incubation period of SARS-CoV-2, post-exposure vaccination would likely not reduce the risk of infection following that specific exposure.

Immunocompromised individuals — We suggest that eligible individuals who have an immunocompromising condition or are taking immunosuppressive agents undergo COVID-19 vaccination. Immunogenicity and effectiveness of COVID-19 vaccines appear lower in such individuals compared with the general population; nevertheless, the potential for severe COVID-19 in this population outweighs the uncertainties. Considerations for immunocompromised patients given the potential for reduced vaccine response include the following:

Additional vaccine dose in the primary series – We agree with recommendations from the Advisory Committee on Immunization Practices (ACIP) that individuals with certain immunocompromising conditions who received a two-dose mRNA vaccine series receive a third dose (if possible, the same vaccine formulation should be used) as part of the primary vaccine series, administered at least 28 days after the second dose [62]; for those who received Ad26.COV2.S, a dose of an mRNA vaccine is recommended at least 28 days later [28]. The vaccine dosage should be the same as that used for all primary series doses (eg, for mRNA-1273 [Moderna COVID-19 vaccine], the 100 mcg dose). (See 'Dose and interval' above.)

Immunocompromising conditions that warrant an additional primary series dose include active use of chemotherapy for cancer, hematologic malignancies, hematopoietic stem cell or solid organ transplant, advanced or untreated HIV infection with CD4 cell count <200 cells/microL, moderate or severe primary immunodeficiency disorder, and use of immunosuppressive medications (eg, mycophenolate mofetil, rituximab, prednisone >20 mg/day for >14 days) (table 3) [63]. This list is not exhaustive; other conditions, such as impaired splenic function [64], may also warrant an additional vaccine dose.

Several other countries, including France, Germany, and Israel, have made similar recommendations [65]. Patients with immunocompromising conditions should be advised to continue other protective measures regardless of the number of vaccine doses received, as immune response may not be optimal even with three doses.

In observational studies of immunocompromised individuals, receipt of three doses of mRNA vaccines is associated with higher vaccine effectiveness than two doses [66]. In studies of transplant recipients who received a third dose of mRNA vaccines, seroconversion rates were higher after the additional dose, although approximately 50 to 70 percent who were seronegative after two doses remained seronegative; adverse effects were similar to those reported after prior doses [67-71]. Receipt of an additional dose following three doses of an mRNA vaccine (akin to a booster dose after a three-dose primary series) has also been associated with improved seroconversion rates [72]. Longitudinal follow-up and evaluation of cellular immune responses are needed to more completely characterize the impact of additional vaccine doses.

Accelerated booster dose – Administering an additional vaccine dose as part of the primary series for certain immunocompromised patients is a distinct issue from the booster vaccine dose. Immunocompromised individuals who received a primary series with the additional dose described above should also receive a booster dose, although the recommended interval for booster administration following the primary series is shorter than in the general population [28] (see 'Role of booster vaccinations/waning efficacy' below):

For immunocompromised patients who received three doses of a primary mRNA vaccine series, a booster dose is recommended three months after the last dose.

For those who received Ad26.COV2.S followed by an mRNA vaccine (or two Ad26.COV2.S vaccines), a booster dose is recommended two months after the last dose.

Data on the accelerated administration of additional vaccine doses are limited; the rationale is to try to maximize vaccine immunogenicity (and thus effectiveness) within a shorter period of time for this vulnerable population.

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 [73]. (See "COVID-19: Care of adult patients with systemic rheumatic disease", section on 'COVID-19 vaccination while on immunosuppressive therapy'.)

Revaccination following hematopoietic cell transplant (HCT) or CAR-T therapy – For those who received COVID-19 vaccination prior to HCT or CAR-T cell therapy, the CDC recommends repeat vaccination with a full primary series at least three months after the transplant or CAR-T administration [28]. Such patients meet criteria for receiving a three-dose primary series with the mRNA vaccines. (See "Immunizations in hematopoietic cell transplant candidates and recipients", section on 'COVID-19 vaccine'.)

Continued use of protective measures and potential pre-exposure prophylaxis – 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 have been vaccinated because of the potential for reduced vaccine effectiveness. Household and other close contacts of immunocompromised patients should be vaccinated.

Immunocompromised patients who are at risk for suboptimal response to vaccination may be eligible for pre-exposure prophylaxis with monoclonal antibodies. This is discussed in detail elsewhere. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Pre-exposure prophylaxis'.)

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 [28]. 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 vaccines remain effective in many immunocompromised patients, although they are less so than in the general population [74-79]. 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 [74]. Lower vaccine effectiveness regarding hospitalization for COVID-19 in immunocompromised patients was also suggested by a smaller case-control study [75]. In studies of individuals hospitalized with COVID-19 despite vaccination, a high proportion (eg, 40 percent) have been immunocompromised [76].

These and other findings suggest that certain immunocompromised patients, including transplant recipients and patients with hematologic malignancies, have suboptimal immunogenicity with COVID-19 vaccination [80-88]. 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 [81]. 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: Considerations in patients with cancer", section on 'COVID-19 vaccination'.)

(See "COVID-19: Care of adult patients with systemic rheumatic disease", section on 'COVID-19 vaccination while on immunosuppressive therapy'.)

(See "COVID-19: Issues related to solid organ transplantation", section on 'Vaccination'.)

(See "Immunizations in patients with primary immunodeficiency", section on 'Issues related to SARS-CoV-2 vaccination'.)

Pregnant individuals — Data on the safety of COVID-19 vaccines in pregnant individuals are accumulating [89]. These data and considerations for COVID-19 vaccination in individuals who are pregnant or breastfeeding are discussed in detail elsewhere. (See "COVID-19: Overview of pregnancy issues", section on 'Vaccination in people planning pregnancy and pregnant or recently pregnant people'.)

Children — We recommend that eligible children undergo COVID-19 vaccination. Specifically, in the United States, the FDA has authorized and the CDC recommends BNT162b2 (Pfizer COVID-19 vaccine) for children and adolescents aged five years and older based on evidence that efficacy and immunogenicity are as high as (or higher than) those in older individuals with rare serious adverse effects [90]. Observational studies also indicate reductions in hospitalization, intensive care unit admission, and death in vaccinated compared with unvaccinated adolescents [91-93]. Studies with other vaccines are underway. Data on the immunogenicity, efficacy, and safety of BNT162b2, including among children, are discussed elsewhere (see 'BNT162b2 (Pfizer-BioNTech COVID-19 vaccine)' below). Dosing in children is also discussed elsewhere. (See 'Dose and interval' above.)

The individual benefit of COVID-19 vaccination in young children may be somewhat less than in adults because COVID-19 tends to be less severe in children than in adults. Nevertheless, the risk of the multisystem inflammatory syndrome in children (MIS-C) following acute infection, the potential for other sequelae of SARS-CoV-2 infection (eg, “long-COVID-19” and indirect effects on mental health and education), the risk of severe disease in children with underlying medical conditions, and the desire to prevent COVID-19 of any severity in children remain compelling reasons for vaccination of children [94]. Furthermore, even with the lower risk of severe disease among children, the number of COVID-19 deaths among those 5 to 11 years old from 2020 to 2021 exceeds the prevaccination era mortality rates of infections for which childhood vaccines are routinely provided (eg, rotavirus, meningococcal disease, varicella) [95].

The association of mRNA COVID-19 vaccines with myocarditis, particularly among male adolescents and young adults, has raised concern about this risk in younger children. Although the precise risk of vaccine-associated myocarditis among 5- to 11-year-olds is unknown, based on the historical age distribution of myocarditis in the pre-COVID-19 era, it is expected to be lower than that among adolescents and young adults, which is already low [95]. In a review of the Vaccine Adverse Event Reporting System (VAERS) following administration of approximately 8.7 million doses of BNT162b2 to children aged 5 to 11 years in the United States, there were 11 verified reports of myocarditis in this age group [96]. As with other reported cases of mRNA COVID-19 vaccine-associated myocarditis, most cases were mild and short lived. The benefits of COVID-19 vaccination in children are estimated to exceed this risk [95,97]. (See 'Myocarditis' below.)

Given the hypothesis that MIS-C is associated with immune dysregulation precipitated by SARS-CoV-2 infection, similar immune-related side effects following vaccination in children are another concern. Vaccine trials in this age group have not identified a potential signal, although rare case reports of MIS in adults following vaccination highlight the importance of monitoring for this possible adverse effect [98]. Nevertheless, some evidence suggests that vaccination may protect against MIS-C [99,100]. In a study of 102 patients aged 12 to 18 years hospitalized with MIS-C, 95 percent were unvaccinated; of the 5 patients with MIS-C who had previously received primary series of BNT162b2, none required invasive respiratory or cardiovascular support [100]. The decision to vaccinate individuals with a history of MIS-C is discussed elsewhere. (See 'History of SARS-CoV-2 infection' above.)

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 [101,102]. 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 [103]. 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 [28]. 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 [104,105]. Aspirin is not recommended for individuals ≤18 years old because of the risk of Reye syndrome.

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: Considerations in patients with cancer", section on 'Relative to radiologic imaging'.)

Syncope – Syncope has been reported following receipt of other injectable vaccines, particularly among adolescents and young adults [106]. 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 and myocarditis with the mRNA vaccines (BNT162b2 and mRNA-1273) and unusual types of thrombotic events with thrombocytopenia and Guillain-Barre syndrome 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 'Specific safety concerns' below.)

Uncommon skin reactions have also been reported following vaccination. These are also discussed elsewhere. (See "COVID-19: Cutaneous manifestations and issues related to dermatologic care", section on 'Considerations for vaccination to prevent SARS-CoV-2 infection'.)

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. Recommendations on public health precautions following vaccination have evolved with new developments in the pandemic (eg, emergence of the highly transmissible Delta and Omicron variants), and the approach should be tailored to the overall rate of transmission in the community. Recommendations on post-exposure management are discussed in detail elsewhere. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Post-exposure management'.)

In the United States, mask mandates are state dependent. The CDC suggests that all individuals, regardless of vaccination status, 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) [107]. 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 [108]; there are similar concerns with the Omicron variant because of the higher risk of breakthrough infection. These data are discussed elsewhere. (See 'Impact on transmission risk' below.)

EUA status of certain vaccines — In addition to standard counseling around vaccine information, vaccine providers are required to inform potential recipients of the COVID-19 mRNA vaccine mRNA-1273 (Moderna COVID-19 vaccine) or the adenoviral vector vaccine Ad26.COV2.S (Janssen COVID-19 vaccine, also referred to as the Johnson & Johnson vaccine) that those vaccines are available under emergency use authorization (EUA) and are not licensed vaccines. It is not necessary, however, for recipients to sign informed consent documents. (See 'Steps to vaccine availability and delivery' below.)

Contraindications and precautions (including allergies)

Contraindications – The following are the only contraindications to COVID-19 vaccination [28]:

A severe allergic reaction (eg, anaphylaxis) to a previous COVID-19 vaccine dose or to a component of the vaccine or a 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 "COVID-19: Allergic reactions to SARS-CoV-2 vaccines", section on 'Delayed urticarial reactions'.)

The mRNA vaccines, BNT162b2 (Pfizer-BioNTech COVID-19 vaccine) and mRNA-1273 (Moderna COVID-19 vaccine), each contain polyethylene glycol, and Ad26.COV2.S (Janssen COVID-19 vaccine, also known as the Johnson & Johnson vaccine) contains polysorbate. Allergic reaction to polysorbate is not a contraindication to mRNA vaccines, but it is a contraindication to Ad26.COV2.S. Other components of COVID-19 vaccines are listed on the CDC website.

A history of thrombosis with thrombocytopenia following an Ad26.COV2.S or any other adenoviral vector COVID-19 vaccine is a contraindication to Ad26.COV2.S.

Precautions – Precautions to a specific COVID-19 vaccine consist of allergic reactions to other vaccines. Patients with such reactions can generally receive a COVID-19 vaccine but 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.

Prior immediate but nonsevere allergic reactions (eg, hives, angioedema that did not affect the airway) to a COVID-19 vaccine is a precaution (not contraindication) to that same vaccine type.

Contraindication to an mRNA COVID-19 vaccine is a precaution to Ad26.COV2.S because of potential cross-reactive hypersensitivity.

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

Allergy consultation can be helpful to evaluate suspected allergic reactions to a COVID-19 vaccine or its components and assess the risk of future COVID-19 vaccination. This is discussed in detail elsewhere. (See "COVID-19: Allergic reactions to SARS-CoV-2 vaccines", section on 'Possible anaphylaxis'.)

Caution may be warranted prior to administering any vaccine in certain rare but life-threatening conditions, such as acquired thrombotic thrombocytopenia purpura and capillary leak syndrome, exacerbations of which have been reported following COVID-19 vaccination [109,110]. (See "Immune TTP: Management following recovery from an acute episode and during remission", section on 'Vaccinations' and "Idiopathic systemic capillary leak syndrome", section on 'Prodromal symptoms and triggers'.)

History of thromboembolic disease is not a contraindication to vaccination. However, very rare cases of unusual types of thrombosis associated with thrombocytopenia have been reported following vaccination with both ChadOx1 nCoV-19/AZD1222 (AstraZeneca COVID-19 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 immune-mediated thrombosis and thrombocytopenia (such as HIT) within the prior 90 days receive an mRNA vaccine rather than Ad26.COV2.S [28]. 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 [111], and individuals with these can receive any approved or authorized COVID-19 vaccine. (See 'Thrombosis with thrombocytopenia' below and "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)", section on 'Prevention (common questions)'.)

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 [112]. This may occur more frequently with mRNA-1273 than with BNT162b2 [113]. 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 [28]. (See "COVID-19: Allergic reactions to SARS-CoV-2 vaccines", section on 'Late local reactions'.)

Facial swelling in areas previously injected with cosmetic dermal fillers has also been rarely reported following vaccination with the mRNA COVID-19 vaccines. Dermal fillers are not a contraindication to COVID-19 vaccination, and no specific precautions are recommended [28]. 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 [114]. 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 5). (See "Anaphylaxis: Acute diagnosis" and "Anaphylaxis: Emergency treatment".)

Anaphylaxis has been reported following administration of both mRNA COVID-19 vaccines [115]. 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 [116-118]. The vast majority of these events occurred in individuals with a history of allergic reactions and occurred within 30 minutes. The mechanism for the anaphylaxis is under investigation and has not been determined. Some suggest that it is IgE mediated, with polyethylene glycol as the inciting antigen. However, other complement-mediated mechanisms have been suggested in individuals without a previous history of allergy. Evaluation of patients with possible anaphylaxis following COVID-19 vaccination is discussed elsewhere. (See "COVID-19: Allergic reactions to SARS-CoV-2 vaccines", section on 'Possible anaphylaxis'.)

Reporting of adverse events — To facilitate ongoing safety evaluation, vaccine providers are responsible for reporting vaccine administration errors, serious adverse events associated with vaccination, cases of multisystem inflammatory syndrome (MIS), and cases of COVID-19 that result in hospitalization or death through the Vaccine Adverse Event Reporting System (VAERS). (See 'Ongoing safety assessment' below.)

Details on the efficacy and safety of available COVID-19 vaccines are discussed elsewhere. (See 'Immunogenicity, efficacy, and safety of select vaccines' below.)

Other countries — Various vaccines are available in different countries. A list of vaccines that have been authorized in at least one country can be found at covid19.trackvaccines.org/vaccines. Data on some of these vaccines can be found elsewhere. (See 'Immunogenicity, efficacy, and safety of select vaccines' below.)

Dosing schedules vary by vaccine. Additionally, different countries may have specific recommendations for vaccine use. As an example, Canadian national guidelines allow administration of an mRNA vaccine to complete a two-dose series following receipt of the adenovirus vector vaccine, ChAdOx1 nCoV-19/AZD1222 (University of Oxford/AstraZeneca COVID-19 vaccine), as studies suggest the combination results in a more robust and broader immune response than a two-dose ChAdOx1 nCOV-19/AZD1222 series without major safety concerns [45,119-121]. (See 'Mixing vaccine types' 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 [122]. However, both mRNA vaccines were studied with two-dose schedules, and the efficacy estimates from those schedules are difficult, if not impossible, to extrapolate to a single-dose schedule. Clinicians should refer to local guidelines for vaccine recommendations in their location. (See 'Society guideline links' below.)

Several countries had paused use of ChAdOx1 nCoV-19/AZD1222 to investigate scattered reports of thromboembolic events; many have since resumed use, in some cases with age restrictions. This is discussed in detail elsewhere. (See 'Thrombosis with thrombocytopenia' below.)

IMMUNOGENICITY, EFFICACY, AND SAFETY OF SELECT VACCINES — Select vaccines that are available for use in different countries are described here (table 2). 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.)

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 2). Clinical use of the vaccine is discussed elsewhere. (See 'Approach to vaccination' above.)

Efficacy and immunogenicity – Randomized trials in children and adults demonstrate a substantially reduced risk of symptomatic and severe COVID-19 in the first several months after BNT162b2 vaccination. In a large placebo-controlled trial, vaccine efficacy of the two-dose primary series in preventing symptomatic COVID-19 at a median of two-month follow-up was 95 percent (95% CI 90.3-97.6) for individuals aged 16 years or older [123,124], 100 percent (95% CI 75.3-100) for individuals aged 12 to 15 years [125], and 91 percent for individuals aged 5 to 11 years [126]. Among adults ≥65 years of age who had other medical comorbidities or obesity, vaccine efficacy was 91.7 percent (95% CI 44.2-99.8). On longer follow-up, vaccine efficacy remained high but slightly decreased to 90 percent at two to four months post-vaccination and 84 percent at four to six months [127]. Of 30 severe infections (ie, with hypoxia, organ dysfunction, or critical illness) among nearly 50,000 trial participants over six months, only 1 occurred in a vaccinated individual.

Observational data from various countries following their national roll-outs of BNT162b2 support the trial findings in adults and adolescents [19,22-24,91,93,128-136]. Specifically, BNT162b2 has been associated with approximately 90 percent or higher vaccine effectiveness in preventing COVID-19-related hospitalization, intensive care unit admissions, and death among adolescents and adults.

Vaccine effectiveness wanes over time and may be decreased in protecting against certain SARS-CoV-2 variants. These issues are discussed in detail elsewhere. (See 'Role of booster vaccinations/waning efficacy' below and 'Efficacy against variants of concern' below.)

These efficacy data are consistent with evidence from immunogenicity studies that demonstrated robust binding and neutralizing antibody responses with BNT162b2, with some variability by age [125,126,137]. Responses in participants ≥65 years old were generally lower than in younger subjects, but still comparable or higher than titers in convalescent plasma. Neutralizing antibody titers also decline with time following BNT162b2 vaccination; in one study, steeper declines in neutralizing titers over six months were observed among males, individuals ≥65 years old, and immunocompromised individuals [138]. Neutralizing activity is lower against the Delta variant (B.1.617.2) [139-141] and substantially lower against the Omicron variant (B.1.1.529) compared with activity against previously circulating strains.

Common 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 [103,118,123]. Injection site reactions (mainly pain, but also redness, swelling, and pruritus) occur in approximately 65 percent; fatigue, headache, and myalgias in approximately 40 to 50 percent; and fevers, chills, and joint pain in approximately 20 percent [103]. Rates are slightly higher among adolescents aged 12 through 15 years and slightly lower among children aged 5 through 11 years [125,126]. Local and systemic reactions occur less frequently among recipients 65 years or older but are still relatively common.

Serious adverse effects – Myocarditis and pericarditis, mainly in male adolescents and young adults, have been reported more frequently than expected following receipt of BNT162b2. This is discussed in detail elsewhere. (See 'Myocarditis' below.)

Anaphylaxis following vaccination has been reported at an approximate rate of 5 events per 1 million doses; 80 percent of anaphylaxis cases have occurred in individuals with a history of allergic reactions and 90 percent occurred within 30 minutes [116]. Other reported allergic reactions included pruritus, rash, scratchy sensations in the throat, and mild respiratory symptoms [142]. (See "COVID-19: Allergic reactions to SARS-CoV-2 vaccines", section on 'mRNA vaccines'.)

Other major adverse events have not been consistently associated with BNT162b2 receipt [143]. Rare cases of Bell's palsy were noted in the phase III trial (four in vaccine and zero in placebo recipients) [123]; 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 [116]. As of April 12, 2021, there had been no reports in the United States of cerebral venous sinus thrombosis with thrombocytopenia following nearly 98 million doses of BNT162b2 administered [144]. In a large cohort study from Israel, BNT162b2 receipt was most strongly associated with myocarditis, lymphadenopathy, appendicitis, and herpes zoster [145].

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 2). Clinical use of the vaccine is discussed elsewhere. (See 'Approach to vaccination' above.)

Efficacy and immunogenicity Randomized trials in adults demonstrate a substantially reduced risk of symptomatic and severe COVID-19 in the first several months after mRNA-1273 vaccination. In a large placebo-controlled trial, vaccine efficacy of the two-dose primary series in preventing symptomatic COVID-19 at a median of two-month follow-up was 94.1 percent (95% CI 89.3-96.8) among adults 18 years or older [146]. Among adults ≥65 years of age, vaccine efficacy was 86.4 percent (95% CI 61.4-95.5). After a median follow-up of 5.2 months, vaccine efficacy was 93.2 percent for symptomatic infection (9.6 versus 136.6 cases per 100 person-years with placebo) and 98.2 percent for severe disease (ie, with hypoxia, organ dysfunction, or critical illness; 2 versus 106 cases with placebo) [147].

Observational data evaluating vaccine effectiveness also support the trial findings [19,133,134,136,148-150]. Specifically, mRNA-1273 has been associated with approximately 90 percent or higher vaccine effectiveness in preventing COVID-19-related emergency visits, hospitalization, intensive care unit admission, and death.

Vaccine effectiveness wanes over time and may be decreased in protecting against certain SARS-CoV-2 variants. These issues are discussed in detail elsewhere. (See 'Role of booster vaccinations/waning efficacy' below and 'Efficacy against variants of concern' below.)

These efficacy data are consistent with evidence from immunogenicity studies that demonstrated robust binding and neutralizing antibody responses with mRNA-1273 in adults of all ages [151,152]. Immunogenicity in adolescents aged 12 to 17 years is comparable to or higher than that seen in young adults [153]. Over six months, antibody titers decline slightly but remain high and neutralizing activity persists [154]. Vaccination with mRNA-1273 is associated with higher antibody titers after the second dose compared with BNT162b2 [155,156]. Neutralizing activity is lower against Delta (B.1.617.2) [140] and substantially lower against Omicron (B.1.1.529) compared with activity against previously circulating strains.

Common 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 [103,118,157]. Injection site reactions (mainly pain, but also redness, swelling, and pruritus) occur in approximately 75 to 80 percent; fatigue, headache, and myalgias in approximately 50 to 60 percent; and fevers, chills, and joint pain in approximately 30 to 40 percent [103]. Local and systemic reactions occur less frequently among recipients 65 years or older but were still relatively common.

Severe adverse effects – Myocarditis and pericarditis, mainly in male adolescents and young adults, have been reported more frequently than expected following receipt of mRNA-1273. This is discussed in detail elsewhere. (See 'Myocarditis' below.)

Anaphylaxis following vaccination has been reported at an approximate rate of 2.8 events per one million doses; 86 percent of anaphylaxis cases have occurred in individuals with a history of allergic reactions, and 90 percent occurred within 30 minutes [116,142]. (See "COVID-19: Allergic reactions to SARS-CoV-2 vaccines", section on 'mRNA vaccines'.)

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 [116].

No other major vaccine-associated adverse events have been identified in post-vaccine surveillance [143]. As of June 29, 2021, a single case of cerebral 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 [158].

Ad26.COV2.S (Janssen/Johnson & Johnson COVID-19 vaccine) — This vaccine is based on a replication-incompetent adenovirus 26 vector that encodes a stabilized spike protein (table 2). Clinical use of the vaccine is discussed elsewhere. (See 'Approach to vaccination' above.)

Efficacy and immunogenicity – Randomized trials in adults demonstrate a substantially reduced risk of symptomatic and severe COVID-19 in the first several months after Ad26.COV2.S vaccination. In a large placebo-controlled trial, vaccine efficacy of the one-dose primary series in preventing moderate to severe/critical COVID-19 (which included patients with pneumonia, dyspnea, tachypnea, or at least two symptoms of COVID-19) at a median of two-month follow-up was 66.9 percent efficacy (95% CI 59.0-73.4) in adults age 18 years or older [159]. Vaccine efficacy against severe/critical infection (ie, with hypoxia, organ dysfunction, or critical illness) trended higher at 78 and 85 percent after 14 and 28 days post-vaccination. Efficacy estimates after a median of four months follow-up were 56.3 percent (95% CI 51.3-60.8) for at least moderate COVID-19 and 74.6 percent (95% CI 64.1-82.1) for severe/critical COVID-19 [160]. A press release suggested higher efficacy rates with a two-dose series (75 and 100 percent against symptomatic and severe COVID-19), but published trial details are necessary to critically assess these results [161].

Observational data evaluating vaccine effectiveness largely support the trial findings; Ad26.COV2.S has been associated with vaccine effectiveness of 73 and 68 percent against COVID-19-related emergency care and hospitalization, respectively [19,162]. These efficacy data are consistent with evidence from immunogenicity studies that demonstrated post-vaccination binding and neutralizing antibody responses that overlapped with but were slightly lower than those in convalescent plasma [163,164]. These neutralizing responses are largely stable over eight months with both one- and two-dose regimens [165], in contrast to the neutralizing antibody levels following mRNA vaccination, which wane over time (although remain higher than after Ad26.COV2.S) [166]. Neutralizing activity is also retained against the Delta (B.1.617.2) variant at only a slightly lower level than against previously circulating strains but is substantially reduced against Omicron (B.1.1.529).

Waning vaccine effectiveness and impact of SARS-CoV-2 variants are discussed in detail elsewhere. (See 'Role of booster vaccinations/waning efficacy' below and 'Efficacy against variants of concern' below.)

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 [167]. 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 [168].

In the phase III efficacy trial, serious adverse event rates in the vaccine and placebo group were similar [159]. 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 [169]. 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. 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 [170].

Efficacy and immunogenicity – Randomized trials in adults demonstrate a substantially reduced risk of symptomatic COVID-19 in the first several months after vaccination. In large placebo-controlled trials, vaccine efficacy of a two-dose primary series in preventing symptomatic COVID-19 at a median of two-month follow-up was 70 to 76 percent (95% CI 54.8-80.6) at or after 14 days following the second dose [171,172]. Additional analysis of this trial suggested that 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) [173]. These findings lend support to extending the time interval between the first and second dose to 12 weeks.

Observational data from various countries following their national roll-outs of ChAdOx1 nCoV-19/AZD1222 also support the trial findings [23,174], although they suggest that effectiveness, even against severe infection, wanes over time [175]. Waning vaccine effectiveness and impact of SARS-CoV-2 variants are discussed in detail elsewhere. (See 'Role of booster vaccinations/waning efficacy' below and 'Efficacy against variants of concern' below.)

These efficacy data are consistent with evidence from immunogenicity studies that demonstrated robust binding and neutralizing antibody responses in vaccine recipients [176-178]. The Delta (B.1.617.2) and Omicron (B.1.1.529) variants evade immune responses in some vaccinated individuals [141,179].

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 [176]. In the phase III trial, there were two cases of transverse myelitis in ChAdOx1 nCoV-19 vaccine recipients [171]. One was thought to be possibly related to vaccination and was described as an idiopathic, short-segment spinal cord demyelination; the other was in a participant with previously unrecognized multiple sclerosis and thought to be unrelated to the vaccine. The vaccine also may be associated with an extremely small risk of thrombotic events associated with thrombocytopenia, which is discussed in detail elsewhere. (See 'Thrombosis with thrombocytopenia' below.)

The general thromboembolic risk with ChadOx1 nCoV-19/AZD1222 is uncertain. 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 [180]. However, separate analyses from Denmark suggested a slightly higher total rate of thromboembolic events following ChadOx1 nCoV-19/AZD1222 than expected [181,182].

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.

NVX-CoV2373 (Novavax) – This is a recombinant protein nanoparticle vaccine composed of trimeric spike glycoproteins and a potent Matrix-M1 adjuvant. In 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 in seronegative individuals aged 18 to 84 years [183]. The four severe cases occurred in the placebo group. Similar vaccine efficacy (89.7 percent, 95% CI 80.2-94.6) was reported in a phase III trial in the United Kingdom [184].

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, 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 [185]. In a randomized phase III trial, vaccine efficacy was 57.5 percent (95% CI 39.7-70.0) for symptomatic infection and 91.7 percent (95% CI 36.1-99.0) for severe disease [186]. 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 2). 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 [187]. This vaccine is available in Russia and several other countries, including Mexico. According to interim analysis of a phase III trial, this vaccine had 91.6 percent (95% CI 85.6-95.2) efficacy in preventing symptomatic COVID-19 at the time of the second dose [188]. All 20 cases of severe COVID-19 that occurred 21 days after the first dose were in the placebo group. 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. In a phase III efficacy trial, vaccine efficacy 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 [189]. 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. According to interim results of a phase III trial in Turkey, vaccine efficacy was 83.5 percent (95% CI 65.4–92.1) [190]; however, lower efficacy rates have been reported in small trials from different countries [191,192]. 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 [193]; a subsequent study in Brazil reported lower vaccine effectiveness among adults older than 70 years in the context of prevalent Gamma variant (47, 56, and 61 percent against COVID-19, hospitalization, and death, respectively) [194]. 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 (also called BBV152) 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 randomized trial, vaccine efficacy against symptomatic COVID-19 was 78 percent (95% CI 65-86); there was 1 case of severe COVID-19 in the vaccine group and 15 in the placebo group [195]. Serious adverse events were not deemed related to vaccine except for one possibly related case of immune thrombocytopenic purpura.

ZyCoV-D (Zydus Cadila) – This is the first DNA COVID-19 vaccine made available, first authorized in India in August 2021 [196]. A needleless device delivers the vaccine subcutaneously with a high-pressure stream. Data from efficacy trials had not been published at the time of authorization, but vaccine efficacy against symptomatic COVID-19 was reportedly 67 percent following three doses in a trial among 28,000 participants (60 cases with placebo and 21 with vaccine). Trial details essential for critical review of these results are not yet public.

GENERAL EFFICACY ISSUES

Role of booster vaccinations/waning efficacy — 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, several countries have initiated or announced plans to administer a booster vaccine for individuals who have received a complete primary series [197]. In the United States, the Food and Drug Administration (FDA) has authorized and the CDC recommends a booster dose for all individuals 12 years or older, regardless of the vaccine received (table 2) [31,32].

Among individuals who received a primary BNT162b2 (Pfizer COVID-19 vaccine) series, the United States Centers for Disease Control and Prevention (CDC) recommends a booster dose at least five months after the last dose [10,11,28,31,32,198].

Among individuals who received a primary mRNA-1273 (Moderna COVID-19 vaccine) series, the CDC recommends a booster dose at least five months after the last dose [10,11,28,31,32,198].

Among individuals who received a primary vaccine series with Ad26.COV2.S (Janssen/Johnson & Johnson COVID-19 vaccine), the CDC recommends a booster dose at least two months after the dose [12,28].

Booster doses following a primary vaccine series are a distinct issue from administering an additional dose in the primary series (eg, three doses of a primary mRNA vaccine series) for certain immunocompromised patients. A booster dose is also recommended in immunocompromised individuals who received an additional vaccine dose in the primary series, although at a shorter interval than recommended for the general population [28]. This is discussed in detail elsewhere. (See 'Immunocompromised individuals' above.)

The rationale for booster doses is to reduce waning immunity and to try to overcome partial immune evasion of circulating variants:

Waning effectiveness – Data from observational studies have suggested that vaccine protection against SARS-CoV-2 infection wanes over time [21,199-208]. However, protection against hospitalization and severe COVID-19 remains high.

As an example, a review of data on nursing home residents reported to a national database in the United States suggested that vaccine effectiveness against laboratory-confirmed SARS-CoV-2 infection among this population declined from 75 percent in March to May 2021 to 53 percent during June to July 2021 [200]. Similarly, in a study of state-wide data in New York that included approximately 10 million vaccinated adults, age-adjusted vaccine effectiveness against SARS-CoV-2 infection declined from 92 to 75 percent from May to July 2021; however, effectiveness against hospitalization remained stable over that time at 90 to 95 percent [199]. Another study of 3000 hospitalized patients estimated vaccine effectiveness against COVID-19-related hospitalization as 86 percent 2 to 14 weeks after vaccination and 84 percent 13 to 24 weeks after vaccination [209].

Although overall vaccine effectiveness against severe disease and hospitalization remains high over time, some observational data suggest that there may be a relative decline, particularly among individuals older than 65 years and those with risk factors for severe disease [13,210-212].

Effectiveness/immunogenicity of booster doses – Accumulating data suggest that a booster vaccine improves vaccine effectiveness in the short term [213-217]. In an unpublished trial that was presented to the Advisory Committee on Immunization Practices (ACIP) by the manufacturer, 10,000 recipients who had completed a primary series of BNT162b2 at least six months previously, were randomly assigned to receive a booster BNT162b2 dose or placebo [213]. Efficacy of the booster dose against symptomatic COVID-19 from one week through two months after the dose was 95 percent (95% CI 90-98; 7 versus 124 infections); only two severe cases occurred, both in the placebo group, and neither patient was hospitalized. Similarly, in an observational study from Israel of over four million individuals aged 16 years or older who had received two doses of BNT162b2 at least five months previously, receipt of a booster dose was associated with a 10-times lower rate of infection in all age groups compared with those who did not receive a booster (adjusted rate difference of 57 to 90 infections per 100,000 days, depending on age group) and among individuals 60 years or older, an 18-times lower rate of severe illness (absolute difference 5.4 cases per 100,000 days) [214]. Several other observational studies from Israel have reported that a booster dose is associated with a lower risk of COVID-19-related death, particularly among adults ≥60 years old in long-term care facilities [215,218,219]. Direct data on booster doses in individuals 12 to 16 years are lacking, but it is reasonable to expect further reductions in infection risk in this age group as well.

Efficacy data from trials evaluating two doses of AD26.COV2.S also support use of a booster for this vaccine (see 'Ad26.COV2.S (Janssen/Johnson & Johnson COVID-19 vaccine)' above). Data on immunogenicity with booster doses of BNT162b2, mRNA-1273, and AD26.COV2.S are consistent with the clinical outcomes reported in these trials and observational studies [220-222]. Data on immunogenicity also suggest improved neutralizing activity against Omicron variant in sera from individuals who received booster doses. (See 'Efficacy against variants of concern' below.)

Data informing the use of heterologous booster vaccines are discussed elsewhere. (See 'Mixing vaccine types' above.)

Duration of booster effect – As observed after the primary series, vaccine effectiveness following a booster dose also appears to wane with time. In one study performed during the circulation of the Omicron variant, vaccine effectiveness against COVID-19-associated hospitalization was 91 versus 78 percent among those who had received their third mRNA vaccine dose within two months versus more than four months previously [223].

Safety of booster doses – The rate and severity of adverse reactions following booster doses are similar to those reported following a primary series. For mRNA vaccines, local and systemic reactions were reported slightly less frequently after the booster dose than the second dose [224]. The risk of myocarditis also appears lower after a booster dose than the second dose of an mRNA vaccine [30,224]. Following 82.6 million booster doses administered to adults in the United States, there were 37 reports to the CDC that met criteria for myocarditis [224]. The highest rate was among males aged 18 to 24 years following an mRNA-1273 boost (8.7 per 1 million doses), considerably lower than that reported after the primary series. In a preliminary study from Israel, there were no cases of myocarditis in 12- to 15-year-olds after >6000 booster doses administered [30]. (See 'Myocarditis' below.)

Efficacy against variants of concern — Several SARS-CoV-2 variants that are concerning for their potential for immune escape have emerged over the course of the pandemic (table 6). For the Omicron (B.1.1.529) and Delta (B.1.617.2) variants, COVID-19 vaccines remain effective in preventing severe disease, but effectiveness in preventing symptomatic infection is variably attenuated.

Omicron – Clinical data indicate that vaccination has reduced effectiveness against symptomatic infection with Omicron compared with other variants; effectiveness against severe disease (as reflected by hospitalization) remains substantial, particularly among those who received a booster dose, although is also lower compared with other variants. As an example, according to a report from a South African private health system, two doses of BNT162b2 (Pfizer COVID-19 vaccine) were associated with 33 percent effectiveness against any infection and 70 percent effectiveness against COVID-19-associated hospitalization during the Omicron surge; vaccine effectiveness against hospitalization during the Delta surge was 93 percent [225,226]. Similarly, in a case-control from the United States of over 12,000 individuals with either Omicron or Delta infection, receipt of three mRNA COVID-19 vaccine doses was associated with a smaller risk reduction for infection with Omicron (OR 0.33) than with Delta (OR 0.065) [227]; in another observational study from the United States, vaccine effectiveness of three mRNA COVID-19 vaccine doses against emergency care visits and hospitalization was 82 and 90 percent during the Omicron surge compared with 94 percent for both when only the Delta variant was prevalent [228]. In these and other studies, receipt of a booster dose is associated with greater vaccine effectiveness against Omicron than a primary series alone [227-230].

Attenuated vaccine effectiveness against Omicron is also supported by accumulating reports that demonstrate that neutralizing activity of sera from vaccinated individuals is reduced against Omicron compared with the original Wuhan strain virus and the Delta variant; the majority of infection-naïve individuals who received a primary vaccine series have no detectable neutralizing activity against Omicron [231-239]. However, these studies also suggest that previously infected individuals who received a primary series and individuals who receive booster vaccination retain adequate neutralizing titers against Omicron.

The discrepancy between the lack of neutralizing activity against Omicron in sera from vaccinated individuals and the persistence of protection against severe disease with vaccination may be in part because neutralizing activity is not the only immune measure of vaccine protection. Vaccine- or infection-induced cellular immunity appears robust against Omicron [240-243]. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Omicron (B.1.1.529 lineage)'.)

Delta – Observational evidence suggests that vaccine effectiveness against symptomatic infection with the Delta variant is lower than that with Alpha and original wild-type virus [244-248]. However, data from North America, the United Kingdom, and the Middle East suggest that vaccine effectiveness against severe disease, hospitalization, and death remains high with Delta and is comparable to that with Alpha [13,210,249-253]. As an example, in an analysis of SARS-CoV-2 infections in Los Angeles, California from May to July 2021, over which time Delta became the dominant variant, the age-adjusted rate of hospitalization among unvaccinated individuals was 29 times that among vaccinated individuals [249]. Another study of over 30,000 hospital, emergency, or urgent care encounters in the United States over a period when Delta predominated estimated vaccine effectiveness of 86 percent against COVID-19-associated hospitalization and 82 percent against emergency or urgent care [13]. (See 'BNT162b2 (Pfizer-BioNTech COVID-19 vaccine)' above and 'ChAdOx1 nCoV-19/AZD1222 (University of Oxford, AstraZeneca, and the Serum Institute of India)' above.)

Breakthrough infections after vaccination — Since no COVID-19 vaccine is 100 percent effective, some infections in vaccinated individuals are expected, and the risk of breakthrough infection is higher with certain variants, such as Delta and Omicron. Nevertheless, the individual risk of severe breakthrough infection with the Delta variant remains very low [254-256], and preliminary evidence suggests the same for Omicron, particularly among those who received a booster vaccine. (See 'Efficacy against variants of concern' above.)

Breakthrough infection after vaccination is substantially less likely to cause severe disease than infection in unvaccinated individuals [257-259]. In a study of over 1 million vaccinated members of a large health system in the United States, the rates of severe disease and death due to breakthrough COVID-19 were 1.5 and 0.3 per 10,000, respectively [260]. Risk factors for poor outcomes are similar to those for unvaccinated individuals: older age (>65 years) and multiple comorbidities [260,261].

Other observational data suggest that breakthrough infection is associated with a lower number of symptoms, shorter duration of symptoms, lower likelihood of persistent symptoms for >28 days, and a higher likelihood of asymptomatic infection compared with infection in unvaccinated individuals [59,262].

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, breakthrough infection with the more transmissible Delta variant is associated with a substantial risk of transmission that may be comparable to that of infection in unvaccinated individuals; the risk of transmission with a breakthrough Omicron infection is uncertain.

In a study of over 100,000 patients with SARS-CoV-2 and their contacts, a history of mRNA vaccine receipt was associated with lower secondary attack rates with Delta compared with no vaccination (adjusted relative risk 0.5), although the effect was not as great as with Alpha (adjusted relative risk 0.32) and further decreased by 12 weeks after vaccination [263]. In other studies, levels of upper respiratory tract SARS-CoV-2 RNA in vaccinated individuals with breakthrough Delta infection are similar to those in unvaccinated individuals with Delta infection [108,249,264-266]. 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. However, some studies also suggest that despite viral RNA levels being similar at the time of diagnosis, they decline more rapidly in vaccinated individuals, suggesting a shorter period of infectiousness [264,266,267]. Another unpublished study suggested that despite similar viral RNA levels, levels of infectious Delta virus in the upper respiratory tract were lower in breakthrough infection after vaccination than in infection in unvaccinated individuals [268]. Additional data are needed to evaluate the impact of vaccination on the viral kinetics of Omicron breakthrough infection and better understand their clinical implications.

Studies performed when the Delta variant was not circulating had suggested a lower transmission risk with breakthrough infection, with lower associated secondary household attack rates from vaccinated index cases [269-271].

Immune correlates of protection — Although data remain limited, analyses of vaccine trials support the concept that binding and neutralizing antibody levels against the spike protein and its receptor-binding domain are the primary immune predictors of protection against symptomatic infection, with increasing levels associated with progressively higher vaccine efficacy [272,273]. Data from these studies can help assess likely efficacy of new vaccines or regimens in different patient populations when large efficacy trials cannot be performed. However, the application to clinical care is uncertain; it is unknown how well results from the various commercially available serologic tests correspond to the measurement of antibody levels in these studies. Furthermore, the immune correlates of protection against severe infection have not been fully elucidated.

SPECIFIC SAFETY CONCERNS — COVID-19 vaccines are exceedingly safe. The primary safety concerns are a very rare risk of myocarditis with mRNA vaccines and very rare risks of thrombosis with thrombocytopenia and possibly Guillain-Barre syndrome with adenoviral vector vaccines. Although myriad adverse events have been reported in individuals following vaccine administration, no other severe events have been clearly associated with vaccination after hundreds of millions of doses administered.

As an example, many patients of child-bearing potential are concerned that COVID-19 vaccination could adversely impact fertility because of specious reports on social media. However, in epidemiologic studies, there is no association between COVID-19 vaccination and fertility problems in either females or males [274,275].

Thrombosis with thrombocytopenia — ChadOx1 nCoV-19/AZD1222 (AstraZeneca COVID-19 vaccine) and Ad26.COV2.S (Janssen COVID-19 vaccine, also referred to as the Johnson & Johnson vaccine) have each been associated with an extremely small risk of unusual types of thrombotic events associated with thrombocytopenia. A similar risk has not been identified with the mRNA vaccines. Many of these cases have been associated with autoantibodies directed against the platelet factor 4 (PF4) antigen, similar to those found in patients with autoimmune heparin-induced thrombocytopenia (HIT) [276-279]. Some experts refer to this syndrome as vaccine-associated immune thrombotic thrombocytopenia (VITT); others have used the term thrombosis with thrombocytopenia syndrome (TTS).

In reported cases, thrombosis often occurred at unusual sites, including the cerebral venous sinuses and mesenteric vessels, and at more than one site [280-282]. Most of the initially reported events occurred within two weeks of receipt of the initial vaccine dose and in females under 60 years of age, although subsequent cases have been reported following a longer post-vaccine interval and in males and older females. Some fatal cases have been reported.

In the United States, the risks of this syndrome following Ad26.COV2.S receipt was assessed as 3.8 cases and 0.57 deaths per million doses overall, and 9 to 10.6 cases and 1.8 to 1.93 deaths per million doses for females 30 to 49 years old [283]. Regulatory bodies in the United States and Europe have concluded that the population and individual benefits of these vaccines (compared with no vaccination), including reductions in death and critical illness, outweigh the risk of these rare events [284-286]. Nevertheless, recipients of these vaccines should be aware of the possible association and seek immediate care for signs and symptoms suggestive of thrombocytopenia (eg, new petechiae or bruising) or thrombotic complications (including shortness of breath, chest pain, lower extremity edema, persistent severe abdominal pain, unabating severe headache, severe backache, new focal neurologic symptoms, and seizures) [286].

The incidence, risk factors, clinical features, evaluation, and management of VITT/TTS are discussed in detail elsewhere. (See "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)".)

A clear, causal relation between either of these vaccines and thromboembolic disorders overall (eg, pulmonary embolism and deep vein thrombosis) has not been identified [144,180]. For ChadOx1 nCoV-19/AZD1222, studies have reported conflicting findings regarding this risk, as discussed elsewhere. (See 'ChAdOx1 nCoV-19/AZD1222 (University of Oxford, AstraZeneca, and the Serum Institute of India)' above.)

Myocarditis — Myocarditis and pericarditis, mainly in male adolescents and young adults, have been reported more frequently than expected following receipt of the mRNA vaccines, BNT162b2 (Pfizer vaccine) and mRNA-1273 (Moderna vaccine) [287,288]. 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 [288]. 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 [28]. 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, among over 192 million people who had received an mRNA vaccine between December 2020 and August 2021, there were 1626 cases that met the definition of myocarditis following vaccine receipt [289]. The majority of these cases occurred after the second dose, the median age was 21 years, and 82 percent occurred in males. The estimated rate among males by age group was:

12 to 16 years old – 70.7 cases per million doses of BNT162b2

16 to 17 years old – 105.9 cases per million doses of BNT162b2

18 to 24 years old – 52.4 to 56.3 cases per million doses BNT162b2 and mRNA-1273, respectively

Among females of the same age groups, the estimated case rates ranged from 6.4 to 11 cases per million doses. The number of events observed exceeded the expected baseline rate among males aged 18 to 49 years and females aged 19 to 29 years.

Studies from other countries have also suggested an increased rate of myocarditis following BNT162b2 vaccination compared with the expected background rate [290-293]. Observational data from Canada and Denmark suggest that the risk may be very slightly higher with mRNA-1273 than BNT162b2 (2.55 to 4.2 versus 1.4 cases per 100,000 people vaccinated) [294,295].

Among the cases that have been reported, most were mild [288,290,291]. Onset was generally within the first week after vaccine receipt. Most patients who presented for care responded well to medical treatment and had rapid symptom improvement. There have been very rare reports of fulminant myocarditis in individuals who had received an mRNA vaccine within the preceding weeks, although a causal relationship is difficult to establish [296].

The clinical presentation was illustrated in a retrospective study of 139 adolescents and young adults ≤21 years old with suspected vaccine-associated myocarditis based on elevated troponins within 30 days of vaccination without alternative diagnosis [297]. Almost all presented with chest pain, with symptom onset a median of two days after vaccine receipt. Electrocardiogram was abnormal in 70 percent (ST segment elevations or T wave abnormalities), cardiac magnetic resonance imaging was abnormal in 77 percent (late gadolinium enhancement and myocardial edema), but systolic function on echocardiogram was normal in 80 percent. Nineteen percent were managed in the intensive care unit, although only two patients required inotropic or vasopressor support. Median hospital stay was two days, and those with decreased systolic function had normalized ejection fraction on follow-up. Ongoing monitoring is necessary to assess for long-term sequelae.

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 Food and Drug Administration (FDA) and Centers for Disease Control and Prevention (CDC) and European regulators affirm that the benefits of these vaccines outweigh their risks [298,299]. Cases of GBS, including recurrent cases, have also been reported in the setting of SARS-CoV-2 infection [300,301], and observational data suggest the risk of GBS after infection exceeds the risk after vaccination [302]. 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, as of July 24, 2021, there had been 132 preliminary reports of GBS among Ad26.COV2.S recipients after approximately 13.2 million doses [303]. The estimated rate was 9.8 cases per million doses, a rate that is approximately four times the background rate. The median age was 56 years (interquartile range 45 to 62 years), the median time to onset was 13 days following vaccination, 35 percent had a life-threatening case, and 1 patient died. In an earlier report of 100 cases, a quarter of the patients reported bilateral facial weakness [304].

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 [299]. Other scattered reports have also described GBS, including variant GBS with bilateral facial weakness, following ChAdOx1 nCoV-19/AZD1222 vaccination [305,306].

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 [307]. The World Health Organization (WHO) has proposed the same minimal efficacy targets [308].

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 [309]. 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 [310].

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 [311-313]. 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 [313].

Vaccine reimbursement – In the United States, COVID-19 vaccines will be free of charge for any individual for whom the Advisory Committee on Immunization Practices (ACIP) recommends vaccination [314]. 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 [315].

POST-LICENSURE ISSUES

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 World Health Organization (WHO) as a top 10 global health threat in 2019 [316]. 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 [317,318].

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 [319]. 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 [320]. 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 [321-324].

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 [320,321,325,326]. 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 [320].

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) [327]. 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 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 [328,329]. 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 [330,331].

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") [332]. Therefore, if someone is injured by vaccine, society owes that person compensation. This is the basis for the National Vaccine Injury Compensation Program (NVICP) [333]. 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 [334].

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

Antigenic target – 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 (figure 2). (See 'Pace of COVID-19 vaccine development' above and 'Antigenic target' above.)

Indications – Several vaccines using different platforms (figure 3) have high vaccine efficacy against laboratory-confirmed symptomatic COVID-19 and substantially reduce the risk of severe COVID-19 (table 2). (See 'Immunogenicity, efficacy, and safety of select vaccines' above.)

For individuals 12 years and older, we recommend COVID-19 vaccination (Grade 1A). For individuals 5 to 11 years old, we also recommend COVID-19 vaccination (Grade 1B). (See 'Approach to vaccination' above and 'Immunogenicity, efficacy, and safety of select vaccines' above.)

Selection and administration of the primary series – In the United States, the following COVID-19 vaccines are available (table 2) (see 'Indications and vaccine selection' above and 'Dose and interval' above):

Two mRNA vaccines:

-BNT162b2 (Pfizer COVID-19 vaccine): The primary series includes two intramuscular injections given at least three weeks apart for individuals aged five years or older. This vaccine is associated with a rare risk of myocarditis. (See 'BNT162b2 (Pfizer-BioNTech COVID-19 vaccine)' above.)

-mRNA-1273 (Moderna COVID-19 vaccine): The primary series includes two intramuscular injections given at least one month apart for individuals 18 years or older. This vaccine is associated with a rare risk of myocarditis. (See 'mRNA-1273 (Moderna COVID-19 vaccine)' above.)

An adenoviral vector vaccine Ad26.COV2.S (Janssen COVID-19 vaccine, also referred to as the Johnson & Johnson vaccine): The primary series includes a single intramuscular injection for individuals 18 years or older. This vaccine is associated with a rare risk of thrombosis with thrombocytopenia and possibly Guillain-Barre syndrome. (See 'Ad26.COV2.S (Janssen/Johnson & Johnson COVID-19 vaccine)' above.)

If both mRNA and adenoviral vector vaccines are available, we suggest an mRNA vaccine (BNT162b2 or mRNA-1273) rather than Ad26.COV2.S (Grade 2C). All three are highly effective, but data suggest that the mRNA vaccines may have higher effectiveness against severe disease. The rare adverse effects associated with Ad26.COV2.S appear more severe than those with the mRNA vaccines. Nevertheless, Ad26.COV2.S is an effective and safe option for most individuals if mRNA vaccines are unavailable or contraindicated. (See 'Specific safety concerns' above.)

Different vaccines are available elsewhere; a list of vaccines that have been authorized in at least one country can be found at covid19.trackvaccines.org/vaccines. Clinicians outside the United States should refer to local guidelines for vaccine recommendations in their location. (See 'Other countries' above.)

Booster doses – We recommend booster vaccination for eligible individuals (Grade 1B). Effectiveness of the primary series wanes over time, and a booster dose can further reduce the risk of symptomatic infection. In the United States, a booster dose has been authorized for those 12 years of age and older. For most individuals, the booster dose is given at least five months after a primary BNT162b2 or mRNA-1273 series and at least two months after a primary Ad26.COV2.S series. Any one of the three vaccines can be used as a booster dose, regardless of the vaccine used for the primary series, as long as it is approved or authorized for the age group. However, as above, we favor one of the mRNA vaccines. (See 'Role of booster vaccinations/waning efficacy' above.)

Adjustments for immunocompromised patients – For individuals with certain immunocompromising conditions (table 3), we suggest administering a three-dose primary mRNA vaccine series rather than a two-dose series (Grade 2C). Similarly, we suggest an additional mRNA vaccine dose for such individuals who previously received a single Ad26.COV2.S dose (Grade 2C). Immunocompromised individuals are less likely to respond adequately to routine vaccination; additional doses are associated with improved vaccine effectiveness. These additional doses do not replace the booster vaccine dose, which is also given two to three months after the last dose of the primary series. (See 'Immunocompromised individuals' above.)

Deviations from dosing recommendations – If the vaccine is administered in a manner different from the recommended approach, the dose or series generally does not have to be repeated. Centers for Disease Control and Prevention (CDC) recommendations on how to manage vaccination errors or deviations are presented in the table (table 4). (See 'Dose and interval' above.)

Expected side effects 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.)

Contraindications and precautions – The primary 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.)

Impact of variants on vaccine efficacy Several SARS-CoV-2 variants with potential for immune escape have been identified worldwide. Vaccine effectiveness against Delta is reduced against overall infection but largely retained against severe disease. Preliminary evidence suggests attenuated vaccine effectiveness, particularly against overall infection, with Omicron (B.1.1.529) (table 6). (See 'Efficacy against variants of concern' above and 'Role of booster vaccinations/waning efficacy' above.)

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Topic 129849 Version 140.0

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71 : Randomized Trial of a Third Dose of mRNA-1273 Vaccine in Transplant Recipients.

72 : Antibody Response to a Fourth Messenger RNA COVID-19 Vaccine Dose in Kidney Transplant Recipients: A Case Series.

73 : Antibody Response to a Fourth Messenger RNA COVID-19 Vaccine Dose in Kidney Transplant Recipients: A Case Series.

74 : The Effectiveness of the Two-Dose BNT162b2 Vaccine: Analysis of Real-World Data.

75 : Effectiveness of SARS-CoV-2 mRNA Vaccines for Preventing Covid-19 Hospitalizations in the United States.

76 : BNT162b2 vaccine breakthrough: clinical characteristics of 152 fully vaccinated hospitalized COVID-19 patients in Israel.

77 : Effectiveness of 2-Dose Vaccination with mRNA COVID-19 Vaccines Against COVID-19-Associated Hospitalizations Among Immunocompromised Adults - Nine States, January-September 2021.

78 : Clinical effectiveness of COVID-19 vaccination in solid organ transplant recipients.

79 : Association Between Immune Dysfunction and COVID-19 Breakthrough Infection After SARS-CoV-2 Vaccination in the US.

80 : Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia.

81 : Antibody Response to 2-Dose SARS-CoV-2 mRNA Vaccine Series in Solid Organ Transplant Recipients.

82 : Safety and immunogenicity of one versus two doses of the COVID-19 vaccine BNT162b2 for patients with cancer: interim analysis of a prospective observational study.

83 : Short-term antibody response after 1 dose of BNT162b2 vaccine in patients receiving hemodialysis.

84 : Safety and Immunogenicity of Anti-SARS-CoV-2 Messenger RNA Vaccines in Recipients of Solid Organ Transplants.

85 : Absence of Humoral Response After Two-Dose SARS-CoV-2 Messenger RNA Vaccination in Patients With Rheumatic and Musculoskeletal Diseases: A Case Series.

86 : Antibody response after second BNT162b2 dose in allogeneic HSCT recipients.

87 : Poor Antibody Response after Two Doses of SARS-CoV-2 vaccine in Transplant Recipients.

88 : Effect of Immunosuppression on the Immunogenicity of mRNA Vaccines to SARS-CoV-2 : A Prospective Cohort Study.

89 : Preliminary Findings of mRNA Covid-19 Vaccine Safety in Pregnant Persons.

90 : Preliminary Findings of mRNA Covid-19 Vaccine Safety in Pregnant Persons.

91 : Effectiveness of BNT162b2 Vaccine against Delta Variant in Adolescents.

92 : Effectiveness of Pfizer-BioNTech mRNA Vaccination Against COVID-19 Hospitalization Among Persons Aged 12-18 Years - United States, June-September 2021.

93 : Effectiveness of BNT162b2 Vaccine against Critical Covid-19 in Adolescents.

94 : Warp Speed for Coronavirus Disease 2019 (COVID-19) Vaccines: Why Are Children Stuck in Neutral?

95 : Warp Speed for Coronavirus Disease 2019 (COVID-19) Vaccines: Why Are Children Stuck in Neutral?

96 : COVID-19 Vaccine Safety in Children Aged 5-11 Years - United States, November 3-December 19, 2021.

97 : COVID-19 Vaccine Safety in Children Aged 5-11 Years - United States, November 3-December 19, 2021.

98 : Multisystem Inflammatory Syndrome after SARS-CoV-2 Infection and COVID-19 Vaccination.

99 : Multisystem Inflammatory Syndrome in Children by COVID-19 Vaccination Status of Adolescents in France.

100 : Effectiveness of BNT162b2 (Pfizer-BioNTech) mRNA Vaccination Against Multisystem Inflammatory Syndrome in Children Among Persons Aged 12-18 Years - United States, July-December 2021.

101 : Effectiveness of BNT162b2 (Pfizer-BioNTech) mRNA Vaccination Against Multisystem Inflammatory Syndrome in Children Among Persons Aged 12-18 Years - United States, July-December 2021.

102 : Benefits from immunization during the vaccines for children program era - United States, 1994-2013.

103 : Reactogenicity Following Receipt of mRNA-Based COVID-19 Vaccines.

104 : Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: two open-label, randomised controlled trials.

105 : Effects of prophylactic and therapeutic paracetamol treatment during vaccination on hepatitis B antibody levels in adults: two open-label, randomized controlled trials.

106 : Syncope after vaccination--United States, January 2005-July 2007.

107 : Syncope after vaccination--United States, January 2005-July 2007.

108 : Outbreak of SARS-CoV-2 Infections, Including COVID-19 Vaccine Breakthrough Infections, Associated with Large Public Gatherings - Barnstable County, Massachusetts, July 2021.

109 : Acquired thrombotic thrombocytopenic purpura: A rare disease associated with BNT162b2 vaccine.

110 : Severe Exacerbations of Systemic Capillary Leak Syndrome After COVID-19 Vaccination: A Case Series.

111 : Severe Exacerbations of Systemic Capillary Leak Syndrome After COVID-19 Vaccination: A Case Series.

112 : Delayed Large Local Reactions to mRNA-1273 Vaccine against SARS-CoV-2.

113 : Delayed Large Local Reactions to mRNA Vaccines. Reply.

114 : Safety of intramuscular influenza vaccine in patients receiving oral anticoagulation therapy: a single blinded multi-centre randomized controlled clinical trial.

115 : mRNA Vaccines to Prevent COVID-19 Disease and Reported Allergic Reactions: Current Evidence and Suggested Approach.

116 : mRNA Vaccines to Prevent COVID-19 Disease and Reported Allergic Reactions: Current Evidence and Suggested Approach.

117 : Allergic reactions including anaphylaxis after receipt of the first dose of Moderna COVID-19 vaccine - United States, December 21, 2020-January 10, 2021.

118 : First Month of COVID-19 Vaccine Safety Monitoring - United States, December 14, 2020-January 13, 2021.

119 : First Month of COVID-19 Vaccine Safety Monitoring - United States, December 14, 2020-January 13, 2021.

120 : SARS-CoV-2 delta variant neutralisation after heterologous ChAdOx1-S/BNT162b2 vaccination.

121 : Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial.

122 : Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial.

123 : Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial.

124 : Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine.

125 : Safety, Immunogenicity, and Efficacy of the BNT162b2 Covid-19 Vaccine in Adolescents.

126 : Safety, Immunogenicity, and Efficacy of the BNT162b2 Covid-19 Vaccine in Adolescents.

127 : Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine through 6 Months.

128 : COVID-19 vaccine coverage in health-care workers in England and effectiveness of BNT162b2 mRNA vaccine against infection (SIREN): a prospective, multicentre, cohort study.

129 : Early rate reductions of SARS-CoV-2 infection and COVID-19 in BNT162b2 vaccine recipients.

130 : Reduction in COVID-19 Patients Requiring Mechanical Ventilation Following Implementation of a National COVID-19 Vaccination Program - Israel, December 2020-February 2021.

131 : Effectiveness of the Pfizer-BioNTech COVID-19 Vaccine Among Residents of Two Skilled Nursing Facilities Experiencing COVID-19 Outbreaks - Connecticut, December 2020-February 2021.

132 : BNT162b2 mRNA Covid-19 Vaccine Effectiveness among Health Care Workers.

133 : Effectiveness of Pfizer-BioNTech and Moderna Vaccines Against COVID-19 Among Hospitalized Adults Aged≥65 Years - United States, January-March 2021.

134 : SARS-CoV-2 Vaccine Effectiveness in a High-Risk National Population in a Real-World Setting.

135 : Assessment of Effectiveness of 1 Dose of BNT162b2 Vaccine for SARS-CoV-2 Infection 13 to 24 Days After Immunization.

136 : Effectiveness of BNT162b2 and mRNA-1273 covid-19 vaccines against symptomatic SARS-CoV-2 infection and severe covid-19 outcomes in Ontario, Canada: test negative design study.

137 : Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates.

138 : Waning Immune Humoral Response to BNT162b2 Covid-19 Vaccine over 6 Months.

139 : Neutralising antibody activity against SARS-CoV-2 VOCs B.1.617.2 and B.1.351 by BNT162b2 vaccination.

140 : Infection and Vaccine-Induced Neutralizing-Antibody Responses to the SARS-CoV-2 B.1.617 Variants.

141 : Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization.

142 : Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Pfizer-BioNTech COVID-19 Vaccine - United States, December 14-23, 2020.

143 : Surveillance for Adverse Events After COVID-19 mRNA Vaccination.

144 : Surveillance for Adverse Events After COVID-19 mRNA Vaccination.

145 : Safety of the BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting.

146 : Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine.

147 : Efficacy of the mRNA-1273 SARS-CoV-2 Vaccine at Completion of Blinded Phase.

148 : Interim Estimates of Vaccine Effectiveness of Pfizer-BioNTech and Moderna COVID-19 Vaccines Among Health Care Personnel - 33 U.S. Sites, January-March 2021.

149 : Prevention and Attenuation of Covid-19 with the BNT162b2 and mRNA-1273 Vaccines.

150 : Effectiveness of mRNA-1273 against delta, mu, and other emerging variants of SARS-CoV-2: test negative case-control study.

151 : An mRNA Vaccine against SARS-CoV-2 - Preliminary Report.

152 : Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults.

153 : Evaluation of mRNA-1273 SARS-CoV-2 Vaccine in Adolescents.

154 : Antibody Persistence through 6 Months after the Second Dose of mRNA-1273 Vaccine for Covid-19.

155 : Comparison of SARS-CoV-2 Antibody Response Following Vaccination With BNT162b2 and mRNA-1273.

156 : Comparison of SARS-CoV-2 Antibody Response by Age Among Recipients of the BNT162b2 vs the mRNA-1273 Vaccine.

157 : Comparison of SARS-CoV-2 Antibody Response by Age Among Recipients of the BNT162b2 vs the mRNA-1273 Vaccine.

158 : Thrombosis With Thrombocytopenia After the Messenger RNA-1273 Vaccine.

159 : Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19.

160 : Final Analysis of Efficacy and Safety of Single-Dose Ad26.COV2.S.

161 : Final Analysis of Efficacy and Safety of Single-Dose Ad26.COV2.S.

162 : Analysis of the Effectiveness of the Ad26.COV2.S Adenoviral Vector Vaccine for Preventing COVID-19.

163 : Interim Results of a Phase 1-2a Trial of Ad26.COV2.S Covid-19 Vaccine.

164 : Immunogenicity of the Ad26.COV2.S Vaccine for COVID-19.

165 : Durable Humoral and Cellular Immune Responses 8 Months after Ad26.COV2.S Vaccination.

166 : Differential Kinetics of Immune Responses Elicited by Covid-19 Vaccines.

167 : Safety Monitoring of the Janssen (Johnson&Johnson) COVID-19 Vaccine - United States, March-April 2021.

168 : Anxiety-Related Adverse Event Clusters After Janssen COVID-19 Vaccination - Five U.S. Mass Vaccination Sites, April 2021.

169 : Thromboembolic Events in the South African Ad26.COV2.S Vaccine Study.

170 : Thromboembolic Events in the South African Ad26.COV2.S Vaccine Study.

171 : Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

172 : Phase 3 Safety and Efficacy of AZD1222 (ChAdOx1 nCoV-19) Covid-19 Vaccine.

173 : Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.

174 : Effectiveness of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines on covid-19 related symptoms, hospital admissions, and mortality in older adults in England: test negative case-control study.

175 : Two-dose ChAdOx1 nCoV-19 vaccine protection against COVID-19 hospital admissions and deaths over time: a retrospective, population-based cohort study in Scotland and Brazil.

176 : Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial.

177 : Reactogenicity and immunogenicity after a late second dose or a third dose of ChAdOx1 nCoV-19 in the UK: a substudy of two randomised controlled trials (COV001 and COV002)

178 : Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial.

179 : AZD1222-induced neutralising antibody activity against SARS-CoV-2 Delta VOC.

180 : AZD1222-induced neutralising antibody activity against SARS-CoV-2 Delta VOC.

181 : Arterial events, venous thromboembolism, thrombocytopenia, and bleeding after vaccination with Oxford-AstraZeneca ChAdOx1-S in Denmark and Norway: population based cohort study.

182 : Association of AZD1222 and BNT162b2 COVID-19 Vaccination With Thromboembolic and Thrombocytopenic Events in Frontline Personnel : A Retrospective Cohort Study.

183 : Efficacy and Safety of NVX-CoV2373 in Adults in the United States and Mexico.

184 : Safety and Efficacy of NVX-CoV2373 Covid-19 Vaccine.

185 : Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial.

186 : Final efficacy analysis, interim safety analysis, and immunogenicity of a single dose of recombinant novel coronavirus vaccine (adenovirus type 5 vector) in adults 18 years and older: an international, multicentre, randomised, double-blinded, placebo-controlled phase 3 trial.

187 : Final efficacy analysis, interim safety analysis, and immunogenicity of a single dose of recombinant novel coronavirus vaccine (adenovirus type 5 vector) in adults 18 years and older: an international, multicentre, randomised, double-blinded, placebo-controlled phase 3 trial.

188 : Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia.

189 : Effect of 2 Inactivated SARS-CoV-2 Vaccines on Symptomatic COVID-19 Infection in Adults: A Randomized Clinical Trial.

190 : Efficacy and safety of an inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac): interim results of a double-blind, randomised, placebo-controlled, phase 3 trial in Turkey.

191 : What do we know about China's covid-19 vaccines?

192 : A phase III, observer-blind, randomized, placebo-controlled study of the efficacy, safety, and immunogenicity of SARS-CoV-2 inactivated vaccine in healthy adults aged 18-59 years: An interim analysis in Indonesia.

193 : Effectiveness of an Inactivated SARS-CoV-2 Vaccine in Chile.

194 : Effectiveness of the CoronaVac vaccine in older adults during a gamma variant associated epidemic of covid-19 in Brazil: test negative case-control study.

195 : Efficacy, safety, and lot-to-lot immunogenicity of an inactivated SARS-CoV-2 vaccine (BBV152): interim results of a randomised, double-blind, controlled, phase 3 trial

196 : India's DNA COVID vaccine is a world first - more are coming.

197 : India's DNA COVID vaccine is a world first - more are coming.

198 : India's DNA COVID vaccine is a world first - more are coming.

199 : New COVID-19 Cases and Hospitalizations Among Adults, by Vaccination Status - New York, May 3-July 25, 2021.

200 : Effectiveness of Pfizer-BioNTech and Moderna Vaccines in Preventing SARS-CoV-2 Infection Among Nursing Home Residents Before and During Widespread Circulation of the SARS-CoV-2 B.1.617.2 (Delta) Variant - National Healthcare Safety Network, March 1-August 1, 2021.

201 : Waning of BNT162b2 Vaccine Protection against SARS-CoV-2 Infection in Qatar.

202 : Effectiveness of mRNA BNT162b2 COVID-19 vaccine up to 6 months in a large integrated health system in the USA: a retrospective cohort study.

203 : Phase 3 Trial of mRNA-1273 during the Delta-Variant Surge.

204 : SARS-CoV-2 vaccine protection and deaths among US veterans during 2021.

205 : Elapsed time since BNT162b2 vaccine and risk of SARS-CoV-2 infection: test negative design study.

206 : Waning mRNA-1273 Vaccine Effectiveness against SARS-CoV-2 Infection in Qatar.

207 : Risk of infection, hospitalisation, and death up to 9 months after a second dose of COVID-19 vaccine: a retrospective, total population cohort study in Sweden.

208 : Duration of effectiveness of vaccines against SARS-CoV-2 infection and COVID-19 disease: results of a systematic review and meta-regression

209 : Sustained Effectiveness of Pfizer-BioNTech and Moderna Vaccines Against COVID-19 Associated Hospitalizations Among Adults - United States, March-July 2021.

210 : Effectiveness of COVID-19 mRNA Vaccines Against COVID-19-Associated Hospitalization - Five Veterans Affairs Medical Centers, United States, February 1-August 6, 2021.

211 : Waning Immunity after the BNT162b2 Vaccine in Israel.

212 : Duration of Protection against Mild and Severe Disease by Covid-19 Vaccines.

213 : Duration of Protection against Mild and Severe Disease by Covid-19 Vaccines.

214 : Protection against Covid-19 by BNT162b2 Booster across Age Groups.

215 : Effectiveness of a third dose of the BNT162b2 mRNA COVID-19 vaccine for preventing severe outcomes in Israel: an observational study

216 : Odds of Testing Positive for SARS-CoV-2 Following Receipt of 3 vs 2 Doses of the BNT162b2 mRNA Vaccine.

217 : Association of a Third Dose of BNT162b2 Vaccine With Incidence of SARS-CoV-2 Infection Among Health Care Workers in Israel.

218 : BNT162b2 Vaccine Booster and Mortality Due to Covid-19.

219 : Effects of BNT162b2 Covid-19 Vaccine Booster in Long-Term Care Facilities in Israel.

220 : Effects of BNT162b2 Covid-19 Vaccine Booster in Long-Term Care Facilities in Israel.

221 : SARS-CoV-2 Neutralization with BNT162b2 Vaccine Dose 3.

222 : Antibody Titers Before and After a Third Dose of the SARS-CoV-2 BNT162b2 Vaccine in Adults Aged≥60 Years.

223 : Waning 2-Dose and 3-Dose Effectiveness of mRNA Vaccines Against COVID-19-Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults During Periods of Delta and Omicron Variant Predominance - VISION Network, 10 States, August 2021-January 2022.

224 : Safety Monitoring of COVID-19 Vaccine Booster Doses Among Adults—United States, September 22, 2021–February 6, 2022.

225 : Safety Monitoring of COVID-19 Vaccine Booster Doses Among Adults—United States, September 22, 2021–February 6, 2022.

226 : Effectiveness of BNT162b2 Vaccine against Omicron Variant in South Africa.

227 : Association Between 3 Doses of mRNA COVID-19 Vaccine and Symptomatic Infection Caused by the SARS-CoV-2 Omicron and Delta Variants.

228 : Effectiveness of a Third Dose of mRNA Vaccines Against COVID-19-Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults During Periods of Delta and Omicron Variant Predominance - VISION Network, 10 States, August 2021-January 2022.

229 : COVID-19 Incidence and Death Rates Among Unvaccinated and Fully Vaccinated Adults with and Without Booster Doses During Periods of Delta and Omicron Variant Emergence - 25 U.S. Jurisdictions, April 4-December 25, 2021.

230 : SARS-CoV-2 Infection and Hospitalization Among Adults Aged≥18 Years, by Vaccination Status, Before and During SARS-CoV-2 B.1.1.529 (Omicron) Variant Predominance - Los Angeles County, California, November 7, 2021-January 8, 2022.

231 : mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant.

232 : Third BNT162b2 Vaccination Neutralization of SARS-CoV-2 Omicron Infection.

233 : Reduced neutralisation of SARS-CoV-2 omicron B.1.1.529 variant by post-immunisation serum.

234 : The Omicron variant is highly resistant against antibody-mediated neutralization: Implications for control of the COVID-19 pandemic.

235 : SARS-CoV-2 Omicron Variant Neutralization in Serum from Vaccinated and Convalescent Persons.

236 : Neutralization of SARS-CoV-2 Omicron by BNT162b2 mRNA vaccine-elicited human sera.

237 : Three-dose vaccination elicits neutralising antibodies against omicron.

238 : SARS-CoV-2 Omicron Variant Neutralization after mRNA-1273 Booster Vaccination.

239 : SARS-CoV-2 breakthrough infections elicit potent, broad, and durable neutralizing antibody responses.

240 : mRNA vaccines induce durable immune memory to SARS-CoV-2 and variants of concern.

241 : mRNA vaccines induce durable immune memory to SARS-CoV-2 and variants of concern.

242 : Vaccines Elicit Highly Conserved Cellular Immunity to SARS-CoV-2 Omicron.

243 : T cell responses to SARS-CoV-2 spike cross-recognize Omicron.

244 : Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant.

245 : Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant.

246 : SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness.

247 : Resurgence of SARS-CoV-2 Infection in a Highly Vaccinated Health System Workforce.

248 : Effectiveness of COVID-19 Vaccines in Preventing SARS-CoV-2 Infection Among Frontline Workers Before and During B.1.617.2 (Delta) Variant Predominance - Eight U.S. Locations, December 2020-August 2021.

249 : SARS-CoV-2 Infections and Hospitalizations Among Persons Aged≥16 Years, by Vaccination Status - Los Angeles County, California, May 1-July 25, 2021.

250 : Monitoring Incidence of COVID-19 Cases, Hospitalizations, and Deaths, by Vaccination Status - 13 U.S. Jurisdictions, April 4-July 17, 2021.

251 : BNT162b2 and ChAdOx1 nCoV-19 Vaccine Effectiveness against Death from the Delta Variant.

252 : BNT162b2 and mRNA-1273 COVID-19 vaccine effectiveness against the SARS-CoV-2 Delta variant in Qatar.

253 : Covid-19 Vaccine Effectiveness in New York State.

254 : Covid-19 Vaccine Effectiveness in New York State.

255 : Trajectory of Growth of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Variants in Houston, Texas, January through May 2021, Based on 12,476 Genome Sequences.

256 : Outbreak of SARS-CoV-2 B.1.617.2 (Delta) Variant Infections Among Incarcerated Persons in a Federal Prison - Texas, July-August 2021.

257 : COVID-19 Vaccine Breakthrough Infections Reported to CDC - United States, January 1-April 30, 2021.

258 : Covid-19 Breakthrough Infections in Vaccinated Health Care Workers.

259 : Association Between mRNA Vaccination and COVID-19 Hospitalization and Disease Severity.

260 : Risk Factors for Severe COVID-19 Outcomes Among Persons Aged≥18 Years Who Completed a Primary COVID-19 Vaccination Series - 465 Health Care Facilities, United States, December 2020-October 2021.

261 : Characteristics and risk of COVID-19-related death in fully vaccinated people in Scotland.

262 : Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study.

263 : Effect of Covid-19 Vaccination on Transmission of Alpha and Delta Variants.

264 : Community transmission and viral load kinetics of the SARS-CoV-2 delta (B.1.617.2) variant in vaccinated and unvaccinated individuals in the UK: a prospective, longitudinal, cohort study

265 : Community transmission and viral load kinetics of the SARS-CoV-2 delta (B.1.617.2) variant in vaccinated and unvaccinated individuals in the UK: a prospective, longitudinal, cohort study

266 : Community transmission and viral load kinetics of the SARS-CoV-2 delta (B.1.617.2) variant in vaccinated and unvaccinated individuals in the UK: a prospective, longitudinal, cohort study

267 : Viral Dynamics of SARS-CoV-2 Variants in Vaccinated and Unvaccinated Persons.

268 : Viral Dynamics of SARS-CoV-2 Variants in Vaccinated and Unvaccinated Persons.

269 : Initial report of decreased SARS-CoV-2 viral load after inoculation with the BNT162b2 vaccine.

270 : Effect of Vaccination on Household Transmission of SARS-CoV-2 in England.

271 : Effect of Vaccination on Transmission of SARS-CoV-2.

272 : Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection.

273 : Immune correlates analysis of the mRNA-1273 COVID-19 vaccine efficacy clinical trial.

274 : A prospective cohort study of COVID-19 vaccination, SARS-CoV-2 infection, and fertility.

275 : Effects of COVID-19 and mRNA vaccines on human fertility.

276 : Effects of COVID-19 and mRNA vaccines on human fertility.

277 : Effects of COVID-19 and mRNA vaccines on human fertility.

278 : Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination.

279 : Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination.

280 : Thrombotic Thrombocytopenia after Ad26.COV2.S Vaccination.

281 : US Case Reports of Cerebral Venous Sinus Thrombosis With Thrombocytopenia After Ad26.COV2.S Vaccination, March 2 to April 21, 2021.

282 : Clinical Features of Vaccine-Induced Immune Thrombocytopenia and Thrombosis.

283 : Clinical Features of Vaccine-Induced Immune Thrombocytopenia and Thrombosis.

284 : Updated Recommendations from the Advisory Committee on Immunization Practices for Use of the Janssen (Johnson&Johnson) COVID-19 Vaccine After Reports of Thrombosis with Thrombocytopenia Syndrome Among Vaccine Recipients - United States, April 2021.

285 : Updated Recommendations from the Advisory Committee on Immunization Practices for Use of the Janssen (Johnson&Johnson) COVID-19 Vaccine After Reports of Thrombosis with Thrombocytopenia Syndrome Among Vaccine Recipients - United States, April 2021.

286 : Updated Recommendations from the Advisory Committee on Immunization Practices for Use of the Janssen (Johnson&Johnson) COVID-19 Vaccine After Reports of Thrombosis with Thrombocytopenia Syndrome Among Vaccine Recipients - United States, April 2021.

287 : Updated Recommendations from the Advisory Committee on Immunization Practices for Use of the Janssen (Johnson&Johnson) COVID-19 Vaccine After Reports of Thrombosis with Thrombocytopenia Syndrome Among Vaccine Recipients - United States, April 2021.

288 : Use of mRNA COVID-19 Vaccine After Reports of Myocarditis Among Vaccine Recipients: Update from the Advisory Committee on Immunization Practices - United States, June 2021.

289 : Myocarditis Cases Reported After mRNA-Based COVID-19 Vaccination in the US From December 2020 to August 2021.

290 : Myocarditis after BNT162b2 mRNA Vaccine against Covid-19 in Israel.

291 : Myocarditis after Covid-19 Vaccination in a Large Health Care Organization.

292 : Carditis After COVID-19 Vaccination With a Messenger RNA Vaccine and an Inactivated Virus Vaccine : A Case-Control Study.

293 : Myocarditis after BNT162b2 Vaccination in Israeli Adolescents.

294 : SARS-CoV-2 vaccination and myocarditis or myopericarditis: population based cohort study.

295 : SARS-CoV-2 vaccination and myocarditis or myopericarditis: population based cohort study.

296 : Myocarditis after Covid-19 mRNA Vaccination.

297 : Clinically Suspected Myocarditis Temporally Related to COVID-19 Vaccination in Adolescents and Young Adults: Suspected Myocarditis After COVID-19 Vaccination.

298 : Clinically Suspected Myocarditis Temporally Related to COVID-19 Vaccination in Adolescents and Young Adults: Suspected Myocarditis After COVID-19 Vaccination.

299 : Clinically Suspected Myocarditis Temporally Related to COVID-19 Vaccination in Adolescents and Young Adults: Suspected Myocarditis After COVID-19 Vaccination.

300 : Guillain-Barrésyndrome spectrum associated with COVID-19: an up-to-date systematic review of 73 cases.

301 : COVID-19 as a Trigger of Recurrent Guillain-BarréSyndrome.

302 : Neurological complications after first dose of COVID-19 vaccines and SARS-CoV-2 infection.

303 : Association of Receipt of the Ad26.COV2.S COVID-19 Vaccine With Presumptive Guillain-BarréSyndrome, February-July 2021.

304 : Use of COVID-19 Vaccines After Reports of Adverse Events Among Adult Recipients of Janssen (Johnson&Johnson) and mRNA COVID-19 Vaccines (Pfizer-BioNTech and Moderna): Update from the Advisory Committee on Immunization Practices - United States, July 2021.

305 : Guillain-BarréSyndrome Variant Occurring after SARS-CoV-2 Vaccination.

306 : Guillain-BarréSyndrome following ChAdOx1-S/nCoV-19 Vaccine.

307 : Guillain-BarréSyndrome following ChAdOx1-S/nCoV-19 Vaccine.

308 : Guillain-BarréSyndrome following ChAdOx1-S/nCoV-19 Vaccine.

309 : Answering Key Questions About COVID-19 Vaccines.

310 : Answering Key Questions About COVID-19 Vaccines.

311 : Answering Key Questions About COVID-19 Vaccines.

312 : Answering Key Questions About COVID-19 Vaccines.

313 : Answering Key Questions About COVID-19 Vaccines.

314 : Answering Key Questions About COVID-19 Vaccines.

315 : Answering Key Questions About COVID-19 Vaccines.

316 : Answering Key Questions About COVID-19 Vaccines.

317 : Answering Key Questions About COVID-19 Vaccines.

318 : Answering Key Questions About COVID-19 Vaccines.

319 : A global survey of potential acceptance of a COVID-19 vaccine.

320 : COVID-19 Vaccination Intent, Perceptions, and Reasons for Not Vaccinating Among Groups Prioritized for Early Vaccination - United States, September and December 2020.

321 : Public Trust and Willingness to Vaccinate Against COVID-19 in the US From October 14, 2020, to March 29, 2021.

322 : National Trends in the US Public's Likelihood of Getting a COVID-19 Vaccine-April 1 to December 8, 2020.

323 : Cross-sectional Assessment of COVID-19 Vaccine Acceptance Among Health Care Workers in Los Angeles.

324 : Assessment of US Healthcare Personnel Attitudes Towards Coronavirus Disease 2019 (COVID-19) Vaccination in a Large University Healthcare System.

325 : Attitudes Toward a Potential SARS-CoV-2 Vaccine : A Survey of U.S. Adults.

326 : COVID-19 vaccine acceptance among adults in four major US metropolitan areas and nationwide.

327 : COVID-19 vaccine acceptance among adults in four major US metropolitan areas and nationwide.

328 : Monitoring vaccine safety using the Vaccine Safety Datalink: utilizing immunization registries for pandemic influenza.

329 : Surveillance for adverse events following receipt of pandemic 2009 H1N1 vaccine in the Post-Licensure Rapid Immunization Safety Monitoring (PRISM) System, 2009-2010.

330 : Postapproval Vaccine Safety Surveillance for COVID-19 Vaccines in the US.