COVID-19: Vaccines

INTRODUCTION — 

Vaccines to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are considered the most promising approach for curbing the coronavirus disease 2019 (COVID-19) pandemic. Several COVID-19 vaccines are available globally. The World Health Organization (WHO) maintains an updated list of vaccine candidates under evaluation and available for administration [1].

This topic will cover vaccines for SARS-CoV-2, with a focus on vaccines available in the United States. Other aspects related to the 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 (WHO; 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 must give approval before a candidate vaccine can advance to the next phase of evaluation.

●Calculation of vaccine efficacy – Vaccine efficacy in percent is defined as 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 prevent attachment to the host cell and neutralize the virus [3]. Over time, all the approved vaccines have been reformulated to target the mutations in the spike proteins of the various SARS-CoV-2 variants. (See 'Available vaccines' below.)

●Vaccine platforms – COVID-19 vaccines have been and are being developed using several different platforms [3]. Some of these are traditional approaches, such as inactivated virus or live attenuated viruses, which have been used for influenza vaccines and measles vaccines, 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 mRNA and DNA (deoxyribonucleic acid) vaccines, had never been employed in a licensed vaccine prior to the COVID-19 vaccine, although they had been studied for many years. 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 to protect 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 respiratory virus vaccines, however, are administered intramuscularly and elicit primarily a systemic immune response, with less robust protection in the upper respiratory mucosa than after natural infection. Some live-attenuated respiratory virus vaccines can be administered intranasally, approximating natural infection, and these may elicit additional mucosal immune responses, although they typically do not induce as high of a systemic antibody response as systemically administered inactivated vaccines [4,5]. Live-attenuated COVID-19 vaccines administered to the respiratory tract are under development.

●Vaccine-enhanced disease – Animal studies of certain vaccines for SARS-CoV (severe acute respiratory syndrome coronavirus) and MERS-CoV (Middle East respiratory syndrome-related coronavirus) raised concerns for enhanced disease with vaccination when some vaccinated animals developed non-neutralizing antibody and Th2 cell responses that were associated with eosinophilic lung inflammation following challenge with wild-type virus [6-8]. No vaccine-enhanced disease was seen in any human COVID-19 vaccine studies. Nevertheless, specific immunologic parameters were targeted for animal and human studies to reduce the risk of enhanced disease [9]. The desired immune responses included neutralizing antibody and Th1-polarized cellular immune responses.

APPROACH TO VACCINATION IN THE UNITED STATES

Available vaccines — In the United States, the following COVID-19 vaccines are available (table 2):

●Two mRNA vaccines:

•Moderna COVID-19 vaccine (2024-2025 Formula, based on KP.2) – This is approved for individuals 12 years and older and available under emergency use authorization (EUA) for children aged 6 months to 11 years [10,11].

•Pfizer-BioNTech COVID-19 vaccine (2024-2025 Formula, based on KP.2) – This is approved for individuals 12 years and older and available under EUA for children aged 6 months to 11 years [12,13].

Each mRNA vaccine began as a monovalent formulation with an antigenic target based on the original Wuhan SARS-CoV-2 strain. In September 2022, bivalent formulations with antigenic targets based on the original Wuhan SARS-CoV-2 strain and the BA.4/BA.5 Omicron subvariants were also introduced and became the only mRNA COVID-19 vaccine formulations available in April 2023. In September 2023, the bivalent formulations were replaced with a monovalent formulation with an antigenic target based on the XBB.1.5 Omicron variant. In August 2024, the vaccines were updated to target the KP.2 Omicron variant, which is a descendant of the JN.1 sublineage and had been circulating in summer and early fall 2024 [14]. Variants circulating in 2025 are also descendants of the JN.1 sublineage (table 3).

●An adjuvanted recombinant protein vaccine

•Novavax COVID-19 vaccine, adjuvanted (2024-2025 Formula, based on JN.1) – This is available under EUA for individuals aged 12 years or older [15], and licensure is pending FDA approval. The Novavax COVID-19 vaccine was previously available as a monovalent formulation with an antigenic target based on the original Wuhan SARS-CoV-2 strain and subsequently updated to target the XBB.1.5 Omicron variant. In August 2024, the vaccine was again updated to target the JN.1 Omicron variant, which had been circulating in summer and early fall 2024.

Indications and vaccine selection — We suggest vaccination with a 2024-2025 formula COVID-19 vaccine for all individuals aged six months and older; this is consistent with recommendations from the Centers for Disease Control and Prevention (CDC). We particularly encourage vaccination in individuals 65 years or older, immunocompromised individuals, and individuals with multiple medical comorbidities, as they are at highest risk of severe outcomes with COVID-19 and are most likely to benefit from vaccination (table 4). In the United States, the available vaccines are the Moderna COVID-19 vaccine 2024-2025 Formula, the Pfizer COVID-19 vaccine 2024-2025 Formula, and the Novavax COVID-19 vaccine 2024-2025 Formula (table 2). The CDC provides online clinician and patient resources for all seasonal respiratory viral vaccinations.

Vaccines available in the United States reduce the risk of COVID-19, especially severe/critical disease, and have been associated with substantial reductions in COVID-19-associated hospitalizations and deaths [16-23], even in the context of variants that partially evade vaccine-induced immune responses. The vaccines are safe, with only very rare associated severe adverse events [24]. The benefits and potential risks of vaccines are discussed elsewhere. (See 'Benefits of vaccination' below and 'Risks of vaccination' below.)

Although the risk of severe disease has decreased substantially since the start of the pandemic, COVID-19 remains an important cause of hospitalization and death, with the highest rates in individuals older than 65 years or younger than six months. In hospitalized patients, COVID-19 is associated with similar or higher rates of intensive care unit (ICU) admission and death compared with influenza [25,26]. Although most individuals with COVID-19-associated hospitalization have medical comorbidities (and most hospitalized adults have multiple comorbidities), approximately 40 to 60 percent of hospitalized children aged six months to four years had no underlying conditions, and 15 to 50 percent of those aged 6 months to 49 years admitted to the ICU had no underlying conditions. Thus, although the potential benefit of COVID-19 vaccination in reducing the risk of severe disease is greatest in those at highest risk, the risk of severe disease exists for all individuals.

Dose and interval (for immunocompetent individuals) — Vaccine dosing and intervals are also listed in the table (table 2). Recommended vaccine schedules for individuals with immunocompromising conditions are discussed elsewhere. (See 'Immunocompromised individuals' below.)

Children aged six months to four years — For children under five years of age, the CDC recommends 2024-2025 formula mRNA vaccines for all vaccine doses (algorithm 1) [27]. The dosing schedule depends on their prior COVID-19 vaccination status.

●For immunocompetent children who have not previously received a COVID-19 vaccine:

•Moderna COVID-19 vaccine (2024-2025 Formula) – Two intramuscular doses of 25 mcg (0.25 mL) given four to eight weeks apart [11].

•Pfizer COVID-19 vaccine (2024-2025 Formula) – Three intramuscular doses of 3 mcg (0.3 mL of the yellow capped vial) [13]. The first two doses are given three to eight weeks apart, and the third dose is given at least eight weeks after the second.

●For immunocompetent children who have previously received at least one vaccine dose, the number of subsequent doses with the 2024-2025 formula mRNA vaccines depends on how many doses and which vaccine they had previously received:

•Prior Moderna COVID-19 vaccine doses (that are not the 2024-2025 Formula) [11]:

-Those who have received a single prior dose receive a single intramuscular dose of 25 mcg (0.25 mL) Moderna COVID-19 vaccine (2024-2025 Formula) four to eight weeks later.

-Those who have received two or more prior doses receive a single intramuscular dose of 25 mcg (0.25 mL) Moderna COVID-19 vaccine (2024-2025 Formula) at least eight weeks after the last dose.

•Prior Pfizer COVID-19 vaccine doses (that are not the 2024-2025 Formula) [13]:

-Those who have received a single prior dose receive two intramuscular doses of 3 mcg (0.3 mL of the yellow-capped vial) Pfizer COVID-19 vaccine (2024-2025 Formula): one dose three to eight weeks after the last dose and a second dose at least eight weeks later.

-Those who have received two or more prior doses receive a single intramuscular dose of 3 mcg (0.3 mL of the yellow-capped vial) Pfizer COVID-19 vaccine (2024-2025 Formula). It is given at least eight weeks after the last dose.

Immunocompetent children in this age group who have received at least two doses of Moderna COVID-19 vaccine, at least one of which is the 2024-2025 formula mRNA vaccine, or at least three doses of Pfizer COVID-19 vaccine, at least one of which is the 2024-2025 formula mRNA vaccine, do not need additional vaccinations. All vaccine doses should be from the same manufacturer [27].

Vaccine recommendations for children with immunocompromising conditions (table 5) are discussed in detail elsewhere [27]. (See 'Immunocompromised individuals' below.)

Clinical data evaluating COVID-19 vaccine effectiveness in young children are limited. Support for their use comes mainly from immunogenicity bridging studies, some unpublished, in these age groups. (See 'Children' below.)

Although a single mRNA vaccine dose is recommended for other age groups, serologic surveillance suggests that young children in the United States are less likely to have pre-existing immunity (whether from infection or vaccination) than older children and adults, so they may be more likely to need more than one dose to maximize immunogenicity [28]. Additionally, a prime-boost model of vaccination in general is considered important for optimizing vaccine response in young children.

Children aged 5 to 11 years — For children aged 5 to 11 years, the CDC recommends a single dose of a 2024-2025 formula mRNA vaccine, regardless of whether the recipient is unvaccinated or had previously received one or more other COVID-19 vaccine doses (algorithm 1) [27]. If the individual had received prior vaccine doses, the 2024-2025 formula vaccine dose is given at least two months after the last dose:

●Moderna COVID-19 vaccine (2024-2025 Formula) – A single intramuscular dose of 25 mcg (0.25 mL) [10].

●Pfizer COVID-19 vaccine (2024-2025 Formula) – A single intramuscular dose of 10 mcg (0.3 mL of the blue-capped vial) [12].

Vaccine recommendations for children with immunocompromising conditions (table 5) are discussed in detail elsewhere [27]. (See 'Immunocompromised individuals' below.)

Prior recommendations had included a two-dose vaccine series for unvaccinated individuals. However, seroprevalence data suggest that the vast majority (over 96 percent) of individuals in the United States have pre-existing immunity to SARS-CoV-2, either through vaccination or infection [28]. Thus, a single vaccine dose, which has been associated with increases in relative effectiveness against infection and severe disease in individuals with pre-existing immunity from prior vaccination, is expected to be sufficient to improve protection for immunocompetent individuals who have not yet been vaccinated. (See 'Protection against severe disease or death' below.)

Rationale for vaccination in children is discussed elsewhere. (See 'Children' below.)

Adolescents and adults aged 12 to 64 years — For immunocompetent individuals 12 to 64 years of age or older, the CDC recommends a single dose of a 2024-2025 formula vaccine, regardless of whether the recipient is unvaccinated or had previously received one or more vaccine doses (algorithm 1) [27]. If the individual had previously received other COVID-19 vaccine doses, the 2024-2025 formula vaccine dose is given at least two months after the last dose:

●Moderna COVID-19 vaccine (2024-2025 Formula) – A single intramuscular dose of 50 mcg (0.5 mL) [10].

●Pfizer COVID-19 vaccine (2024-2025 Formula) – A single intramuscular dose of 30 mcg (0.3 mL) [12].

●Novavax COVID-19 vaccine (2024-2025 Formula) – A single intramuscular dose of 5 mcg spike protein/50 mcg adjuvant [15]. For individuals who have not previously received any COVID-19 vaccine, a second dose is given three to eight weeks later.

Vaccine recommendations for individuals with immunocompromising conditions (table 5) are discussed in detail elsewhere [27]. (See 'Immunocompromised individuals' below.)

Although prior recommendations had included a two-dose primary series of the mRNA vaccines for unvaccinated individuals, seroprevalence data suggest that the vast majority (over 96 percent) of individuals in the United States have pre-existing immunity to SARS-CoV-2, either through vaccination or infection [29,30]. Thus, a single mRNA vaccine dose, which has been associated with increases in relative effectiveness against infection and severe disease in individuals with pre-existing immunity from prior vaccination, is expected to be sufficient to improve protection in immunocompetent individuals without a history of COVID-19 vaccination. Recommendations for the Novavax vaccine are different (two doses are recommended for previously unvaccinated individuals), pending US Food and Drug Administration (FDA) reassessment.

Among individuals who have already been vaccinated, the rationale for an additional updated vaccine dose is to restore protection that wanes with time and to try to improve the immune response against currently circulating viral variants. (See 'Protection against severe disease or death' below.)

Adults aged 65 years and older — For individuals 65 years and older, the CDC recommends two doses of a 2024-2025 formula vaccine, regardless of whether the recipient is unvaccinated or had previously received one or more vaccine doses (algorithm 1) [27].

●Moderna COVID-19 vaccine (2024-2025 Formula) – Two intramuscular doses of 50 mcg (0.5 mL); the second is given approximately six months (and a minimum of two months) after the first [10].

●Pfizer COVID-19 vaccine (2024-2025 Formula) – Two intramuscular doses of 30 mcg (0.3 mL); the second is given approximately six months (and a minimum of two months) after the first [12].

●Novavax COVID-19 vaccine (2024-2025 Formula) – Two intramuscular doses of 5 mcg spike protein/50 mcg adjuvant; the second is given approximately six months (and a minimum of two months) after the first [15]. For individuals who had not previously received any COVID-19 vaccine, three doses of Novavax vaccine are recommended (with the second given at least three weeks after the first and the third given approximately six months and a minimum of two months after the second).

Vaccine recommendations for individuals with immunocompromising conditions (table 5) are discussed in detail elsewhere [27]. (See 'Immunocompromised individuals' below.)

Among persons ≥65 years old, the rate of COVID-19-associated hospitalization and death is higher than in any other age group [31]. According to preliminary evidence presented to the CDC, this age group accounted for approximately 70 percent of hospitalizations and 80 percent of in-hospital deaths related to COVID-19 between late 2023 and mid-2024 [32]. Given the disproportionate burden of severe disease in this population, a second 2024-2025 vaccine dose is recommended; the intention is to improve protection by restoring an immune response that wanes with time and by improving the response against currently circulating viral variants. Booster doses have been associated with increases in relative effectiveness against both infection and severe disease, as discussed in detail elsewhere. (See 'Protection against severe disease or death' below.)

Other administration issues

Technique and potential administration errors — 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 3). (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 6).

Mixing vaccine types — For individuals six years of age and older who had previously received an older monovalent or bivalent vaccine, any of the 2024-2025 formula vaccines that are approved for the individual’s age group can be subsequently used; they do not have to use the vaccine from the same manufacturer as the original doses. (See 'Dose and interval (for immunocompetent individuals)' above.)

Timing with relation to non-COVID-19 vaccines — The CDC specifies that COVID-19 vaccines can be administered at any time in relation to most other non-COVID-19 vaccines and, if needed, can be administered simultaneously with other vaccines [27].

●Coadministration – 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). Data suggest that coadministration of COVID-19 vaccines with other vaccines is safe [33]. In a randomized trial, frequency of adverse effects and immunogenicity were largely similar when a COVID-19 vaccine was given concomitantly with either an influenza vaccine or placebo [34].

●Additional considerations with orthopoxvirus vaccination – For individuals who have received an orthopoxvirus vaccine to prevent mpox (formerly known as monkeypox), particularly adolescent or young adult males, the CDC suggests that it is reasonable to defer COVID-19 vaccination for four weeks because of the uncertain risk of myocarditis with closely spaced administration [27]. However, recent COVID-19 vaccination should not delay orthopoxvirus vaccination if indicated, given the potential health burden of mpox in the at-risk population.

Limited role for post-vaccination testing — 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'.)

However, 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 of days following vaccination or that last several days could be indicative of COVID-19 and warrant testing. (See "COVID-19: Diagnosis", section on 'Choosing an initial diagnostic test'.)

Additional considerations for 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 [27].

●Timing of vaccination – Individuals with recent, documented SARS-CoV-2 infection (including those who are diagnosed after initiating a vaccine series) should have at least recovered from acute infection and met criteria for discontinuation of isolation precautions before receiving a vaccine dose. Additionally, given the low risk of reinfection soon after prior infection, it is reasonable for individuals with SARS-CoV-2 infection to wait to receive a vaccine dose until three months after infection [27]. Potential reasons not to delay the vaccine dose in this population include high risk for severe infection, high rates of community transmission, and circulating variants associated with a high risk of reinfection. (See 'Other administration issues' above.)

●Individuals with a history of MIS – 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, are at increased risk for SARS-CoV-2 exposure, and if the MIS was not associated with COVID-19 vaccination [27]. In a study of 186 individuals ≥5 years old with a history of MIS ≥90 days prior to vaccine receipt, the side effect profile of mRNA vaccination was similar to that in the general population; no cases of myocarditis or recurrent MIS were observed [35].

Vaccination is still beneficial despite prior SARS-CoV-2 infection. Vaccination appears to further boost antibody levels and cell-mediated responses in those with past infection and likely improves the durability and breadth of protection [36-38]. In multiple observational studies of individuals with prior infection, vaccination has been associated with a lower risk of subsequent reinfection and hospitalization [39-46]; it has also been associated with a lower risk of breakthrough infection and severe disease compared with vaccination in individuals without prior infection [47-49].

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 [50].

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 [27,51,52]. This is not a contraindication or precaution for subsequent vaccine doses.

Immunocompromised individuals — We recommend that individuals who have an immunocompromising condition or are taking immunosuppressive agents undergo COVID-19 vaccination (table 5). 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. Given the potential for reduced vaccine response in such individuals, the recommended vaccine schedule is modified, as outlined below:

●Conditions that warrant an adjusted vaccine schedule – Moderate to severe immunocompromising conditions that warrant a modified vaccine schedule include active use of chemotherapy for cancer, hematologic malignancies, hematopoietic stem cell or solid organ transplant, advanced HIV (human immunodeficiency virus) infection with CD4 cell count <200 cells/microL or untreated HIV, moderate or severe primary immunodeficiency disorder, and use of immunosuppressive medications (eg, mycophenolate mofetil, rituximab, prednisone >20 mg/day for >14 days) (table 5) [53]. This list is not exhaustive, however; other conditions, such as impaired splenic function [54], may also warrant additional vaccine doses than recommended in the general population.

Data suggest that COVID-19 vaccines are effective in many immunocompromised patients, even in the context of the Omicron variant, although they are less so than in individuals without compromised immune systems [55-59]. In a cohort study of over one 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 [60]. Lower vaccine effectiveness against hospitalization for COVID-19 in immunocompromised patients has also been suggested by smaller case-control studies [55]. In studies of individuals hospitalized with COVID-19 despite vaccination, a high proportion (eg, 40 percent) have been immunocompromised [61].

In particular, transplant recipients and individuals taking B cell-depleting agents (particularly within the prior six months) may have a suboptimal vaccine response [57,62-67]. Among transplant recipients, factors associated with a higher rate of nonresponse include use of antimetabolites (eg, mycophenolate mofetil, azathioprine) and a shorter time since transplantation. (See "COVID-19: Issues related to solid organ transplantation", section on 'Vaccination'.)

●Recommended vaccine series in immunocompromised individuals – The CDC recommends that individuals with moderate to severe immunocompromising conditions (table 5) receive at least three vaccine doses, at least one of which is a 2024-2025 formula mRNA vaccine (Moderna COVID-19 vaccine 2024-2025 Formula or Pfizer COVID-19 vaccine 2024-2025 Formula) (algorithm 1). For individuals aged 12 years and older, the Novavax COVID-19 vaccine (2024-2025 Formula) is another option. Initial vaccine recommendations depend on the vaccination history:

•Unvaccinated individuals should receive an “initial series” with two or three 2024-2025 formula vaccine doses.

-If Moderna COVID-19 vaccine is used, the second dose is given four weeks after the first and the third is given at least four weeks later.

-If Pfizer COVID-19 vaccine is used, the second dose is given three weeks after the first, and the third is given at least eight weeks later (for individuals six months to four years of age) or at least four weeks later (for individuals five years of age and older).

-If Novavax COVID-19 vaccine is used, the second dose is given three weeks after the first.

•Individuals who have received only one previous vaccine dose should receive one or two 2024-2025 formula vaccine doses.

-If Moderna COVID-19 vaccine is used, the first 2024-2025 formula dose is given four weeks after the last vaccine dose, and the second 2024-2025 formula dose is given at least four weeks later.

-If Pfizer COVID-19 vaccine is used, the first 2024-2025 formula dose is given three weeks after the last vaccine dose, and the second 2024-2025 formula dose is given at least eight weeks later (for individuals six months to four years of age) or at least four weeks later (for individuals five years of age and older).

-If Novavax COVID-19 vaccine is used, the first 2024-2025 formula dose is given three weeks after the last vaccine dose.

•Individuals who have received two or more previous vaccine doses should receive one 2024-2025 formula vaccine dose.

-For those who received two prior vaccine doses, the 2024-2025 formula vaccine dose is given at least four weeks after the last dose.

-For those who received three or more prior vaccine doses, the 2024-2025 formula vaccine dose is given at least eight weeks after the last dose.

The specific dose given for each vaccine depends on the age of the individual and is the same as for individuals without immunocompromising conditions (table 2).

Support for multiple vaccine doses for individuals with immunocompromising conditions comes from multiple observational studies in which receipt of three doses of mRNA monovalent vaccines was associated with higher vaccine effectiveness than two doses [68,69]. In studies of transplant recipients who received a third dose of mRNA monovalent vaccines, seroconversion rates were higher after the additional dose, although approximately 50 to 70 percent who were seronegative after two doses remained seronegative after the third dose; adverse effects were similar to those reported after prior doses [70-74]. 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 [75].

●Additional vaccine doses in individuals who have received an initial series, including at least one 2024-2025 formula vaccine dose – For individuals with moderate to severe immunocompromising conditions (table 5) who have received the vaccines recommended above, the CDC suggests an additional 2024-2025 formula vaccine dose approximately six months (and a minimum of two months) after the first [27]. The CDC also allows for additional, subsequent 2024-2025 formula vaccine doses at least two months after the last. For such patients, we individualize the decision to administer additional doses beyond the second 2024-2025 formula vaccine dose and are more likely to suggest them for individuals with expected high risk of exposure and profound immunosuppression (such as B cell depletion, recent or complicated hematopoietic stem cell transplant [HCT], or chimeric antigen receptor [CAR]-T cell therapy). The clinical effect of multiple 2024-2025 formula vaccines is uncertain, and data are limited. The rationale is that, in such patients, repeated vaccination can boost the immune response. (See 'Protection against severe disease or death' below.)

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

●Revaccination following certain immunosuppressing therapies – For those who received COVID-19 vaccination prior to hematopoietic stem cell transplant (HCT) or chimeric antigen receptor (CAR)-T cell therapy, the CDC recommends repeat vaccination (with a full series) at least three months after the transplant or CAR-T administration [27]. For those who were vaccinated during a limited course of a B cell-depleting therapy, repeat vaccination is suggested six months following therapy. (See "Immunizations in hematopoietic cell transplant candidates, recipients, and donors", section on 'COVID-19'.)

●Continued use of protective measures – We advise immunocompromised patients to maintain personal measures to try to minimize exposure to SARS-CoV-2 (eg, avoiding crowds when possible, masking if the likelihood of exposure is high) 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 to reduce exposing immunocompromised persons to the virus.

●Limited role for post-vaccination serology – At this time, antibody testing is not recommended to determine response to vaccination [27]. Although undetectable anti-spike antibodies in immunocompromised patients with a history of vaccination has been associated with a higher rate of COVID-associated hospitalization in one study [77], precise immune correlates of protection against severe disease remain uncertain. Vaccination may elicit cellular but not humoral responses among some immunocompromised patients, and those responses may protect against severe infection [78]. Furthermore, heterogeneity in the sensitivity and specificity of available serologic tests complicates interpretation of results. (See 'Antibody responses and immune correlates of protection' below and 'Limited role for post-vaccination testing' above.)

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 inborn errors of immunity".)

Pregnant individuals — Vaccine recommendations for the general population extend to pregnant individuals as well. Data on safety and efficacy of 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. Dosing in children depends on age and is discussed elsewhere. (See 'Dose and interval (for immunocompetent individuals)' above.)

●Benefits of COVID-19 vaccination in children – COVID-19 vaccination is associated with reductions in severe adverse outcomes related to COVID-19 among children and adolescents. Randomized trials demonstrated that antibody responses to the mRNA vaccines in children six months and older are as high as (or higher than) those in older individuals [79-84]. Efficacy data from these trials were limited, in part because of the low number of COVID-19 cases among study participants. However, subsequent observational studies suggest that vaccination is associated with reductions in COVID-19-related hospitalization, ICU admission, and death in adolescents, and reductions in hospitalization in younger school-aged children [85-99]. As an example, in a meta-analysis of 17 studies that included over 11 million vaccinated and 2.5 million unvaccinated children between 5 and 11 years old, COVID-19 vaccination was associated with lower rates of COVID-19 associated hospitalization (OR 0.32) and MIS (OR 0.05) [96]. Limited observational data suggest that vaccination is also associated with reductions in symptomatic, medically attended, and severe infection among children younger than five years old [100-103]. As in adults, vaccine effectiveness in children of all ages wanes over time [94]. (See 'Benefits of vaccination' below.)

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 their vaccination [104]. Furthermore, even with the lower risk of severe disease among children, the number of COVID-19 deaths among those 6 months to 18 years old during the pandemic (even during 2022 when disease severity was lower) exceeded the prevaccination era mortality rates of infections for which childhood vaccines are routinely recommended (eg, rotavirus, meningococcal disease, varicella) [105].

●Risks and concerns in children – The safety profile of COVID-19 vaccines in children is similar to that in older individuals; mild local and systemic reactions are common but serious adverse events are rare. (See 'Risks of vaccination' below.)

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. However, data suggest that the risk is not higher than baseline [106]. No cases of myocarditis thought related to vaccine were reported in the trials of the mRNA vaccines in young children [107,108]. In a review of the Vaccine Adverse Event Reporting System (VAERS) following administration of approximately 8.7 million doses of Pfizer COVID-19 vaccine to children aged 5 to 11 years in the United States, there were 11 verified reports of myocarditis in this age group [109]; no cases were reported following 1.5 million doses among children six months to five years of age [110]. As with other reported cases of mRNA COVID-19 vaccine-associated myocarditis, most cases were mild and of short duration. The benefits of COVID-19 vaccination in children are considered to exceed this risk [111,112]. (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 were another concern. Vaccine trials in this age group have not identified a potential signal, although rare case reports of MIS in children and adults following vaccination highlight the importance of monitoring for this possible adverse effect [113-115]. Nevertheless, evidence suggests that vaccination may protect against MIS-C [116,117]. In a study of 102 patients aged 12 to 18 years hospitalized with MIS-C, 95 percent were unvaccinated; of the five patients with MIS-C who had previously received primary series of Pfizer COVID-19 vaccine, none required invasive respiratory or cardiovascular support [117]. 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 Advisory Committee on Immunization Practices (ACIP)-approved vaccines for eligible children through 18 years of age [118,119]. Eligible children include those on Medicaid, those who are completely uninsured, and American Indian/Alaskan Natives. Approximately 50 percent of United States children are covered by the VFC. In addition, federal grants to states can be used to purchase vaccines to cover other children.

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. Local and systemic side effects may reflect a robust immune response, as some studies suggest that recipients who report symptoms have slightly higher or longer-lasting post-vaccination antibody levels than those who did not [120-122]. Nevertheless, almost all immunocompetent recipients develop sufficiently high antibody levels, regardless of side effects. Among mRNA vaccines, Pfizer COVID-19 vaccine may be associated with slightly lower rates of local and systemic reactions compared with mRNA-1273 [123]. Rates of reactions for the distinct vaccines are discussed in detail elsewhere. (See 'Common adverse effects' 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 [27]. 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 [124,125]. Aspirin is not recommended for individuals ≤18 years old because of the risk of Reye syndrome.

●Syncope – Syncope has been reported following receipt of other injectable vaccines, particularly among adolescents and young adults [126]. Monitoring individuals who have previously had syncope or may be at higher risk (eg, adolescents) for 15 minutes following COVID-19 vaccine receipt 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. These issues and safety concerns with other COVID-19 vaccines are discussed in detail elsewhere. (See 'Rare but serious associated events' 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 venous thromboembolic events without thrombocytopenia, deep vein thrombosis or pulmonary embolism, Bell palsy, and tinnitus) have been reported in adenoviral vector vaccine recipients but have not been identified as causally related vaccine-associated adverse events with the other vaccines. (See 'Other reactions (without established association)' below.)

Contraindications and precautions (including allergies)

●Contraindications – The following are the only contraindications to COVID-19 vaccination [27]:

•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 and do not represent a contraindication to vaccine.

●Precautions – Precautions to a specific COVID-19 vaccine include 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.

•Allergy-related contraindication to one type of COVID-19 vaccine is a precaution to other types of COVID-19 vaccine because of potential cross-reactive hypersensitivity.

The mRNA vaccines, Pfizer-BioNTech COVID-19 vaccine and Moderna COVID-19 vaccine, each contain polyethylene glycol (PEG). However, it is a smaller molecular weight and less allergenic PEG than that present in other products, and multiple studies have documented safe receipt of the mRNA vaccines in individuals with known or suspected allergy to other PEG-containing products. The Novavax COVID-19 vaccine contains polysorbate, which is structurally related to PEG. Allergic reaction to polysorbate remains listed as a contraindication to Novavax COVID-19 vaccine and a precaution to mRNA vaccines. These issues are discussed in detail elsewhere.

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. Many individuals with apparent anaphylaxis after COVID-19 vaccination were able to receive a subsequent dose uneventfully after the reaction was determined not to be immunoglobulin E (IgE)-mediated. This is discussed in detail elsewhere.

Caution is also warranted for those with a history of myocarditis or pericarditis following a COVID-19 vaccine, MIS-C, or Guillain-Barré syndrome (GBS). These issues are discussed elsewhere. (See 'Myocarditis' below and 'History of SARS-CoV-2 infection' above.)

Caution may be warranted prior to administering any vaccine in certain rare but life-threatening conditions, such as acquired thrombotic thrombocytopenic purpura and capillary leak syndrome, exacerbations of which have been reported following COVID-19 vaccination [127,128]. (See "Immune TTP: Management after recovery and treatment of refractory or relapsed disease", 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 with mRNA vaccines or Novavax COVID-19 vaccine. Although very rare cases of unusual types of thrombosis associated with thrombocytopenia have been reported following vaccination with certain adenoviral vector vaccines (which are no longer available in the United States), 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 [129], and individuals with these can receive any approved or authorized COVID-19 vaccine. (See "Virus-induced immune thrombotic thrombocytopenia (VITT) and VITT-like disorders", section on 'History and terminology'.)

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 one week after mRNA COVID-19 vaccination have been reported, with recurrence occurring in some individuals after repeat vaccination [130]. This may occur more frequently with Moderna COVID-19 vaccine than with Pfizer COVID-19 vaccine [131]. 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 [27]. (See "COVID-19: Cutaneous manifestations and issues related to dermatologic care", section on 'Cutaneous adverse events'.)

●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 [27]. 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 'Cutaneous adverse events'.)

●Anticoagulation is not a contraindication to vaccination; excess bleeding is unlikely with intramuscular vaccines in patients taking anticoagulants [132]. 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:

●Allergy-related contraindication to a different type of COVID-19 vaccine (see 'Contraindications and precautions (including allergies)' above)

●Nonsevere, immediate (onset within four hours) allergic reaction after a previous dose of COVID-19 vaccine

●History of anaphylaxis after non-COVID-19 vaccines or injectable therapies

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. (See "Anaphylaxis: Acute diagnosis" and "Anaphylaxis: Emergency treatment" and 'Ongoing safety assessment and reporting of adverse events' below.)

APPROACH TO VACCINATION IN 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/.

Dosing schedules vary by vaccine. Additionally, different countries may have specific recommendations for vaccine use. Clinicians should refer to local guidelines for vaccine recommendations in their location. (See 'Society guideline links' below.)

BENEFITS OF VACCINATION

Protection against severe disease or death — Vaccines available in the United States reduce the risk of severe or critical COVID-19 and have been associated with substantial reductions in COVID-19-associated hospitalizations and deaths [16-23,133], even in the context of variants that partially evade vaccine-induced immune responses. Booster doses have been associated with restoration of vaccine effectiveness against severe infection that wanes over time. Hospitalization and mortality rates for COVID-19 have been consistently higher among unvaccinated compared with vaccinated individuals, particularly in those who received a vaccine dose within the several months preceding [134]. In addition to direct reductions in COVID-19-associated morbidity and mortality, vaccination has been associated with lower non-COVID-19 mortality rates as well [135]. However, observed vaccine effectiveness has declined since the beginning of the pandemic. In addition to the impact of viral evolution and waning immunity, this observation may be related to overall decreases in the baseline risk of severe infection because of a higher prevalence of prior infection (which also provides protection against severe infection) as well as variants more associated with milder infection.

●Risk reduction compared with no vaccination – The large randomized trials evaluating the mRNA vaccines (the Pfizer COVID-19 vaccine and the Moderna COVID-19 vaccine) and the Novavax COVID-19 vaccine demonstrated 96 to 100 percent vaccine efficacy against severe infection; however, rates of severe infection in these trials were very low [136-140]. Most data demonstrating reductions in severe disease and death with vaccination are from large observational and population-based studies [16-23,133].

As an example, in a study that evaluated over 8000 COVID-19-associated deaths in the United States between September 2022 and April 2023, receipt of vaccination, including a booster dose, was consistently associated with lower mortality compared with no vaccination; without vaccination, the risk of death was 7.3 to 16.3 times greater, depending on the prevalent Omicron sublineage [139]. In another study of statewide data in North Carolina that included over 10 million adults, adjusted mRNA vaccine effectiveness at seven months following the primary series was 86 to 90 percent against hospitalization and 90 to 93 percent against death [140]. At 12 months, the same measures were 60 to 65 percent and 70 to 75 percent.

A history of vaccination has also been associated with lower rates of myocardial infarction, acute stroke, and other major adverse cardiovascular/thromboembolic outcomes in patients with COVID-19 [141-144].

●Risk of severe disease among vaccinated individuals – Among vaccinated individuals, the overall risk of severe COVID-19 is low [141,145-148]. In a study of over one 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 [148]. Risk factors for severe COVID-19 after vaccination are similar to those for unvaccinated individuals: older age (>65 years), immunocompromising conditions, and multiple comorbidities [148-150].

●Impact of variants and time since vaccination (and effect of booster doses) – Vaccine effectiveness against severe disease wanes with time since the last vaccination, although the levels of protection against hospitalization and death are higher and sustained for longer than protection against symptomatic infection [151-158]. Booster doses, both with monovalent and bivalent vaccines, have consistently been associated with greater protection against severe disease compared with more remote vaccination, although the effect of boosting also wanes over time [140,159-173]. The pace and degree of waning following primary and booster vaccinations have varied across studies, however, and waning may be faster in the setting of Omicron compared with other variants [174-183]. In a systematic review of observational studies evaluating protection against hospitalization after emergence of the Omicron variants, pooled vaccine effectiveness following a booster dose was 89 percent in the first month and 71 percent by four to six months [184]. However, in another study of over 65,000 hospitalized adults during Omicron prevalence in the United States, vaccine effectiveness (which included a bivalent booster vaccine dose) against COVID-19-associated hospitalization compared with no vaccination waned from 62 percent during the first 60 days after the vaccine dose to 24 percent three to six months later [185].

Data specific to the 2023-2024 vaccines (which targeted the spike protein of the Omicron subvariant XBB.1.5) also indicated protection against severe COVID-19, even in the context of other Omicron subvariants that emerged following XBB.1.5 [186-190]. As an example, in a study from the United States, vaccine efficacy of a single 2023-2024 formulation vaccine against hospitalization and urgent visits was approximately 50 percent up to four months following receipt [187]. However, the 2023-2024 formulations are less effective against the JN.1 variant (and its descendant variants) that emerged in mid-2024 [188,191], and some data suggested more modest efficacy by four months (ie, 16 percent) [192]. Data on the 2024-2025 formulations are limited but also suggest protection against hospitalization among adults ≥65 years of age [193].

Protection against symptomatic infection — Although the initial clinical trials reported extremely high efficacy rates with the Pfizer COVID-19 vaccine (90 to 100 percent [79,80,136,194-196]), the Moderna COVID-19 vaccine (86 to 100 percent [107,137,197]), and the Novavax COVID-19 vaccine (80 to 90 percent [138,198,199]) in preventing laboratory-confirmed symptomatic infection within the first two months of infection, their observed effectiveness against infection has decreased over time because of waning immunity and immune evasion by the emergence of certain circulating SARS-CoV-2 variants.

●Impact of variants and time since vaccination (and effect of booster doses) – Multiple observational studies have consistently suggested that recent vaccination reduces the risk of symptomatic infection over a few months, but protection against symptomatic infection is lower with Omicron than with previous variants and wanes over time in children and adults (after both primary series and booster vaccinations and with both monovalent and bivalent vaccines) [200-213]. In a systematic review of 40 studies evaluating vaccine effectiveness since the emergence of the Omicron variant, pooled estimates for vaccine efficacy against symptomatic disease decreased from 53 to 14 percent at one and six months after completing the primary vaccine series; a booster dose was associated with restoration of effectiveness, although this also waned to <20 percent after nine months [211]. The estimated half-life of vaccine effectiveness was 111 days.

The relative effects of booster doses to temporarily restore vaccine effectiveness against infection are greater in the few months following the booster dose and if more time has elapsed since the prior vaccine dose [85,162,164,167,169,171,214-220]. As an example, in a study in the United States of over 250,000 symptomatic individuals who were tested for SARS-CoV-2 and had received two to four doses of monovalent vaccines, vaccine effectiveness of an additional booster dose (with a bivalent vaccine) against symptomatic COVID-19 was greater if more time had elapsed between the last vaccine dose and the additional booster (28 to 31 percent if the interval was two to three months versus 43 to 56 percent if it was more than eight months) [214].

Updating a vaccine to better match the antigenic target with circulating variants is presumed to be associated with a boost in effectiveness against symptomatic infection, although this is likely short-lived as well. (See 'Antibody responses and immune correlates of protection' below.)

●Impact on character and duration of breakthrough infection (including risk of long-COVID-19) – Multiple observational studies suggest that breakthrough infection in vaccinated individuals is associated with fewer and shorter duration of symptoms, a lower likelihood of "long COVID-19" (otherwise unexplained symptoms that persist at least two to three months after infection), and a higher likelihood of asymptomatic infection compared with infection in unvaccinated individuals [221-229]. (See "COVID-19: Clinical presentation and diagnosis of adults with persistent symptoms following acute illness ("long COVID")", section on 'Vaccination'.)

Impact on transmission risk — Widespread vaccination reduces the overall transmission risk since vaccinated individuals are less likely to become infected. Data accumulated prior to the emergence of the Omicron variant also suggested that individuals who developed infection despite vaccination may be less likely to transmit to others [230-235].

Vaccination may also reduce the likelihood of transmission in the setting of Omicron infection [236-238]. In a study of individuals in a state prison system in the United States conducted when BA.1 and BA.2 Omicron subvariants were dominant, the overall secondary attack rate from 1126 index SARS-CoV-2 cases to their cellmates was 30 percent [236]. The risk of transmission from index cases who had been vaccinated was compared with index cases who had neither vaccination nor previous infection (22 percent lower in those with vaccination without prior infection and 40 percent lower in those with both vaccination and prior infection). The risk of transmission from vaccinated individuals was lower following booster vaccination than primary series alone. Prior infection alone was also associated with a lower transmission risk.

Comparative efficacy between vaccine types — Although precise comparative efficacy is uncertain because the different vaccines have not been compared head to head in clinical trials, limited evidence from observational studies suggests that Moderna COVID-19 vaccine may be slightly more effective than Pfizer COVID-19 vaccine [239-246]. However, it is unclear whether the difference is clinically significant. As an example, in a study from the United States that compared over 400,000 veterans who received one of the two mRNA vaccines, Moderna COVID-19 vaccine 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) [241]. Safety of the mRNA vaccines in the same cohort was largely comparable, with only small differences in serious adverse events of uncertain clinical significance [247].

Because it has not been available for as long as the other vaccines, data on Novavax COVID-19 vaccine are more limited, although large, randomized trials support its safety and efficacy.

Antibody responses and 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 [248,249]. Data from these studies can help assess likely efficacy of new vaccines or formulations (eg, with new antigenic targets) 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 the clinical trials. Furthermore, the immune correlates of protection against severe infection have not been fully elucidated. Vaccine- or infection-induced cellular immunity often appears robust against variants that escape antibody binding, and this may contribute to the reduced risk of severe disease from such variants [250-253].

Using COVID-19 vaccines with altered spike targets to more closely match circulating SARS-CoV-2 variants is analogous to updating the seasonal influenza vaccine each year; influenza vaccines are made available globally based on immunogenicity studies prior to repeated clinical evaluation because of extensive experience with the preceding versions.

RISKS OF VACCINATION

Common adverse effects — Local and systemic adverse effects are relatively common with the mRNA vaccines (Pfizer COVID-19 vaccine and Moderna COVID-19 vaccine) and the recombinant Novavax COVID-19 vaccine. Most are of mild or moderate severity (ie, do not prevent daily activities or require pain relievers) and are limited to the first two to three days after vaccination [123,254,255]. Approximately 10 to 20 percent of recipients have adverse effects that limit school attendance or daily life activities [256,257].

Common injection site reactions include mainly pain, as well as redness, swelling, and pruritus. Among the mRNA vaccines, slightly higher rates have been reported for the Moderna COVID-19 vaccine (in 75 to 80 percent) than for the Pfizer COVID-19 vaccine (65 percent) [123].

Similarly, reported rates of nonsevere systemic adverse effects, such as fatigue, headache, and myalgia (50 to 60 versus 40 to 50 percent), and fevers, chills, and joint pain (30 to 40 versus 20 percent) appear slightly higher with Moderna COVID-19 vaccine than Pfizer COVID-19 vaccine [123]. The Novavax COVID-19 vaccine has been associated with lower rates of both injection site and systemic side effects than the mRNA vaccines, although systematic data for that vaccine are overall more limited [258].

In general, the rates of common reactions are lower among older (eg, >65 years) compared with younger adults and are lower among younger children than adolescents [79,196]. Among young children, irritability, crying, drowsiness, and loss of appetite are common; febrile seizures are rare [107,108].

Review of active and passive surveillance systems in the United States suggests that the safety profile of the bivalent mRNA vaccines was similar to that of the monovalent mRNA vaccines in children and adults [256,257]. Local injection reactions, headache, myalgia, and fever are the most common side effects and are short lived, although they limit school attendance or daily life activities in 10 to 20 percent of recipients.

Rare but serious associated events — COVID-19 vaccines are exceedingly safe. The primary safety concerns are a very rare risk of myocarditis with mRNA vaccines and possibly recombinant protein vaccines and very rare risks of thrombosis with thrombocytopenia and Guillain-Barré syndrome (GBS) with adenoviral vector vaccines (which are not used in the United States). Active and passive surveillance systems in adults and children have failed to find other clear associations with major adverse events [259].

Myocarditis — Myocarditis and pericarditis, mainly in male adolescents and young adults, have been reported more frequently than expected following receipt of the mRNA vaccines, Pfizer COVID-19 vaccine and Moderna COVID-19 vaccine [260,261]. Cases were also noted in Novavax COVID-19 vaccine recipients during the phase III trials [262], and surveillance suggested a possible increased risk following receipt of Janssen/Johnson & Johnson COVID-19 vaccine, which is no longer used in the United States [263]. Given the infrequency and the typically mild nature of the myocarditis and pericarditis cases, the benefits of vaccination greatly exceed the small increased risk [261].

For those who develop myocarditis or pericarditis following an mRNA vaccine or Novavax COVID-19 vaccine, we suggest that any subsequent COVID-19 vaccine dose be deferred in most cases; it is reasonable for such individuals to choose to receive an additional dose (ie, the second dose of the primary series or any booster doses) once the episode has completely resolved if the risk of severe COVID-19 is high [27]. Individuals with a history of resolved myocarditis or pericarditis unrelated to COVID-19 vaccination can receive a COVID-19 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 [264]. 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 15 years old – 70.7 cases per million doses of Pfizer COVID-19 vaccine

●16 to 17 years old – 105.9 cases per million doses of Pfizer COVID-19 vaccine

●18 to 24 years old – 52.4 to 56.3 cases per million doses Pfizer COVID-19 vaccine and Moderna COVID-19 vaccine, 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.

Estimated rates of myocarditis from the Vaccine Safety Datalink (VSD), an active surveillance system in the United States, which recorded a total of 320 cases of myocarditis following seven million vaccine doses, were somewhat higher, possibly because the system does not rely on the patients or providers to make special efforts to report cases [265]. Among males, the estimated rates of myocarditis within the week following a second vaccine dose were 150.5 cases (ages 12 to 15 years), 127.1 (ages 16 to 17 years), and 81.4 (ages 18 to 29 years) per million doses of BNT162b2 and 97.0 (ages 18 to 29 years) per million doses of mRNA-1273. After 2022, however, substantially fewer cases of post-vaccination myocarditis were reported to VAERS and VSD, and in the 2024-2025 season, reported rates did not exceed expected background myocarditis rates [266].

Studies from other countries have also suggested an increased rate of myocarditis following Pfizer COVID-19 vaccine receipt compared with the expected background rate [96,267-271]. Observational data also suggest that the risk may be higher with Moderna COVID-19 vaccine than Pfizer COVID-19 vaccine [272-275]. The risk also appears to be higher following the second dose and with shorter intervals between doses (eg, less than 30 versus more than 60 days) [276].

For all age groups, the risk of myocarditis or pericarditis following mRNA vaccination is estimated in some, but not all [274], studies to be less than the risk associated with SARS-CoV-2 infection [277].

Among the cases that have been reported, most are mild [261,267,268,278,279]. 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 persistent or fulminant myocarditis in individuals who had received an mRNA vaccine within the preceding weeks [280,281]. Although a study from Korea reported that 20 percent of the 480 cases of vaccine-associated myocarditis identified nationwide were severe, with 36 fulminant cases and 21 deaths, that report is an outlier compared with those from other countries [282].

The typical 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 [283]. Almost all presented with chest pain, with symptom onset a median of two days after vaccine receipt, which was often receipt of the second vaccine dose. Electrocardiogram was abnormal in 70 percent (ST-segment elevations or T-wave abnormalities), cardiac magnetic resonance imaging (MRI) 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 (ICU), 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".)

Events associated with discontinued vaccines — The adenovirus-vector vaccines ChadOx1 nCoV-19/AZD1222 (AstraZeneca COVID-19 vaccine) and Ad26.COV2.S (Janssen COVID-19 vaccine, also referred to as the Johnson & Johnson vaccine) were associated with thrombosis with thrombocytopenia and Guillain-Barré syndrome (GBS). Both vaccines have been discontinued worldwide and are no longer available.

●Thrombosis with thrombocytopenia – The adenovirus-vector vaccines were associated with an extremely small risk of unusual types of thrombotic events associated with thrombocytopenia [284]. The condition was variably referred to as vaccine-associated immune thrombotic thrombocytopenia (VITT) or thrombosis with thrombocytopenia syndrome (TTS). Many cases were associated with autoantibodies directed against the platelet factor 4 (PF4) antigen, similar to those found in patients with autoimmune heparin-induced thrombocytopenia (HIT). A similar risk has not been identified with the mRNA vaccines.

●GBS – The adenovirus-vector vaccines were both associated with GBS. However, cases of GBS, including recurrent cases, have also been reported in the setting of SARS-CoV-2 infection [285]. A similar risk of GBS has not been observed with the mRNA COVID-19 vaccines.

Other reactions (without established association) — Although myriad adverse events have been reported in individuals following vaccine administration, no other severe events than those listed above have been clearly associated with vaccination after hundreds of millions of doses administered.

●No clear signal of ischemic stroke with the bivalent mRNA vaccines – Cumulative data do not indicate an increased risk of ischemic stroke with COVID-19 vaccination. One active surveillance system (the VSD) reported a slightly higher-than-expected number of ischemic strokes in individuals ≥65 years of age following receipt of the bivalent Pfizer-BioNTech COVID-19 vaccine; however, the rate excess decreased with time and there was no increased incidence of other cardiovascular events [286,287]. Furthermore, multiple additional analyses have not identified a similar signal in several other surveillance systems or with the bivalent Moderna COVID-19 vaccine [286,288-292].

●Possible anaphylaxis – Anaphylaxis has been reported following administration of both mRNA COVID-19 vaccines [293]. 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 [254,294,295]; rates ranging from 2.5 to 7.9 events per million doses have been reported, depending on the surveillance system [296-298]. The vast majority of these events occurred in individuals with a history of prior allergic reactions and occurred within 30 minutes. However, many of those who had a reaction after the first vaccination did not suffer a similar reaction after the second dose. Data suggest that the majority are not IgE-mediated reactions [299] and complement-mediated mechanisms have not been documented. Some cases have been reported as stress-related events [300,301]. Possible anaphylaxis and other reported allergic reactions (eg, pruritus, rash, scratchy sensations in the throat, and mild respiratory symptoms) are discussed elsewhere [302].

●No clear impact on fertility – Many patients of child-bearing potential had been concerned that COVID-19 vaccination could adversely impact fertility. However, in epidemiologic studies, there is no association between COVID-19 vaccination and fertility problems in either females or males [303-305].

Other major adverse events have also not been consistently associated with mRNA or recombinant protein vaccines. Rare cases of Bell palsy were noted in the trials for both Pfizer COVID-19 vaccine and Moderna COVID-19 vaccine, although 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 palsy [294,296]. No other major vaccine-associated adverse events have been clearly identified in post-vaccine surveillance [296,305].

Ongoing safety assessment and reporting of adverse events — Adequately assessing vaccine safety is critical to the success of immunization programs. Although existing comprehensive systems to monitor vaccine safety are in place, they were 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) [306]. These include:

●Vaccine Adverse Event Reporting System (VAERS) – This is 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. 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 VAERS.

●Vaccine Safety Datalink (VSD) – This 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. Analysis of the VSD can help determine if adverse events are causally or only coincidentally related to vaccination by comparing the incidence of given clinical syndrome in vaccinees at time points soon after vaccination with time points before or well after vaccination [296]. When data support a causal relationship, calculating the actual attributable risk (the incidence of the clinical syndrome in vaccinees minus the incidence in non-vaccinees) helps inform the overall risk-benefit analysis of the vaccine.

●Clinical Immunization Safety Assessment project (CISA) – This 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 individual vaccine providers about specific patient concerns for 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 [307,308]. These systems have been coordinated through the CDC and have enlisted multiple other health care groups to provide ongoing data on vaccine safety. These systems and information sources add an additional layer of safety monitoring [309,310].

●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 FDA – 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") [311]. Therefore, if someone is injured by vaccine, society owes that person compensation. This is the basis for the National Vaccine Injury Compensation Program (NVICP) [312]. 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 [313].

COMBATING VACCINE HESITANCY AND BUILDING VACCINE CONFIDENCE — 

Vaccine hesitancy presents a major obstacle to achieving broad vaccination coverage. 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 [314]. With COVID-19 vaccines, the accelerated nature of development and misinformation have further contributed 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: Caregiver 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 [315,316].

Willingness to accept a COVID-19 vaccine has varied by country [317,318]. In the United States, rates of vaccine hesitancy have decreased over the course of the pandemic but remain substantial [319-322]. 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 [319,323-325]. In a 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 [323]. Vaccination rates in the United States increase with age; rates among children have been especially low. As of April 2023, fewer than 35 percent of children 5 to 11 years had received a primary vaccine series and fewer than 5 percent had received a bivalent vaccine dose; rates among younger children were much lower [326].

Among individuals who have received a primary COVID-19 vaccine series, major reasons for not receiving a booster dose are lack of awareness about eligibility or availability, belief that they remain protected against severe infection without it, and uncertainty about the vaccine safety and efficacy [327]. These findings highlight the role for clinicians in educating patients on emerging vaccine data and recommendations.

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 5^th to 6^th 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 10^th to 12^th 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). Over time, the mRNA vaccines have been reformulated to target the mutations in the spike proteins of various SARS-CoV-2 variants. As of September 2024, COVID-19 vaccines are only available as updated 2024-2025 formulations. Moderna COVID-19 vaccine 2024-2025 Formula and Pfizer COVID-19 vaccine 2024-2025 Formula contain the spike protein from Omicron variant KP.3. Novavax COVID-19 vaccine 2024-2025 Formula contains spike protein from Omicron variant JN.1. (See 'General principles' above and 'Available vaccines' above.)

●Indications for vaccination – For all individuals aged six months and older, we suggest a 2024-2025 formula COVID-19 vaccine (Grade 2C). Vaccines reduce the risk of severe COVID-19 and death, although the baseline risk of those outcomes in the context of pre-existing immunity from prior infection and/or vaccination is uncertain and likely already low for those without risk factors. Individuals who are at highest risk of severe outcomes with COVID-19, specifically individuals 65 years of age or older, immunocompromised individuals, and individuals with multiple medical comorbidities (table 4) are most likely to benefit from vaccination, and we particularly encourage vaccination in these individuals.

Vaccines available in the United States 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, even in the context of variants that partially evade vaccine-induced immune responses. Although effectiveness wanes, vaccine-induced immunity continues to reduce the risk of severe disease, and repeat vaccination is associated with a relative increase in effectiveness over several months. (See 'Indications and vaccine selection' above and 'Benefits of vaccination' above.)

●How to vaccinate – Our approach to COVID-19 vaccination in the United States is in accordance with recommendations from the Centers for Disease Control and Prevention (CDC) (algorithm 1).

•Immunocompetent individuals aged six months to four years – Individuals in this age group should receive at least three vaccine doses, at least one of which is a 2024-2025 formula COVID-19 vaccine. The number of doses of the 2024-2025 formula COVID-19 vaccine depends on their vaccination history. (See 'Children aged six months to four years' above.)

•Immunocompetent individuals aged 5 to 64 years – Individuals in this age group should receive one 2024-2025 formula COVID-19 vaccine. This includes individuals who have already received prior vaccine doses. (See 'Children aged 5 to 11 years' above and 'Adolescents and adults aged 12 to 64 years' above.)

•Immunocompetent individuals aged 65 years or older – Individuals in this age group should receive two 2024-2025 formula COVID-19 vaccine doses, with the second given approximately six months (and a minimum of two months) after the first. (See 'Adults aged 65 years and older' above.)

•Individuals aged six months and older with immunocompromising conditions – Individuals with immunocompromising conditions (table 5) should receive at least three mRNA vaccine doses or at least two Novavax vaccine doses, at least one of which is a 2024-2025 formula COVID-19 vaccine. The number of doses of the 2024-2025 formula COVID-19 vaccine depends on their vaccination history. (See 'Immunocompromised individuals' above.)

Vaccine doses are presented in the table (table 2).

●Vaccine safety – Severe adverse events with available COVID-19 vaccines are extremely rare and do not outweigh their benefit for recommended indications. The mRNA vaccines and Novavax COVID-19 vaccine have all been associated with a small excess risk of myocarditis, mainly in male adolescents and young adults. The majority of vaccine-associated myocarditis cases are mild and improve within days. (See 'Myocarditis' above.)

●Deviations from dosing recommendations – If the vaccine is administered in a manner different from the recommended approach, the dose generally does not have to be repeated. CDC recommendations on how to manage vaccination errors or deviations are presented in the table (table 6). (See 'Technique and potential administration errors' 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.

●Contraindications and precautions – The primary contraindications to COVID-19 vaccination are severe or immediate allergic reactions to the vaccine or any of its components. Individuals without a contraindication who have a history of anaphylaxis to other vaccines or injectable therapies, an allergy-related contraindication to a COVID-19 vaccine class other than the one they are receiving, or a nonsevere immediate allergic reaction to a prior COVID-19 vaccine should be monitored for 30 minutes. (See 'Contraindications and precautions (including allergies)' above and 'Monitoring for immediate reactions to vaccine' above.)