COVID-19 Vaccines

Vaccines are important preventive measures against severe COVID-19 disease, hospitalization, death, and persistent symptoms (ie, long COVID). 

The FDA Vaccines and Related Biological Products Advisory Committee (VRBPAC) continues to assess the optimal composition of COVID-19 primary and booster vaccines. In June 2023, VRBPAC recommended the vaccine composition be updated to a 2023-2024 formulation to target the XBB.1.5 Omicron subvariant. 

Waning immunity from the bivalent mRNA COVID-19 vaccine or previous infection against Omicron subvariants (eg, BA.2.86, EG.5, FL.1.5.1) that emerged mid-2023 prompted development of a new formulation for 2023-2024. ^[1]  

Both revised mRNA vaccine with the XBB.1.5 composition (ie, Spikevax and Comirnaty) received supplemental approval for adolescents and adults in September 2023. The vaccines were also granted Emergency Use Authorization (EUA) for children aged 6 months through 11 years. 

Interim analyses of the COVID-19 mRNA vaccines have demonstrated the XBB.1.5-containing monovalent vaccines elicit potent neutralizing responses against variants of the omicron XBB-lineage (XBB.1.5, XBB.1.6, XBB.2.3.2, EG.5.1, and FL.1.5.1) as well as the recently emerged BA.2.86 variant. ^[2]  

 

On September 12, 2023, the CDC recommended everyone aged 6 months and older get an updated COVID-19 vaccine to protect against potentially serious outcomes of COVID-19 disease this fall and winter. Dosage recommendations are organized by age and COVID-19 vaccination history. Additionally, immunization recommendations differ for people who are moderately to severely immunocompromised. 

The following tables summarize the 2023-2024 COVID-19 vaccine schedule, including those who are immunocompromised. Please refer to the CDC Interim 2023-24 COVID-19 Immunization Schedule for full details. 

General recommendations 

• Unvaccinated: Initial 3-dose homologous COVID-19 vaccine series* 
• Previously received COVID-19 vaccines: Administer at least 1 dose of COVID-19 2023-2024 formulation 
• May receive 1 or more additional 2023-2024 mRNA COVID-19 vaccine doses** 

*COVID-19 vaccination history refers to previous receipt of dose(s) of original monovalent (ancestral) mRNA, bivalent mRNA vaccine, updated (2023–2024 Formula), or a combination of the three, unless otherwise specified 

**Further additional dose(s) may be administered, informed by the clinical judgement of a healthcare provider and personal preference and circumstances; additional doses should be administered at least 2 months after the last 2023-2024 COVID-19 vaccine dose 

People Who are NOT Immunocompromised 

Table 1. COVID-19 vaccine, mRNA-Moderna (Spikevax) - Children aged 6 months through 4 years (Open Table in a new window)

 

Table 2. COVID-19 vaccine, mRNA-Pfizer (Comirnaty) - Children aged 6 months through 4 years (Open Table in a new window)

 

Table 3. COVID-19 vaccines, mRNA - Children aged 5-11 years (Open Table in a new window)

If previously vaccinated with any COVID-19 vaccine, administer at least 2 months after last vaccine dose.

Table 4. COVID-19 vaccines, mRNA - Aged 12 years and older (Open Table in a new window)

If previously vaccinated with any COVID-19 vaccine, administer at least 2 months after last vaccine dose. 

People Who are Moderately to Severely Immunocompromised

People who have received their initial immunization series and are moderately or severely immunocompromised have the option to receive 1 additional dose at least 8 weeks (2 months) following the last recommended dose. 

Further additional dose(s) may be administered, informed by the clinical judgement of a healthcare provider and personal preference and circumstances. Any further additional doses should be administered at least 8 weeks (2 months) after the last COVID-19 vaccine dose. 

Table 5. COVID-19 vaccine, mRNA-Moderna (Spikevax) - Immunosuppressed children aged 6 months through 4 years (Open Table in a new window)

 Table 6. COVID-19 vaccine, mRNA-Pfizer (Comirnaty) – Immunosuppressed children aged 6 months through 4 years (Open Table in a new window)

Table 7. COVID-19 mRNA vaccine – Immunosuppressed children aged 5-11 years (Open Table in a new window)

  Table 8. COVID-19 mRNA vaccine – Immunosuppressed individuals ≥ 12 years  (Open Table in a new window)

 

Introduction

After publication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genetic sequence on January 11, 2020, research and collaboration among scientists and biopharmaceutical manufacturers quickly followed. 

Various methods are used for vaccine discovery and manufacturing. ^[3]  Two mRNA monovalent vaccines (Comirnaty by Pfizer and Spikevax by Moderna) gained full approval by the US Food and Drug Administration (FDA). Two other monovalent vaccines, a viral vector vaccine (Janssen) and an adjuvanted protein subunit vaccine (Novavax), were granted emergency use approval (EUA) in the United States. The U.S. Biomedical Advanced Research and Development Authority (BARDA) continues to partner with biomedical research companies to advance SARS-CoV-2 vaccine development. 

Data collected by the CDC during the Omicron variant surge in January and February 2022 showed profoundly different outcomes on progression to hospitalization and/or death between vaccinated and unvaccinated individuals. Hospitalization was 2.2, 5, 7, and 9 times higher in unvaccinated people aged 12-17 years, 18-49 years, 50-64 years, and ≥ 65 years, respectively. Additionally, those who had received a booster dose had a much lower rate of hospitalization, particularly with advancing age. ^[4]  In January 2022, unvaccinated people aged ≥ 12 years had a 3.5 times higher risk of testing positive for COVID-19 and a 21 times higher risk of dying from COVID-19 compared with people vaccinated with a primary series and a booster dose. ^{[4, 5]}  

Vaccine efficacy declined as the Omicron variant changed into the spring and summer of 2022. Taking into account diminished vaccine efficacy, new bivalent mRNA vaccine boosters were authorized in fall 2022 that contained Omicron BA.4/BA.5 components in addition to the original wild-type spike protein. Real-world data from Israel of the Omicron bivalent mRNA vaccine showed the booster decreased hospitalization in people aged 65 years and older. Those who received the booster (n = 85,000) and tested positive for COVID-19 were 81% less likely to be hospitalized compared with 537,000 others in the same age group who did not receive the booster vaccine. ^[6]  

The FDA Vaccines and Related Biological Products Advisory Committee (VRBPAC) continues to assess the optimal composition of COVID-19 primary and booster vaccines. In June 2023, VRBPAC recommended the vaccine be updated for fall 2023, to target the XBB.1.5 Omicron subvariant. In April 2023, the bivalent mRNA vaccines replaced the original monovalent mRNA vaccines in the United States. Additionally, the Janssen (Johnson & Johnson) is no longer available (or recommended by the CDC) in the United States.

mRNA Vaccines

Comirnaty (BNT-162b2; Pfizer) was the first vaccine to gain full approval in the United States to prevent COVID-19 disease in adolescents and adults. EUAs also were granted for children as young as 6 months. It is a nucleoside-modified messenger RNA (modRNA) vaccine that encodes an optimized SARS-CoV-2 receptor-binding domain (RBD) antigen. It is administered as a 2-dose primary series in individuals aged ≥ 5 years. In children aged 6 months through 4 years, it is administered as a 3-dose primary series. Unvaccinated patients aged 5 years and older require a single dose.

Spikevax (mRNA-1273; Moderna) encodes the S-2P antigen. The FDA approved the vaccine for adults, and EUAs were authorized for children aged 6 months through 17 years. It is administered as a 2-dose primary series in children aged 6 months through 5 years. A single dose is recommended for unvaccinated patients aged 6 years and older. 

Table 8. Efficacy of mRNA Vaccines in Immunocompetent Individuals (Open Table in a new window)

Children and Adolescents 

As of spring 2023, the bivalent mRNA vaccines have been granted EUAs for children as young as 6 months. The bivalent mRNA vaccines have replaced the monovalent mRNA vaccines in the United States. 

Clinical trials for the monovalent mRNA vaccines showing efficacy and safety in children and adolescents advanced rapidly during 2021. High vaccine efficacy of the Pfizer monovalent mRNA vaccine was observed in adolescents ^{[14, 15]}  and school-aged children ^[15] ; however, efficacy was lower in younger children aged 6 months to 5 years owing to Omicron variants during the time of the trials. 

Similarly, the Moderna monovalent mRNA vaccine showed robust efficacy in adolescents ^[16]  and children, ^[17]  with lower efficacy in infants and toddlers due to circulating Omicron variants. 

Protein Subunit Vaccines

NVX-CoV2373 (Novavax) is engineered using recombinant nanoparticle technology from SARS-CoV-2 genetic sequence to generate full-length, prefusion spike (S) protein. This is combined with an adjuvant (Matrix-M). Results of preclinical studies showed that it binds efficiently with human receptors targeted by the original virus. It was administered as a 2-dose series given 21 days apart in adults and adolescents aged 12 years and older. 

Table 9. Clinical trials for primary immunization series (Open Table in a new window)

Adolescents

The vaccine achieved its primary effectiveness endpoint in the adolescent expansion of its PREVENT-19 phase 3 trial and demonstrated 78.29% efficacy overall at a time when the Delta variant was the predominant circulating strain in the United States. The efficacy analysis was supported by assessment of antibody titers that were shown to be higher in adolescents than in young adults. The study enrolled 2,247 participants across 75 sites. ^[21]

A phase 2b/3 global trial (Hummingbird) was initiated mid-summer 2022 in children aged 6 months through 11 years and is continuing to recruit participants. ^[22]  

Viral Vector Vaccines

As of May2023, Ad26.COV2.S is no longer available in the United States. It is an adenovirus serotype 26 (Ad26) recombinant vector-based vaccine (JNJ-78436735, VAC31518; Johnson & Johnson) administered as a single injection.

It was granted an EUA February 27, 2021 for adults. On October 20, 2021, the EUA was revised to recommend a booster (second dose) 2 months after the single-dose primary series of Ad26.COV2.S for adults and to allow heterologous boosters for other available COVID-19 vaccines in the United States after completion of the primary series. 

On May 5, 2022, the EUA indication was further revised to limited use (ie, in individuals for whom other authorized/approved COVID-19 vaccines are not accessible or clinically appropriate, or if the individual elects the AD26.COV2.S vaccine and would otherwise not receive a vaccine). 

Table 10. Efficacy of Ad26.COV2.S (Janssen [Johnson & Johnson]) Viral Vector Vaccine (Open Table in a new window)

 

Mutations

Viral mutations may naturally occur anywhere in the SARS-CoV-2 genome. Unlike the human DNA genome, which is slow to mutate, RNA viruses can readily, and quickly, mutate. A mutation may alter the viral function (eg, enhance receptor binding), or may have no discernable function. A new virus variant emerges when the virus develops 1 or more mutations that differentiate it from the predominant virus variants circulating in a population. The CDC surveillance of SARS-CoV-2 variants includes US COVID-19 cases caused by variants. The CDC tracks variant proportions in the United States. Researchers are studying how variants may or may not alter the extent of protection by available vaccines. 

Variants of concern

Variants of concern (VOCs) may reduce vaccine effectiveness, which may be evident by a high number of vaccine breakthrough cases or a very low vaccine-induced protection against severe disease. VOCs circulating throughout 2020 and 2021 included Alpha, Beta, Lambda, Delta, and Gamma. Since December 2021, the Omicron VOC and subvariants have been predominant. 

Omicron VOCs

The Omicron variant (B.1.1.529), initially identified in South Africa, was declared a variant of concern in the United States by the CDC November 30, 2021. This VOC contains several dozen mutations, including a large number in the spike gene, more than previous VOCs. These mutations include several associated with increased transmission. BA.1 sublineage (including BA.1.1) is causing the largest surge in COVID-19 cases to date. Omicron sublineages BA.2 and BA.2.12.1 emerged later and by late April 2022, accounted for most cases. The VISION Network examined 214,487 emergency department/urgent care visits and 58,782 hospitalizations with a COVID-19–like illness diagnosis among 10 states during December 18, 2021–June 10, 2022, to evaluate vaccine efficacy (VE) of 2, 3, and 4 doses of mRNA COVID-19 vaccines compared with no vaccination among immunocompetent adults. VE during the BA.2/BA.2.12.2 period was lower than that during the BA.1 period. A third vaccine dose provided additional protection against moderate and severe COVID-19–associated illness in all age groups, and a fourth dose provided additional protection in eligible adults aged 50 years and older. ^[25]  

Omicron subvariants (eg, XBB.1.5, EG.5, FL.1.5.1, and BA.2.86) continued to emerge during spring and summer 2023. 

In June 2023, the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) voted to change the COVID-19 vaccine strain composition to include the Omicron XXB.1.5 variant for the fall 2023 vaccine. 

A previous analysis of neutralizing antibody responses to the Omicron lineages circulating during summer 2022 (ie, BA.2.12.1, BA.4, and BA.5) was published. The researchers found neutralizing antibody titers against the BA.4 or BA.5 subvariant and (to a lesser extent) against the BA.2.12.1 subvariant were lower than titers against the BA.1 and BA.2 subvariants, suggesting the SARS-CoV-2 Omicron variant has continued to evolve with increasing neutralization escape. ^[26]  The vaccine was updated for fall 2022 to a bivalent vaccine that included BA.4/5. 

For more information, see COVID-19 Variants. 

Studies in immunocompromised individuals

The mRNA vaccines are highly effective in the general population. As with other vaccines, it is important to determine if immunosuppressed populations (eg, patients who have cancer, are solid organ transplant recipients, on hemodialysis, and/or taking immunosuppressive therapies) are able to mount a sufficient immunologic response following 2 doses of mRNA vaccine. One example of continued study of this population is a multiantigenic SARS-COV-2 vaccine using a synthetic poxvirus platform (COH04S1 [City of Hope Biomedical Research Institute, California]). A phase 2 trial for this vaccine was initiated in August 2021 in stem cell transplant recipients. ^[27]  

Solid organ transplant recipients 

Low or nondetectable anti-spike antibody levels and nucleocapsid antibodies following full vaccination with mRNA vaccines have been described in solid organ transplant recipients. ^{[28, 29, 30]}  

A randomized, placebo-controlled trial at the University Health Network in Canada enrolled 120 transplant recipients between May 25 and June 3, 2021. None had COVID-19 previously and all of them had received 2 doses of mRNA-1273 vaccine. Participants were randomly assigned in a 1:1 ratio to receive a third vaccine dose or placebo 2 months after their second vaccine dose. The primary outcome was a serologic response characterized by an anti-receptor-binding domain (RBD) antibody level ≥ 100 U/mL at Month 4. This outcome was prespecified and was based on the protective anti-RBD titer in a challenge study involving nonhuman primates and further corroborated in a large clinical cohort as the upper boundary of the estimated level required to confer 50% protective neutralization. At Month 4, an anti-RBD antibody level ≥ 100 U/mL was observed in 33 of 60 patients (55%) in the mRNA-1273 group and in 10 of 57 patients (18%) in the placebo group (P < 0.001). ^[31]

Kamar et al reported results of the humoral response of 101 consecutive solid-organ transplant recipients given a third dose of mRNA vaccine (BNT-152b2; Pfizer) 61 days after the second dose. Prevalence of anti–SARS-CoV-2 antibodies was 0% before the first dose, 4% before the second dose, 40% before the third dose, and 68% 4 weeks after the third dose. Among the 59 patients who had been seronegative before the third dose, 26 (44%) were seropositive at 4 weeks after the third dose. All 40 patients who had been seropositive before the third dose were still seropositive 4 weeks later, and their antibody titers increased from 36 ± 12 before the third dose to 2676 ± 350 at 1 month after the third dose (P < 0.001). Patients who did not have an antibody response were older, had a higher degree of immunosuppression, and had a lower estimated glomerular filtration rate compared with patients who had an antibody response. ^[32]  

A case series of 7 solid organ transplant recipients describes confirmed COVID-19 infection after receiving an mRNA vaccine. Two individuals had received 1 dose and the others had received 2 doses. Six patients were tested for anti-spike antibodies, of which 5 had undetectable levels; one patient had received their second mRNA-1273 vaccine 44 days prior and had low titer anti-spike antibody. None of these 6 patients had detectable nucleocapsid antibody. ^[28]  Others have confirmed low or nondetectable anti-spike antibody levels and nucleocapsid antibodies. ^{[29, 30]}  These reports prompted the French National Authority for Health to recommend the use of a third dose in immunosuppressed patients. 

Patients on maintenance hemodialysis 

A national registry in France was used to compare severity of 1474 COVID-19 cases in patients on maintenance hemodialysis (MHD) after 0, 1, or 2 doses of BNT162b2 vaccine. Overall, vaccination reduced disease severity, but 11% of infected patients who had received 2 doses died. Patients on MHD with humoral response similar to healthy volunteers after 2 doses did not generate more immune effectors after a third dose but had more side effects. In contrast, 66% of patients on MHD with suboptimal response after2 doses reached an optimal titer of anti-RBD IgG and/or developed spike-specific CD8+ T cells after a third dose. ^[33]  

On August 11, 2021, the CDC endorsed vaccination for persons who are pregnant, breastfeeding, trying to get pregnant, or who might become pregnant in the future. The American College of Obstetricians and Gynecologists (ACOG) guidelines regarding vaccination concur with the CDC guidelines.

Data from the CDC concluded pregnant individuals are at an increased risk for severe illness from coronavirus disease 2019 (COVID-19) and death, compared with nonpregnant individuals. In addition, pregnant persons may be at increased risk for other adverse outcomes (eg, preterm delivery). Owing to these risks, preventing severe COVID-19 infection is essential for both mother and fetus. 

Preliminary findings regarding safety of mRNA COVID-19 vaccines during pregnancy from the CDC v-safe registry did not show obvious safety signals. ^[34]  Additional data were analyzed from the CDC v-safe registry among 2456 individuals who received an mRNA COVID-19 vaccine preconception or prior to 20 weeks’ gestation. No increased risk for spontaneous abortion was shown. ^[35]

The Canadian National Vaccine Safety Network found no significant difference between miscarriage or stillbirth rates between vaccinated or unvaccinated pregnant females. ^[36]  

Researchers studied placentas of pregnant individuals vaccinated with mRNA vaccines after delivery. mRNA vaccines induce an immune response through activation of TLR3, which has been linked to decidual arteriopathy, growth restriction, preterm delivery, and fetal loss in mouse models. Placental examination in women with vaccination showed no increased incidence of decidual arteriopathy, fetal vascular malperfusion, low-grade chronic villitis, or chronic histiocytic intervillositis compared with women in the control group. Incidence of high-grade chronic villitis was higher in the control group than in the vaccinated group. ^[37]

Immune transfer to neonates

A nationwide, register-based cohort study included all live-born infants born in Norway between September 1, 2021, and February 28, 2022. Of 21,643 live-born infants, 9,739 (45%) were born to women who received a second or third dose of a COVID-19 vaccine during pregnancy. The first 4 months of life incidence rate of a positive test for SARS-CoV-2 was 5.8 per 10 000 follow-up days. Infants of mothers vaccinated during pregnancy had a lower risk for a positive test compared with infants of unvaccinated mothers (0.5% vs 1.5% during Delta phase; 4.2% vs 4.2% during Omicron phase). Evidence showed a lower risk during the Delta variant-dominated period (incidence rate 1.2 vs 3 per 10,000 follow-up days) compared with the Omicron period (7 vs 10.9 per 10,000 follow-up days). ^[38]  

A cohort study (n = 131) by Gray et al found mRNA SARS-CoV-2 vaccines generated humoral immunity in pregnant and lactating persons, similarly to that observed in nonpregnant individuals. All serum titers from vaccination were significantly higher compared with titers induced by SARS-CoV-2 infection during pregnancy (P< 0.0001). Importantly, vaccine-generated antibodies were present in all umbilical cord blood and breastmilk samples, showing immune transfer to neonates vial placenta and breastmilk. ^[39]  In another study, maternal and cord blood sera were collected from 20 parturients who received 2 doses of the mRNA BNT162b2 vaccine. All mothers and infants were positive for anti S- and Anti-RBD-specific IgG. ^[40]  

Additional studies support the above findings in cord blood and provide further information regarding potential timing of maternal vaccination. In one study (n = 27), mean placental IgG transfer ratio following vaccination (mRNA vaccines) provides an infant antibody level about equal to maternal level. It also appears to increase with latency from vaccination, suggesting that earlier vaccination in the third trimester may produce greater infant immunity. ^[41]  A similar study (n = 122) observed women vaccinated with mRNA vaccines produce antibodies as soon as 5 days after the first dose and passive immunity to the neonate as soon as 16 days. The placental IgG transfer ratio increased over time. ^[42]  Collier et al observed binding, neutralizing, and functional nonneutralizing antibody responses; CD4 and CD8 T-cell responses were present in pregnant, lactating, and nonpregnant women following vaccination. Binding and neutralizing antibodies were observed in infant cord blood and human milk. Binding and neutralizing antibody titers against the SARS-CoV-2 B.1.1.7 and B.1.351 variants of concern were reduced, but T-cell responses were preserved against viral variants. ^[43]  

Anti-S IgG titers in the umbilical cord are correlated with maternal titers and are highest after late second and early third trimester vaccination. ^{[41, 42]}  Durability of anti-spike antibodies in infants after maternal COVID-19 vaccination or natural infection has been studied. Vaccination resulted in significantly greater antibody persistence in infants than infection. At 6 months, 57% (16 of 28) of infants born to vaccinated mothers had detectable antibodies compared with 8% (1 of 12) of infants born to infected mothers (P = .005). ^[44]  

The CDC recommends COVID-19 vaccination for all eligible persons as soon as possible, including unvaccinated individuals previously infected with SARS-CoV-2. Vaccinations provide a safer and more reliable way to build antibodies compared with infection. Patients may receive the vaccine once they have recovered from the acute illness (if symptomatic) and meet the criteria to discontinue isolation. Patients who received monoclonal antibodies or convalescent plasma should wait 90 days before receiving the vaccine. 

Supporting evidence for CDC’s recommendation is based on results from the VISION Network trial. The trial compared the early protection against COVID-19 conferred by SARS-CoV-2 infection and by receipt of mRNA COVID-19 vaccines (ie, 90-179 days after infection or vaccination) in adults with confirmed COVID-19 infection from 187 hospitals across 9 states during January to September 2021. The adjusted odds of laboratory-confirmed COVID-19 among unvaccinated adults with previous SARS-CoV-2 infection were 5.49-fold higher than the odds among fully vaccinated recipients of an mRNA COVID-19 vaccine who had no previous documented infection. ^[45]  

Evidence shows vaccines provide substantially higher protection against COVID-19 infection compared with immunity from a previous COVID-19 infection. mRNA vaccinees have higher antibody titers (up to 10 times higher) than convalescent plasmas from donors who recovered from natural infection. ^[46]  

Early studies found vaccination of patients with prior SARS-CoV-2 infection enhances T cell immunity and antibody-secreting memory B cell response, and neutralizing antibodies effective against emerging variants. These data emphasize the importance of vaccinating both uninfected and previously infected persons to elicit cross-variant neutralizing antibodies. ^{[47, 48, 49]}  

Common adverse reactions include pain and swelling at the injection site, fatigue, headache, myalgia, and chills following administration. These symptoms can be treated with acetaminophen or NSAIDs. Severe allergic reactions (eg, anaphylaxis, angioedema) are rare.

The Ad26.COV2.S (Janssen [Johnson & Johnson]) vaccine has also been associated with cases of thrombosis with thrombocytopenia syndrome, Guillain-Barré syndrome, and facial paralysis (including Bell Palsy). 

Myocarditis and pericarditis

Myocarditis and pericarditis have been reported post authorization for each of approved/authorized vaccines in the United States. Most of the data initially were reported with the mRNA vaccines since they were the first authorized and most extensively administered. Post authorization reports of myocarditis and pericarditis also have been reported with the Novavax and Janssen vaccines. 

The CDC vaccine schedule suggests a longer interval (ie, 8 weeks) between the first and second primary series doses of Moderna, Novavax, and Pfizer-BioNTech COVID-19 vaccines may be optimal for some people ages 6 months–64 years, especially for males ages 12-39 years, as it may reduce the small risk for myocarditis and pericarditis associated with these vaccines. 

Myocarditis is an inflammatory disease of the myocardium with a wide range of clinical presentations, from subtle to devastating myocyte damage. Historically, common etiologies include viral, parasitic, bacterial, fungal, and protozoal infectious agents. Noninfectious etiologies include toxins (eg, cocaine), drug hypersensitivity, and immunologic syndromes. ^[50] Acute myocarditis most commonly results from a viral infection, with an age-standardized incidence of 40 per 100,000 individuals. ^[51]  The annual incidence of pediatric myocarditis in adolescents is 0.8 per 100,000, and 66% are males. This incidence gradually decreases with age over the ensuing decades. ^[52]  

Cases of myocarditis and pericarditis emerged in May 2021 with possible correlation of COVID-19 mRNA vaccine administration. A case series of 7 adolescent males presenting with symptomatic acute myocarditis describes similar symptom onset of within a few days (ie, 2-4) after vaccine administration, particularly after the second dose. Diagnostic test results were similar among the group and included elevated troponin, ST elevation, and diffuse myocardial edema. None were critically ill, and all responded quickly to treatment with NSAIDs; several also received glucocorticoids. ^[53]  

Preliminary myocarditis/pericarditis reported to VAERS after approximately 300 million mRNA doses administered through June 11, 2021 total 1226. Most are after the second dose and nearly 80% are in males. Data from December 14, 2020 to July 16, 2021 indicate approximately 8.9 million US adolescents aged 12 to 17 years had received Pfizer-BioNTech vaccine. VAERS received 9246 reports after Pfizer-BioNTech vaccination in this age group; 90.7% of these were for nonserious adverse events and 9.3% were for serious adverse events, including myocarditis (4.3%). ^[54]  The CDC and American Academy of Pediatrics stress the benefit of the vaccine at preventing severe COVID-19 disease, hospitalization, and death, and they recommend vaccination. COVID-19 vaccination also reduces the high risk for myocardial injury (and myocarditis) or arrhythmias associated with COVID-19 disease. ^[55]  

An analysis of myocarditis following mRNA COVID-19 vaccine notes the absolute risk is 1-5 per 100,000 vaccinated individuals; it is a rare event. The analysis also suggests a dose interval of ≥ 2 months may decrease the risk. The authors emphasized additional evidence is needed to explain the reasons why the mRNA-1273-Moderna vaccine has a higher risk for myocarditis compared with the Pfizer preparation. ^[56]

Among 192,405,448 persons receiving a total of 354,100,845 mRNA-based COVID-19 vaccines from December 2020 to August 2021, there were 1,991 reports of myocarditis to VAERS and 1,626 of these reports met the case definition of myocarditis. The median age was 21 years (range 16-31 years) and the median time to symptom onset was 2 days. Males comprised 82% of the myocarditis cases for whom sex was reported. ^[57]  

The CDC has published clinical considerations relevant to myocarditis and pericarditis with mRNA COVID-19 vaccines. Instruct patients to seek immediate medical attention if they experience chest pain, dyspnea, or palpitations after receiving the vaccine. Treatment consists of anti-inflammatory agents including NSAIDs, IVIG, and glucocorticoids. Additionally, athletic activity restrictions may be needed depending on when serum markers of myocardial injury and inflammation, ventricular systolic function, and clinically relevant arrhythmias return to normal. 

Thrombosis with thrombocytopenia syndrome (TTS) 

Cases of thrombosis with thrombocytopenia with the Ad26.COV2.S (Janssen [Johnson & Johnson]) and AZD-1222 (ChAdOx1 nCoV-19; AstraZeneca [not authorized in United States) vaccines have been reported. The FDA temporarily paused use of Ad26.COV2.S in mid-April 2021 to allow the CDC's Advisory Committee on Immunization Practices (ACIP) to evaluate rare cases of cerebral venous sinus thrombosis. After discussing the benefits and risks of resuming vaccination, ACIP reaffirmed its interim recommendation for use of the Janssen COVID-19 vaccine in all persons aged 18 years and older under the FDA’s EUA. The EUA now includes a warning that rare clotting events may occur after vaccination, primarily among women aged 18 to 49 years. The risks for death and serious outcomes of COVID-19, including thrombosis, far outweigh the risk for TTS possibly associated with highly efficacious vaccines. ^[58]  

Thrombocytopenia syndrome is a rare syndrome that involves acute venous or arterial thrombosis and new-onset thrombocytopenia in patients with no known recent exposure to heparin. Although the mechanism that causes TTS is not fully understood, it appears similar to heparin-induced thrombocytopenia, a rare reaction to heparin treatment. In the United States, 12 of 15 persons with TTS that occurred after Janssen COVID-19 vaccination had CVST with thrombocytopenia. ^[58]  

The American Society of Hematology and the American Heart Association/American Stroke Association have published documents for clinicians to be aware of symptoms, diagnosis, and urgent treatment if TTS is suspected. 

Diagnosis includes the following 5 criteria:

• COVID vaccine (Johnson & Johnson/AstraZeneca only to date) 4 to 42 days previously 
• Venous or arterial thrombosis (often cerebral or abdominal) 
• Thrombocytopenia 
• Positive PF4 ‘HIT’ (heparin-induced thrombocytopenia) ELISA 
• Markedly elevated D-dimer (> 4 x ULN) 

The following symptoms associated with TTS may emerge 4 to 30 days after vaccination with Ad26.COV2.S or AZD-1222:

• Severe headache 
• Visual changes 
• Abdominal pain 
• Nausea and vomiting 
• Back pain
• Shortness of breath 
• Leg pain or swelling 
• Petechiae, easy bruising, or bleeding