COVID-19 Vaccines

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. ^[1]  Two mRNA vaccines (Comirnaty by Pfizer and Spikevax by Moderna) have gained full approval by the US Food and Drug Administration (FDA). Two others, a viral vector vaccine (Janssen) and an adjuvanted protein subunit vaccine (Novavax), have emergency use approval (EUA) in the United States. Globally, at least 12 vaccines are approved for full use, more than 20 vaccines are authorized for early or limited use, and as of Fall 2022, 42 vaccines were in phase 3 clinical trials. ^[2]  Numerous antiviral medications and immunotherapies are under investigation for coronavirus disease 2019 (COVID-19). 

Initial data showed effectiveness of full vaccination in older adults to prevent hospitalization was estimated for the period between February through April 2021. Efficacy among adults aged 65 to 74 years was approximately 96% for the mRNA vaccines and 84% for Janssen vaccine. Among adults aged 75 years and older, effectiveness of full vaccination is estimated at 91% for Pfizer-BioNTech, 96% for Moderna. ^[3]  During this same period, the Novavax vaccine showed 90.4% efficacy. ^[4]  

Vaccine efficacy (VE) was shown to wane over time following an initial 2-dose primary series with the mRNA vaccines and the 1-dose regimen with the Janssen vaccine. ^[5]  Booster shots have improved VE. ^{[6, 7]}  Other variables also affect VE (eg, SARS-CoV-2 variant properties, immunosuppressive conditions). Taking into account diminished VE, new bivalent mRNA vaccine boosters were authorized in Fall 2022 containing Omicron BA.4/BA.5 components. The FDA Vaccines and Related Biological Products Advisory Committee (VRBPAC) continues to assess the optimal composition of COVID-19 primary and booster vaccines. 

 

Table 1. Primary Series Immunization with Monovalent COVID-19 for Children Aged 6 Months through 17 Years (Open Table in a new window)

*Individuals who are moderately-to-severely immunocompromised

For more information, see the CDC Interim COVID-19 Immunization Schedule 

Table 2. Primary Series Immunization with COVID-19 Vaccines for Adults Aged 18 Years and Older (Open Table in a new window)

*Individuals who are moderately-to-severely immunocompromised

**People aged 18-49 years: Those who received Janssen COVID-19 Vaccine as both their primary series dose and booster dose may receive a second booster dose using an mRNA COVID-19 vaccine at least 4 months after the Janssen booster dose.

***Age-appropriate mRNA COVID-19 vaccines are preferred over the Janssen COVID-19 Vaccine for all vaccine doses for all vaccine-eligible people 18 years of age and older. Janssen COVID-19 vaccine should only be used in limited situations. 

For more information, see the CDC Interim COVID-19 Immunization Schedule 

Bivalent Booster Vaccines

The FDA authorized Moderna and Pfizer bivalent COVID-19 vaccines for booster doses for adolescents and adults in August 2022, for children as young as 5 years in October 2022, and for children aged ≥ 6 months in December 2022. The bivalent vaccines contain original (wild-type spike protein) plus an Omicron BA.4/BA.5 subvariants spike protein. These vaccines replace the use of the original monovalent vaccines for booster doses. 

Schedule

Bivalent COVID-19 mRNA vaccines are administered as a single dose and authorized for individuals aged ≥ 6 months. 

Administer at least 2 months after either of the following:

• Completion of primary vaccination with any authorized or approved monovalent COVID-19 vaccine, OR
• Receipt of the most recent booster dose with any authorized or approved monovalent COVID-19 vaccine 

Table 3. Bivalent COVID-19 Booster Vaccines (Wild-type plus Omicron BA.4/BA.5 (Open Table in a new window)

Monovalent Booster Vaccines

The FDA authorized COVID-19 vaccine, adjuvanted-Novavax to be used as a first booster (3rd dose) in adults on October 19, 2022. 

Schedule

Administer IM as a single dose

Administer at least 6 months after completion of primary vaccination in the following adults:

• Those for whom an mRNA bivalent COVID-19 booster vaccine is not accessible or clinically appropriate, OR
• Those who elect to receive the Novavax COVID-19 vaccine, adjuvanted because they would otherwise not receive a booster dose of a COVID-19 vaccine 

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. EUA s have also been 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. 

Spikevax (mRNA-1273; Moderna) encodes the S-2P antigen. The FDA approved the vaccine for adults, and an EUA is authorized for children aged 6 months through 17 years. It is administered as a 2-dose primary series. 

Table 4. Efficacy of mRNA Vaccines in Immunocompetent Individuals (Open Table in a new window)

Third Primary Dose for Immunocompromised Individuals

On August 12, 2021, the FDA reauthorized the EUAs for the mRNA SARS-CoV-2 vaccines to allow a third primary dose administered ≥ 28 days after the 2-dose regimen in individuals who have undergone solid organ transplantation or who are diagnosed with conditions that are considered to have an equivalent level of immunocompromise. The Pfizer EUA allows for severely immunocompromised individuals aged 5 years and older, whereas the Moderna EUA allows a third dose for adults aged ≥ 18 years. 

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. ^[19]  

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. ^{[20, 21, 22]}  

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). ^[23]

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. ^[24]   

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. ^[20]  Others have confirmed low or nondetectable anti-spike antibody levels and nucleocapsid antibodies. ^{[21, 22]}  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. ^[25]   

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 virus. It is administered as a 2-dose series given 21 days apart in adults and adolescents aged 12 years and older. 

Table 5. Clinical trials for primary immunization series (Open Table in a new window)

Viral Vector Vaccines

Ad26.COV2.S is an adenovirus serotype 26 (Ad26) recombinant vector-based vaccine (JNJ-78436735, VAC31518; Johnson & Johnson) administered as a single injection, but currently its use is limited. 

On February 27, 2021, the FDA granted an EUA for the Janssen COVID-19 vaccine to prevent COVID-19 in individuals aged 18 years and older. 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 individuals aged 18 years and older and to allow heterologous boosters for other available COVID-19 vaccines in the United States after completion of the primary series at 6 months (mRNA vaccines) or at 2 months (Ad26.COV2.S vaccine). 

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

Table 6. Efficacy of Ad26.COV2.S (Janssen [Johnson & Johnson]) Viral Vector Vaccine (Open Table in a new window)

Adverse Effects

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. Acute myocarditis most commonly results from a viral infection, with an age-standardized incidence of 40 per 100,000 individuals. ^[26]  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. ^[27]   

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. ^[28]    

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%). ^[29]  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. ^[30]   

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. ^[31]

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. ^[32]  

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. ^[36]    

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. ^[36]   

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

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. ^[42]     

Analysis of neutralizing antibody responses to the most recent 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. ^[43]  

The FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) voted to change the original COVID-19 vaccine strain composition to include an Omicron BA.4/5 spike protein component to the current vaccine composition for fall-2022 booster doses. 

Omicron subvariants (eg, BA.4, BA.5, BQ.1, B1.11, and XBB.1.5) continued to emerge during the last half of 2022. 

For more information, see COVID-19 Variants. 

BNT162b2 (Pfizer)

The BNT162b2 mRNA vaccine (Comirnaty) has full FDA approval for individuals aged 12 years and older. It also is authorized for emergency use for children and adolescents aged 6 months and older. It is administered as a 2-dose primary series with a booster dose given 2 months after completing the primary series. 

A 3-dose primary series is recommended for severely immunosuppressed patients aged 5 years and older. 

For children aged 6 months through 4 years, BNT162b2 mRNA vaccine is administered as a 3-dose primary series (3rd dose is the bivalent vaccine).   

Adolescents

The phase 3 trial data lists the vaccine as 100% effective in preventing SARS-CoV-2 infection in the 12-15 year-old age group and it was determined to be noninferior in the 16-25 year-old participants. The study was conducted between October 15, 2020 and January 12, 2021. There were no cases of COVID-19 disease in adolescents aged 12 to 15 years who received the vaccine (n = 1131) compared with 18 cases in those who received placebo (n = 1129). ^[44]  Adverse events after receipt of BNT162b2 vaccine reported to the Vaccine Adverse Event Reporting System (VAERS) and adverse events and health impact assessments reported in v-safe (a smartphone-based safety surveillance system) were reviewed for US adolescents aged 12 to 17 years during December 14, 2020 to July 16, 2021. ^[29]  

Among adolescents aged 12-18 years (median interval since vaccination, 162 days) during the Omicron-predominant period, vaccine efficacy was 40% against hospitalization, 79% against critical Covid-19, and 20% against noncritical Covid-19. ^[45]  

The EUA for the Pfizer mRNA vaccine also recommends a single homologous booster dose ≥ 5 months after completing a primary series with the Pfizer-BioNTech COVID-19 vaccine for individuals aged 12 years and older. Heterologous boosters are not part of the EUA for patients younger than 18 years.

School-aged children 

On October 29, 2021, the FDA authorized the BNT162b2 vaccine for children aged 5 to 11 years. The CDC Advisory Committee on Immunization Practices unanimously endorsed use for this population on November 2, 2021. The dose for this age group is smaller than the dose for adults and adolescents (ie, 10 mcg vs 30 mcg). As with adults and adolescents, the primary vaccine series consists of 2 doses administered 3 weeks apart. A 3-dose primary series is recommended for severely immunosuppressed individuals aged 5 years and older. The vaccine is packaged in a smaller vial size and strength specific for younger children. 

In May 2022, the EUA for the Pfizer mRNA vaccine was updated to recommend a single homologous booster dose ≥ 5 months after completing a primary series with the Pfizer-BioNTech COVID-19 vaccine to individuals aged 5-11 years. Heterologous boosters are not part of the EUA for patients younger than 18 years. 

The phase 2/3 trial in the United States included approximately 4500 children aged 5 to 11 years (2268 from the initial enrollment group [1518 vaccine; 750 placebo] and 2379 from the supplemental safety group who entered the study later than the initial enrollment group). Participants were randomly assigned in a 2:1 ratio to receive active vaccine or placebo. The vaccine efficacy rate was 90.7% in the initial enrollment participants without prior SARS-CoV-2 infection (n = 1968), measured from 7 days after the second dose. Among these participants, the number testing positive for SARS-CoV-2 was 3 of 1273 in the vaccine group and 16 of 637 in the placebo group. The cutoff date for the data in the initial group was October 8, 2021, during a period when the Delta variant was prevalent and pediatric cases accounted for approximately 25% of cases in the United States. 

During the Omicron period, vaccine effectiveness against hospitalization among children aged 5 to 11 years was 68% (median interval since vaccination, 34 days). ^[45]  

Younger children 

On June 17, 2022, the FDA extended the EUA for the BNT162b2 vaccine to include children aged 6 months through 4 years. It is administered as a 3-dose primary series

Clinical trials for 2 doses (3 mcg/dose) of the BNT162b2 vaccine in younger children aged 6 months through 4 years have been completed. Wheras 2 doses of the vaccine generated antibody responses comparable to older groups in children ages 6 months to 2 years, adequate antibody responses did not develop in children ages 2 to 5 years. A third 3-mcg dose was well tolerated among 1,678 children aged 6 months to 5 years with safety similar to placebo. Vaccine efficacy was 80.3% with 3 doses during a time when the Omicron variant was predominant. ^[46]  

Vaccine efficacy, a secondary endpoint in the trial, was 73.2% among children 6 months through 4 years without evidence of prior COVID-19 infection. This analysis was based on 13 cases in the active vaccine group (n = 794) and 21 cases in the placebo group (n = 351), diagnosed from March to June 2022. Consistent with the period when the cases occurred, sequencing of viral RNA from illness visit nasal swabs indicated that observed cases primarily were caused by Omicron BA.2, Omicron BA.4, and Omicron BA.5 strains. ^[47]   

While the above results confirm a high level of protection at a time when BA.2 was highly prevalent, an EUA application for an Omicron BA.4/BA.5-adapted bivalent vaccine for children aged 6 months through 11 years is in progress as of August 2022. 

mRNA-1273 (Moderna)

On June 17, 2022, the FDA authorized the mRNA-1273 vaccine for children aged 6 months and older as a 2-dose primary series. A 3-dose primary series is recommended for patients aged 6 months through 17 years with certain kinds of immunocompromise. The bivalent Omicron-containing booster vaccine has been authorized for children as young as 6 months as of late 2022.  

Adolescents

The Teen COVE trial showed mRNA-1273 vaccine (Moderna) to be 93.3% effective 14 days after receiving 2 doses in adolescents aged 12 to 17 years. Vaccine efficacy of 92.7% in seronegative participants was observed starting 14 days after the first dose, using the secondary CDC case definition of COVID-19, which tested for milder disease. The phase 2/3 trial included 3732 participants randomly assigned in a 2:1 ratio to receive mRNA-1273 or placebo between December 9, 2020 and February 28, 2021. ^[48]  An EUA was submitted June 10, 2021 to expand the current EUA to include this population. However, the decision to expand the EUA to include adolescents has been delayed to determine whether there is heightened risk for myocarditis among younger males. 

Children aged 6-11 years

Interim analysis of the KidCOVE phase 2/3 trial (n = 4753) for the mRNA-1273 vaccine in children aged 6 through 11 years neutralizing antibody response after two 50-mcg doses administered 28 days apart, with a favorable safety profile. These responses were noninferior to those in young adults. ^[49]  

Canada, Australia, and the European Union have also authorized use for this age group. 

Children 6 months through 5 years 

The mRNA-1273 vaccine successfully met its primary endpoint in the KidCOVE study in children 6 months to under 6 years. Two 25-mcg doses showed robust neutralizing antibody titers similar to adults. Although not a primary endpoint, statistically significant vaccine efficacy was observed during the Omicron wave that was consistent with the lower 2-dose effectiveness against Omicron seen in adults. ^[50]   

SARS-Cov-2-neutralizing antibody geometric mean ratio (GMR) comparing the response in children 6 months to under 2 years to the response in young adults (aged 18-25 years) from the Phase 3 COVE study was 1.3 and was 1.0 for the 2 to under 6 years age group. This also predicts protection from COVID-19 and severe COVID-19 disease down to 6 months of age. 

The Omicron variant predominated in the United States during the study in these younger age groups. The secondary endpoint of vaccine efficacy confirms statistically significant, but lower efficacy against COVID-19 infection as expected during the Omicron wave and consistent with adult observational data. Using the Phase 3 COVE study COVID-19 definition, vaccine efficacy was 43.7% in children 6 months to 2 years and vaccine efficacy was 37.5% in the 2 to under 6 years age group. Similar to adults, a booster trial is anticipated. ^[51]   

Infants 3-6 months 

The BabyCOVE clinical trial in children aged 3-6 months is ongoing.

NVX-CoV2373

NVX-CoV2373 (Novavax) is a recombinant protein-based vaccine and is available via EUA for adults and adolescents in the United States. 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. ^[52]   

A phase 2b/3 global trial (Hummingbird) was initiated mid-summer 2022 in children aged 6 months through 11 years. ^[53]

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. ^[54]  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. ^[55]

The Canadian National Vaccine Safety Network found no significant difference between miscarriage or stillbirth rates between vaccinated or unvaccinated pregnant females. ^[56]  

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. ^[57]  

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. The study found 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). ^[58]  

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. ^[59]  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. ^[60]  

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. ^[61]   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. ^[62]  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. ^[63]  

Anti-S IgG titers in the umbilical cord are correlated with maternal titers and are highest after late second and early third trimester vaccination. ^{[61, 62]}  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). ^[64]    

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. ^[65]  

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. ^[66]  

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. ^{[67, 68, 69]}  

mRNA vaccines

Bivalent mRNA boosters

Vaccines are in development to provide booster doses with improved efficacy against a broader range of viral variants. The FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) voted to change the original COVID-19 vaccine strain composition to include an Omicron BA.4/5 spike protein component to the current vaccine composition for fall 2022 booster doses. As of August 2022, the mRNA vaccines are those with data to include an Omicron-containing component.  

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. ^[70]   

Previous (monovalent) mRNA booster doses

Following an aggressive mass immunization program starting in December 2020 resulting in a sharp decline of COVID-19 cases, waning immunity was observed in Israel across all age groups by mid-June 2021. ^[5]   

Booster doses were implemented in the United States in the autumn of 2021 and provided protection from severe COVID-19 disease, hospitalization, and death. A second mRNA booster (ie, 4th dose) was authorized in March 2022. ^[6]  

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. ^[16]  In January 2022, unvaccinated people aged ≥ 12 years and older 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. ^{[16, 17]}  

NVX-CoV2373 (Novavax) 

Authorized for limited use as a monovalent booster

On October 19, 2022, the FDA authorized NVX-CoV2373 to be used as a first booster (3rd dose) in adults ≥ 6 months after completion of primary vaccination. Use as a booster is specifically for situations when an mRNA bivalent COVID-19 booster vaccine is not accessible or clinically appropriate, or for those who elect this vaccine, because they would otherwise not receive a booster dose. The FDA's decision was based on data from the Phase 3 PREVENT-19 and COV-BOOST trials. 

Following a booster dose, antibody levels increased significantly relative to preboost levels, rising above levels associated with protection in the COV-BOOST Phase 3 trials. Neutralizing antibodies also increased by 34- to 27-fold compared with preboost levels when boosted at 8 or 11 months. In the trials, NVX-CoV2373 increased antibody titers when used as a third dose following initial dosing with another authorized COVID-19 vaccine (heterologous boosting). ^{[37, 38]}  

Similarly, a study in the United States and Australia found IgG geometric mean titers (GMT) had increased by 4.7-fold and MN50 GMT by 4.1-fold for the ancestral SARS-CoV-2 strain at Day 217 compared with the Day 35 titers. ^[39]  

Ad26.COV2.S (Janssen [Johnson & Johnson]) 

Not recommended as booster

Ad26.COV2.S is not recommended for use as a booster. Vaccine efficacy against COVID-19–associated emergency department/urgent care visits was 24% after 1 Janssen dose, 54% after 2 Janssen doses, and 79% after 1 Janssen/1 mRNA dose, compared with 83% after 3 mRNA doses. Efficacy for the same strategies against COVID-19–associated hospitalization was 31%, 67%, 78%, and 90%, respectively. ^[35]

 

Table 7. Investigational Booster Vaccine Candidates in the United States (Open Table in a new window)

 

Routes of vaccine administration other than injection are also undergoing development.

Table 8. Noninjectable Investigational Vaccines (Open Table in a new window)

 

Additional vaccine candidates are in various stages of development and clinical testing. Examples of these vaccines are provided in Table 2.

Table 9. Other Investigational Vaccines (Open Table in a new window)