A Review of the Data Supporting Use of COVID-19 Vaccinations in the Pediatric Population

Abstract

Objective:

The objective of this study was to review the effectiveness and safety of COVID-19 vaccinations in the pediatric population.

Data Sources:

PubMed/Medline (September 2020 to December 2022), the Centers for Disease Control and Prevention, and Food and Drug Administration (FDA) websites.

Study Selection and Data Extraction:

Publications regarding the safety and efficacy of COVID-19 vaccinations in children were included.

Data Synthesis:

Vaccines authorized for use in children include two monovalent mRNA vaccines (≥6 months old) and one monovalent protein subunit adjuvant vaccine (adolescents only). Omicron-specific mRNA bivalent boosters are authorized for children ≥6 months old. Studies after monovalent vaccine authorization illustrated efficacy in children >5 to 6 years of age, specifically decreased severe COVID-19 (including mortality) and multisystem inflammatory response syndrome occurrence (including during Omicron predominance). Available data for children <5 to 6 years suggests efficacy, although data are limited. Monovalent vaccine efficacy against Omicron infections may wane as early as 2 months, but protection against severe disease complications may last longer, and bivalent Omicron boosters are anticipated to increase effectiveness. Myocarditis/pericarditis is a safety concern associated with the COVID-19 vaccinations but occurs less frequently then COVID-19 complications and thus the benefit outweighs the risks.

Relevance to Patient Care and Clinical Practice:

Caregivers seek information from health care professionals regarding vaccine safety and efficacy. Pharmacists can use the objective information in this review to educate caregivers and effectively administer COVID-19 vaccines to patients.

Conclusions:

There is sufficient and continually growing safety and efficacy data available to recommend COVID-19 vaccinations for children ≥6 months of age.

Introduction

The coronavirus (COVID-19) pandemic began in the United States in 2020. This disease is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and transmitted via the respiratory route through small liquid particles.¹ When infected, patient presentations vary widely from mild to moderate respiratory symptoms to more severe disease requiring hospitalization and potentially death. More than 1.1 million people have died from COVID-19 in the United States.² Patients with underlying health conditions (e.g., cardiovascular disease, chronic respiratory diseases, diabetes, and cancer) and those older may experience severe disease.

Children who are at increased risk of severe disease include those with special health care needs such as genetic, neurologic, and congenital heath conditions.³ In addition, pediatric patients with obesity, diabetes, asthma, chronic lung disease, immunosuppression, and sickle cell disease are also at risk for severe disease like adults. However, any age patient can be infected with the virus and develop mild to severe symptoms. From the beginning of the pandemic to February 9, 2023, 15 400 581 children have tested positive for COVID-19, with approximately 127 000 cases being reported November to December 2022.⁴ Children represent 18% of all COVID-19 cases. Case numbers from the Omicron variant have decreased since the January 2022 peak. Since January 4, 2020, 1658 children (0-4 years: 659; 5-18 years: 999) have died from COVID-19.⁵ The majority of patients were male (55%).⁵

Some patients infected with COVID-19 experience long-term effects (symptoms at least 4 weeks after the infection), which is called long COVID or post-COVID conditions.⁶ In the pediatric population, a significant post-COVID condition is multisystem inflammatory syndrome in children (MIS-C). Not all children with MIS-C present the same similarly, but it can require lengthy hospitalizations, and severe cases may include hypotension, shock, cardiac dysfunction, myocarditis, and acute kidney injury. A summary of the US Centers for Disease Control and Prevention (CDC) updated 2023 definition of MIS-C is provided in Table 1.⁷

Table 1.

CDC Case Definition for MIS-C.⁷

An individual aged <21 years presenting with:

Clinical criteria

Fever (>38.0°C documented or subjective), AND

Evidence of clinically severe illness requiring hospitalization or resulting in death, AND

New onset multisystem (≥2) organ involvement (cardiac, gastrointestinal, hematologic, mucocutaneous, or shock), AND

C-reactive protein (CRP) ≥3.0 mg/dL (evidence of systemic inflammation), AND

No alternative plausible diagnoses

Laboratory criteria

Positive SARS-CoV-2 RNA (using a diagnostic molecular amplification test) or specific antigen in clinical specimen (current, recent (up to 60 days before hospitalization), or postmortem) OR

Positive SARS-CoV-2 specific antibodies in serum, plasma, or whole blood (current or during hospitalization)

Epidemiological Linkage Criteria

Close contact (within 6 feet for at least 15 minutes over a 24-hour period) with a suspected/confirmed patient with COVID-19 within 60 days of hospitalization

Vital record criteria

Death certificate lists MIS-C or multisystem inflammatory syndrome as significant condition contributing to death or underlying cause of death

Case definitions:

Confirmed: Meets clinical and laboratory criteria; Probable: Meets clinical and epidemiologic linkage criteria; Suspect: Meets vital records criteria

Abbreviations: MISC, multisystem inflammatory syndrome in children; OR, odds ratio.

Patients can present with MIS-C during an active COVID-19 infection or weeks after an infection. As of January 3, 2023, there have been 9344 patients who met the original 2020 case definition of MIS-C and 76 patients classified as a MIS-C death.⁸ The median age at onset of MIS-C is 9 years with half of children with the condition being 5-13 years old. Sixty percent of the patients were male. Of those children with reported MIS-C and race/ethnicity data, patients were White, non-Hispanic (34.7%), Hispanic/Latino (26.4%) or Black, Non-Hispanic (30.4%). Most patients (98%) tested positive for SARS CoV-2 and 2% of the population with MIS-C had contact with someone with a COVID-19 infection. Importantly, reports suggest 45% to 68.5% of reported cases also occur in patients without comorbidities or chronic medical conditions.^9,10

Vaccinations against COVID-19 have emergency use authorizations (EUA) or approval by the US Food and Drug Administration (FDA) for children as young as 6 months of age (Table 2 and Figure 1) and are being utilized in countries across the world. As of February 9, 2023, 73.3%, 77.4%, and 78.9% of patients in the United States at the age of ≥5, 12, and 18 years have completed their COVID-19 vaccination primary series, respectively.¹⁷ Only 16.8%, 18.1%, and 19.2% of patients in the United States at age of ≥5, 12, and 18 years have received the bivalent booster dose, respectively.¹⁷ For children younger than 5 years, 1.83 million have received at least 1 dose of the COVID-19 vaccines since June 18, 2022.¹⁷

Table 2.

COVID-19 Vaccines Authorized in Pediatric Patients in the United States as of February 14, 2023.^11-16

Vaccine brand and generic names	Comirnaty COVID-19 vaccine (BNT162b2 for monovalent) COVID-19 vaccine bivalent	Spikevax COVID-19 vaccine (mRNA-1273 for monovalent) COVID-19 vaccine bivalent	Novavax COVID-19 vaccine (NVX-CoV2373)
Vaccine manufacturer	Pfizer-BioNTech	Moderna	Novavax
Type of vaccine	mRNA	mRNA	Protein subunit with adjuvant
Age of indication and approval status	6 months to 4 years (monovalent, bivalent, EUA) 5-11 years (monovalent, bivalent, EUA) ≥12 years (monovalent, FDA approved; bivalent, EUA)	6 months to 5 years (monovalent, bivalent, EUA) 6-11 years (monovalent, bivalent, EUA) 12-17 years (monovalent, bivalent, EUA) ≥18 years (monovalent, FDA approved; bivalent, EUA)	≥12 years (monovalent, EUA)
Primary schedule and dose (monovalent vaccine)	3 doses (Dose 1 to 2: 21-56 days apart; Dose 2 to 3: at least 56 days) • 6 months to 4 years: 3 μg, third dose replaced with bivalent 2 doses (21-56 days apart) • 5-11 years: 10 μg • ≥12 years: 30 μg	2 doses (28-56 days apart) • 6 months to 5 years: 25 μg • 6-11 years: 50 μg • ≥12 years: 100 μg	2-dose series (21 days apart) • 0.5 mL (5 μg rS and 50 μg of Matrix-M adjuvant)
Additional dose for immunocompromised patients	No additional doses recommended for ages 6 months to 4 years at this time Third primary series dose (EUA) for ≥ 5 years and older who are moderately or severely immunocompromised; at least 28 days after the second dose	Third primary series dose (EUA) for ≥ 6 months who are moderately to severely immunocompromised age at least 28 days after second dose	NA
Booster (brand name) schedule and dose	Bivalent only (dosage is combination of ½ original strain and ½ Omicron BA.4/BA.5) ≥ 5 years as a single booster at least 2 months after primary series completion or last monovalent booster - 6 months to 4 years: 3 μg only as third dose in primary series (not indicated if all 3 monovalent doses were received) - 5-11 years: 10 μg - ≥ 12 years: 30 μg	Bivalent only (dosage is combination of ½ original strain and ½ Omicron BA.4/BA.5) ≥6 years as a single booster at least 2 months after primary series or last monovalent booster - 6 months to 5 years: 10 μg after second dose of primary series - 6-11 years: 25 μg - ≥12 years: 50 μg	Monovalent only Pfizer-BioNTech or Moderna bivalent booster recommended per FDA for 12-17 years - ≥18 years as single booster at least 6 months after primary series; use only in limited situations
Pearls	- Different cap and label colors may be use for primary and booster series for each age group - Volume for dosages in children <12 years but different dosages for 6 months-4 years and 5-11 years - After thawing, stability varies dependent on temperature use for storage and if the vial has been used - Multidose vials require dilution	- Different cap and label colors may be use for primary and booster series for each age group - After thawing, stability varies dependent on temperature use for storage and if the vial has been used - Multidose vials required dilution	- Generally only recommended for booster if receipt of mRNA bivalent booster vaccines are not possible

Abbreviations: EUA, emergency use authorization; FDA, US Food and Drug Administration; NA, not applicable.

Figure 1.

Timeline with variant expression and most significant COVID-19 pediatric vaccination authorizations.^11-13

Abbreviations: BV, bivalent; EUA, emergency use authorization; mRNA, messenger RNA; MV, monovalent.

Refusal or hesitancy among parents to have their children receive recommended vaccinations occurred before the introduction of vaccines for COVID-19. The reasons behind it are multifactorial but include safety concerns and the need for more information from health care providers.¹⁸ Of surveyed parents before vaccination authorizations in children, 69.5% were more hesitant to receive the COVID-19 vaccinations compared with the seasonal influenza vaccine.¹⁹ For COVID-19 vaccinations, hesitancy/refusal may be higher in parents with younger children.^20,21 Common reasons surrounding parent refusal or hesitancy for COVID-19 vaccines are related safety and efficacy concerns, with some survey research suggesting parents worry the risks may outweigh the benefit in their children.²² A survey done after a COVID-19 vaccine was available in the United States for adolescents illustrates that having a trusted source of information was associated with COVID-19 vaccine acceptance.²¹ While COVID-19 vaccine safety and efficacy data are publicly available, practitioners play a large role as a trusted source of information to interpret and distill the vast amount of information for parents to make educated decisions. This review aims to summarize for practitioners the available safety and efficacy profiles of the COVID-19 vaccines currently authorized in the United States for use in the pediatric population.

Data Sources

PubMed/Medline was searched using COVID filters from January 2020 to December 2022 to identify peer-reviewed studies assessing the safety and efficacy of COVID-19 vaccinations in pediatric patients. The FDA website was also searched for details regarding study data used in the decision memorandums for vaccine authorizations in the pediatric population that were not available in PubMed/Medline. The CDC website was also searched for relevant post-authorization data regarding pediatric COVID-19 vaccinations.

Data Synthesis

Authorization Process Overview and History

Table 2 summarizes COVID-19 vaccines with EUAs or approvals for use in the pediatric population as of February 14, 2023. Figure 1 illustrates approximately when each EUA occurred (approvals were not included as they have a lesser impact on the availability of vaccines for use). The initial EUA of the Pfizer-BioNTech monovalent vaccine included adolescents 16 to 17 years of age at the same time it was approved in the adult population.¹¹ The Pfizer-BioNTech monovalent vaccine was then authorized in a stepwise manner from older age categories to younger ages over time. The Moderna monovalent vaccine was not authorized until June 2022 for any patients <18 years, but the authorization encompassed patients 6 months to 17 years at the same time.¹² The Novavax vaccine is the only protein-based conjugate vaccine available and indicated for adolescents ≥12 years.¹³ The bivalent mRNA boosters were the most recent to be approved for use in the pediatric population.^11,12

The mRNA based monovalent primary series and bivalent booster vaccines are authorized in the largest number of pediatric age groups. The youngest indicated age of any currently available vaccine is 6 months. Different age groups may only be authorized under an EUA while other age groups have approval including a branded name.^11-13 There are important variations between vaccines including the dose and age for specific dosages (5-11 years for the Pfizer-BioNTech vaccine vs 6-11 years for the Moderna product for the middle pediatric age category).^11,12 The number of doses recommended for the initial series also varies between vaccines. These differences can make choosing the correct product based on age error prone. The CDC does not recommend interchanging products for the primary series doses. Additional schedule complications include the recent approval of bivalent boosters, which replace any monovalent booster after the primary series is complete in any of the authorized ages and also the third dose in the Pfizer-BioNTech series for those 6 months to 4 years.¹¹ This can also lead to confusion as to which vaccine should be given depending on where a patient is in their vaccination series. Different products from the primary series may be used for the bivalent booster doses, but only the mRNA-based bivalent boosters are authorized for pediatric patients.

Safety Analyses

For the primary series vaccinations, detailed safety data were collected in the studies leading to authorization.^23-28 These data provide appropriate comparisons to placebo regarding adverse events close to the administration of the vaccines. Due to strict inclusion criteria, relatively small samples sizes, and relative short follow-up periods, rare adverse events could be difficult to detect. In addition to continued review of initial or ongoing studies from the manufacturer sponsored studies, post-authorization review data are also obtained via voluntary submissions to the FDA.^29-31 These mechanisms are the vaccine adverse event reporting system (VAERS) and the V-safe surveillance system. The VAERS system includes unsolicited adverse events, and submissions are reviewed and summarized by the FDA periodically. The V-safe is a voluntary system where users can register and submit data post-vaccination. The V-safe has a total number of vaccine recipients to estimate proportional occurrence among the subset of patients receiving the vaccine, while VAERS does not.

Table 3 provides a summary of relevant safety considerations regarding COVID-19 vaccines in children identified either in studies used for authorization or post-marketing analyses. The most common adverse effects expected are mild-moderate local and systemic immunologic response reactions (e.g., fever, injection site pain, headache, fatigue), similar to other vaccines. Most occurred higher than placebo (normal saline intramuscular injection) and thus could be due to the vaccine versus a general injection adverse effect. While differences in studied vaccines and method of adverse event identification play a role, there was a general trend toward more adverse effects with the second dosages of vaccines compared with the first across the available vaccines (although not all adverse effects had higher proportional occurrence). Some adverse effects were proportionally higher in Moderna versus Pfizer-BioNTech (e.g., fever, nausea/vomiting), but there are no studies designed to compare adverse effects between the two and thus one vaccine is not definitively known to have more adverse effects compared with another. Most adverse effects only last 1 to 2 days, and typically 16% or less of the time (<10% in multiple prospective studies) the adverse effects impacted the patient’s ability to perform daily activities (e.g., the ability to attend school) (Table 3).

Table 3.

Notable Adverse Events Potentially Associated With COVID-19 Vaccinations.^23-31

Adverse events	Relevant pearls
Common but usually mild-moderate (typically lasting for 1-2 days, and occurring within 7 days)
Unable to perform daily duties for at least 1 day	- Usually <16%.
Fever	- <18% for first doses for both mRNA vaccines; Pfizer-BioNTech remained <14% in patients <11 years with subsequent doses. - Possibly higher for second dose for Pfizer-BioNTech in adolescents and second dose of Moderna in all age groups (20%-30%). - Novavax 12-17 years: <1% first dose, 17% second dose. - Temperatures are rarely >40°C.
Pain, irritation, swelling (irritability/fussiness)	- Most common adverse events (up to 94% for pain, redness, and swelling typically <21%) and higher than placebo injections. - Possibly higher redness and swelling in Moderna and with second doses. - Irritability/fussiness could present as pain in infants.
Headache	- Up to 70% in adolescents, less in children although it is harder to elucidate in younger children
Muscle/joint pain	- Typically <43%
Fatigue/sleepiness	- Up to 66% in adolescents for fatigue, ~40% in younger children.
Nausea/vomiting/diarrhea	- <24%, possibly higher in adolescents with the second Moderna dose.
Rare, but potentially severe ADEs
Myocarditis/pericarditis (occurring up to 21 days post)32	- Minimally reported in patients <5 years. - Identified via post-authorization analyses and ranges from 0% to 0.036%, but less than due to MIS-C.
Seizures	- Reported in post-authorization voluntary reports in children <12 years, with some patients having underlying concerns for neurologic or seizure disorders.
Hypersensitivity reactions	- <5% in all vaccinations, most commonly reported as generalized rashes or urticaria with anaphylaxis rarely reported (<0.5/million doses).
MIS-C33	- Case reports suggest a possible cause, but not reported otherwise.

Abbreviation: MIS-C, multisystem inflammatory syndrome in children.

Of the serious adverse events seen at the time of authorization, rarely were they deemed to be associated with the vaccines. There were seizures noted in the safety analyses for children <12 years, but in general were very infrequent or possibly related to underlying disease states (e.g., history of neurologic disorders or febrile seizures), so it is difficult to ascertain if they were definitively due to the vaccines.^29,31 Although outside of this review, it is important to note that other “adverse effects” initially spread largely through social infrastructures such as infertility, teratogenicity, and DNA remodeling, have no founded scientific merit but often cause reluctance for parents. It is important that pharmacists are aware these concerns may exist among parents, and it is important that pharmacists educate parents on the evidence-based adverse effects described in Table 3 which could occur. Analyses of booster vaccines using the original monovalent strains did not yield any significant new adverse events compared with the primary series vaccinations.³⁴ Safety data for the bivalent boosters were not available at the time of writing.

Myocarditis or pericarditis was a known potential adverse event described in the young adult population prior to authorization of any of the vaccines in children. It was not described in a significant proportion of patients in the pediatric safety analyses at the time of authorization, but larger post-authorization analyses suggested a possible association.^9,32 These adverse events can be rationalized because they are also severe outcomes associated with COVID-19 disease. When comparing the myocarditis associated with COVID-19 vaccines with both classic (e.g., non-COVID related disease) and COVID-19 associated myocarditis, the vaccine-associated myocarditis is a significantly milder disease compared with the other two types of myocarditis.⁹ The age category with the highest incidence of myocarditis or pericarditis was adolescents at 21 days post a second mRNA-based vaccine dose (35.9/100 000 vaccinated adolescents), while rates in other subcategories were lower or reported no cases of myocarditis or pericarditis (e.g., females 5-11 year at any point, or males 5-11 years 21 days after the second dose).³²

Efficacy Analyses Used for Authorizations

For the available primary series COVID-19 vaccines authorized in the pediatric population, the primary outcomes used to illustrate efficacy during the authorization process (excluding the 16- to 17-year-old age group) were immunologic response outcomes. Neutralizing antibody geometric mean titers and seroresponse rates were the primary immunologic outcomes. By illustrating a similar immunologic response in each pediatric age group compared with other age groups, efficacy results were thought to likely be extrapolated from those populations. This extrapolation method is similar method to how other vaccine approvals were completed, and other drugs have been approved for use in the pediatric population. For example, the pneumococcal vaccines were approved based on the immunologic responses (geometric mean concentration of IgG antibodies) for each serotype compared with immunologic responses for other serotypes and efficacy extrapolated from the initial studies in potentially different populations or using a prior version of the pneumococcal vaccine targeting different serotypes.³⁵ Importantly, all of the available COVID-19 vaccines were able to elicit similar responses as the adult population and achieved their primary immunologic endpoints based on the authorized dosing schedules. Of note, the Pfizer-BioNTech dose finding studies illustrated potential differences in immunologic response in children 2 to 4 years, and a third dose was needed to achieve equivalent immunologic responses.²⁴ Thus, the primary monovalent series for this specific brand utilized a third dose in this age group.

The efficacy data supporting booster doses authorized was slightly different, such that immunologic responses were only provided for patients 5 to 11 years for the monovalent Pfizer-BioNTech COVID-19 vaccine and compared with responses in older populations. Immunologic responses were provided for the Moderna bivalent COVID-19 vaccines in the pediatric population but using a different strain (Omicron BA.1) compared with what was included in the authorized vaccine and circulating at the time of authorization (Omicron BA.4/BA.5). The FDA’s decision letters described that due to the same manufacturing technique, safety and efficacy are likely similar and clinical or administration safety data were not needed.^36,37 This approach is also not a new concept to vaccine approval and vaccination practices, because each year different influenza strains are included using the same process in the yearly vaccine without additional studies.

While immunologic responses were the primary outcomes in each EUA, descriptive frequencies of infection occurrence in each pediatric age group were provided for all primary vaccine series. Table 4 summarizes the provided infection-based comparisons between vaccine and placebo groups from the studies used to gain vaccine authorization for each vaccine and the specified age group. It is important to note that overall, when compared with studies including adults, the total sample sizes and number of infections are lower. This could be due to multiple reasons. Recruitment for pediatric studies can be more difficult. Because there was a higher chance the vaccines would be effective, a 1:1 randomization was not ethically possible and thus the studies used 2:1 randomization in favor of the vaccine group. This creates smaller cohorts to compare.

Table 4.

Efficacy Data Used for COVID-19 Vaccine Authorizations for the Pediatric Population.

Age group	Vaccine	Study dates for infection-based outcomes data (predominant strain)	Data summary for efficacy at the time of authorization
Primary series vaccinations
6-23 months	Pfizer-BioNTech24	June 21, 2021-April 29, 2022 (Delta then beginning of Omicron)	- 75.5% efficacy post third dose: 2 infections/596 patients in placebo group vs 1/1178 in vaccine. - 100% seroresponse after 3 doses.
6-23 months	Moderna28	October 18, 2021-February 21, 2022 (Delta then beginning of Omicron)	- 50.4% efficacy post second dose: 40 infectionsa/480 patients in placebo group vs 62/1439 in vaccine. - 100% seroresponse after 2 doses.
2-4 years	Pfizer-BioNTech24	June 21, 2021-April 29, 2022 (Delta then beginning of Omicron)	- 82% efficacy post third dose: 5 infectionsa/915 patients in placebo group vs 2/1835 in vaccine. - 100% seroresponse after 3 doses.
2-5 years	Moderna28	October 18, 2021-February 21, 2022 (Delta then beginning of Omicron)	36.8% efficacy post second dose: 61 infectionsa/858 patients in placebo group vs 119/2594 in vaccine. - 98.9% seroresponse after 2 doses (3 males were the only patients without a seroresponse).
5-11 years	Pfizer-BioNTech25	June 7, 2021-September 6, 2021 (Delta predominance)	90.7% efficacy post second dose: 16 infections/663 patients in placebo group vs 3/1305 in vaccine. - 99.2% seroresponse after 2 doses.
6-11 years	Moderna28	March 15, 2021-August 9, 2021 (Alpha then beginning of Delta)	- 76.8% efficacy post second dose: 4 infectionsa/853 patients in placebo vs 3/2644 in vaccine. - 99.1% seroresponse after 2 doses.
12-15 years	Pfizer-BioNTech26	October 15, 2020-March 13, 2021 (wildtype or Alpha)	- 100% efficacy post dose 2: 16 infections/978 in placebo group vs 0/1005 in vaccine. - 97.9% seroresponse after 2 doses.
16-17 years	Pfizer-BioNTech27	September 16, 2020-November 14, 2020 (wildtype or Alpha)	100% efficacy post second dose as subgroup of adult study; 1 infection/61 patients in placebo group vs 0/58 in vaccine.
12-17 years	Moderna28	December 9, 2020-May 21, 2021 (wildtype or Alpha)	- 93.3% efficacy post second dose: 7 infectionsa/1042 patients in placebo group vs 1/2139 in vaccine. - 98.8% seroresponse after 2 doses.
12-17 years	Novavax23	April 26, 2021-August 9, 2021 (Mostly Alpha, ended begging of Delta)	- 78.4% efficacy poster second dose: 11 infections/594 patients in placebo group vs 5/1205 in vaccine. - 98.7% seroresponse after 2 doses.
Booster vaccinations
5-11 years	Pfizer-BioNTech monovalent38	N/A	- Extrapolated efficacy data from study in patients ≥16 for patients 12-15 years. - In patients 5-11 years, immunologic response goals were achieved in response to the booster.
12-17 years	Pfizer-BioNTech monovalent39-41	Study up to October 5, 2021 for 16-17 years (Delta predominance) July 30, 2021-October 10, 2021 for >15 years (Delta predominance, study from Israel)	- Patients 5-15 years all data extrapolated from data below. - Randomized ongoing study included 78 patients 16-17 years with 2 infections in placebo group (95% efficacy in entire cohort including adults). - Reduction in 72.2 infections/100 000 person days for patients 16-29 years in study from Israel unrandomized implementation analysis. - Immunologic responses extrapolated from data in patients >17 years.
6 months-17 years	Pfizer-BioNTech bivalent37	N/A	- Infection efficacy outcomes not submitted. - Efficacy extrapolated from prior study of bivalent vaccine with Omicron BA.1 in adults >55 years (assessed via mean titers and 85% efficacy comparing the bivalent to the monovalent forms).
6 months-17 years	Moderna bivalent36	N/A	- Infection efficacy outcomes not submitted. - Efficacy based on adult data. - Immunogenicity targets were achieved in age groups from a bivalent vaccine containing Omicron BA.1 variant.

Abbreviation: N/A, not applicable.

^aInfections based on the definition provided by the United States Centers for Disease Control and Prevention.

As illustrated in Figure 1 and Table 4, there were changes in the predominant strain of COVID-19 circulating during the studied periods. This includes strains that may have altered the efficacy of the vaccines. For these reasons, interpretation and applicability of the infection-based outcomes at the time of authorization were more difficult compared with the studies in the adult population. General trends, albeit with limitations as previously described, seen in the infection-based efficacy outcomes are that efficacy at preventing infections was similar between vaccines and when compared with adult studies if the pediatric study was done during circulation of the wildtype or alpha COVID-19 strain (i.e., studies in adolescents using the mRNA vaccines had efficacy for preventing infections >93%). The studies done in children <12 years occurred during Delta and Omicron predominance and described lower efficacy percentages, although they still described efficacy compared with placebo (Table 4). This may be due to differences in strains and/or small sample sizes included. The Moderna COVID-19 vaccines when compared with Pfizer-BioNTech vaccines for the same age group are numerically lower, but this could be again due to slight differences in study time periods and small sample sizes. It is important to note that comparative studies are not available and so it is difficult to draw comparative conclusions comparing between vaccines.

At the time of authorization for the Pfizer-BioNTech vaccine in the <16 year age groups and the Moderna vaccine, immunologic efficacy of the monovalent vaccines against the more prevalent COVID predominant strains were performed when applicable. As a general trend, some decreases in immunologic responses were described against the Delta strain, but significantly lower responses against the Omicron variant were described. This did lead to some concerns about vaccine efficacy against the Omicron strains and led to the development and authorization of the revised bivalent vaccine stepwise and most recently in all children ≥ 6 months of age. The bivalent vaccines also replaced boosters based on the monovalent vaccine and the third dose in children <5 years of age for Pfizer-BioNTech COVID-19 vaccine primary series.

In all of the studies included in the summaries regarding authorizations, severe COVID-19 requiring hospitalization and/or resulting in death were rare or did not occur. This is potentially due to lower disease severity or mortality rates in children and also the strict inclusion criteria of clinical trials. It is important to note that mortality outcomes were also difficult to ascertain in adult studies used for authorization. Follow-up in the studies used for authorization in the pediatric population was also potentially not long enough to illustrate differences in outcomes like MIS-C. This is a significant and unpredictable (as it occurs in patients with no significant underlying disease states) concern in the pediatric population and among the most relevant outcomes of interest related to vaccine efficacy in this population.

Post Authorization Efficacy and Risk-Benefit Analyses

Post-authorization studies have focused on assessing vaccine efficacy in the pediatric population after large-scale vaccination efforts. At the time of writing, these data are more prevalent in children ≥5 to 6 years as the vaccines have been used in this population for a longer time compared with those ≤5 to 6 years of age.

Significant studies illustrating efficacy in pediatric patients are summarized in Table 5. Most of the studies are based on the Pfizer-BioNTech primary vaccination series, as it was the first to be approved in children <18 years. In general, vaccine efficacy against infections due to Alpha and Delta strains (studies from 2021) were high (>90%), although against Omicron efficacy decreased significantly and some studies (mainly patients 5-11 years) report low (e.g., <30%) or no efficacy against infections 60-90 days from vaccination.^42,51 Importantly, a study has illustrated reduced MIS-C occurrence over 120 days after vaccination during a period of Omicron predominance.¹⁰

Table 5.

Select Chronologic Post-Authorization Studies Related to Vaccine Efficacy.

Analysis	Age group, dates, vaccine, and location	Significant findings
Chemaitelly et al42	12-17 years; February 2021-July 2022; Pfizer-BioNTech, Qatar 5-11 years February 2022-July 2022; Pfizer-BioNTech; Qatar	- Vaccine efficacy in adolescents was 87.6% pre-Omicron and 30.6% during Omicron; Vaccine efficacy decreased after 3 months and did not offer protection (efficacy was as high as 95% the first month post vaccination). - Vaccine efficacy in children 5-11 was 25.7% during Omicron (up to 49.1% within the first month post dose); Vaccine was ineffective after 3 months.
Delahoy et al43	12-17 years; June 20-July 31, 2021; Pfizer-BioNTech; US	- Unvaccinated adolescents were at 10.1 times higher odds of hospitalization compared with those unvaccinated.
Kildegaard et al44	12-17 years; Up to October 1, 2021; Pfizer-BioNTech; Denmark	- Comparing a cohort of 175 176 fully vaccinated to 1 748 086 unvaccinated adolescents, efficacy was 93% after both doses during Delta variant. - No myocarditis outside of MIS-C was noted.
Levy et al45	12-17 years; September 2021-October 31, 2021; 95% Pfizer-BioNTech; France	- Lower risk of MIS-C among those with at least 1 dose of vaccine, hazard ratio 0.09 (95% CI 0.04-0.21.)
Zambrano et al46	12-17 years; July 1, 2021-December 9, 2021; Pfizer-BioNTech; US, 20 states	- Vaccine efficacy at preventing MIS-C was 91%. - 95% of 102 MIS-C cases were in unvaccinated patients.
Block et al32	5-11 and 12-17 years; January 1, 2021-January 31, 2022; Pfizer-BioNTech; US	- Among males, relative risk of myocarditis, pericarditis, or MIS-C within 42 days from COVID-19 infection is higher than from vaccinations, RR of 20.5 and 4.9 for 5-11 and 12-17 years, respectively. - Among females, relative risk of myocarditis, pericarditis, or MIS-C within 42 days from COVID-19 infection is higher than from vaccinations for ages 12-17 years (RR 12.4). - No cases of adverse cardiac outcomes related to vaccines in 5- to 11-year-old females, but incidence of COVID-19 related myocarditis, pericarditis, and MIS-C was 93 cases/100 000 persons.
Klein et al47	5-17 years; April 2021-January 2022; Pfizer-BioNTech (with monovalent booster for 16-17 years); 10 states in the US	- 5-11 years: Delta data minimally available; 51% efficacy before 67 days post-dose 2 at prevent ED or urgent care encounters; 74% efficacy at preventing hospitalizations. - 12-15 years: 92% and 45% efficacy at prevention ED or urgent care encounters 14-150 days, 79% effective during delta ≥150 days, not effective ≥150 days post dose against Omicron; 92% and 73% effective <150 and ≥150 days, respectively, at preventing hospitalizations during both periods combined. - 16-17 years; 85% and 77% effective against ED or urgent care encounters <150 and ≥150 days post dose 2 during delta, 34% and not effective against Omicron <150 and ≥150 days post dose 2, respectively, efficacy ≥7 days post booster dose 3 was 81%; 94% and 88% effective <150 and ≥150 days post dose 2 at preventing hospitalization, respectively.
Miller et al48	5-17 years (likely more 12-17 years; July 2021-January 2022; Pfizer-BioNTech; US	- Among 763 MIS-C cases in vaccine-eligible patients, 91.3% were unvaccinated and 5.2% were partially vaccinated.
Shi et al49	5-11 years; March 2020-February 2022; Pfizer-BioNTech bnt162b2; US	- Hospitalization rates (normalized to 100 000 population) were half that in vaccinated children vs unvaccinated during Omicron predominance. - 1/2 of unvaccinated hospital children were Black or Hispanic.
Nygaard et al50	5-17 years; August 1, 2021-February 1, 2022; Pfizer-BioNTech; Denmark	- Estimated vaccine effectiveness at preventing MIS-C (n = 51 cases) was 94%.
Zambrano et al10	5-18 years; July 1, 2021-April 7, 2022; Pfizer-BioNTech; US	- Reduction in odds of severe MIS-C in 5-11 years (OR 0.22, n = 144 MIS-C cases) and 12-18 years (OR 0.1, n = 160 MIS-C cases). - In patients 12-18 years, risk of MIS-C remained lower in vaccinated group between delta and Omicron periods, respectively, OR 0.06 and 0.08. - Protection against MIS-C persisted beyond 120 days for adolescents. - 92% of vaccine-eligible patients with MIS-C were unvaccinated.
Castelli et al51	12-17 years (Pfizer-BioNTech or Moderna); 3-11 years alternative protein-based vaccine (not available in the United States); September 2021-April 2022; Argentina	- Among 91 108 adolescent (48.5% with infections), Pfizer-BioNTech or Moderna had 66.8% and 26% efficacy in preventing infection during Delta and Omicron predominance, respectively. - Efficacy against infection decreased down to <13% ≥60 days post vaccination. - 97% protection against deaths in adolescents (11/20 deaths unvaccinated vs 6/80 controls were unvaccinated) during Omicron. - 66.9% protection in children 3-11 at preventing death during Omicron (data based on protein-based vaccine).

Abbreviations: CI, confidence interval; ED, emergency department; MIS-C, multisystem inflammatory syndrome in children; OR, odds ratio; RR, risk ratio; US, United States.

When assessing population-level initiatives like vaccines, studies will typically focus on the most severe risk associated with the disease course compared with the most severe risk associated with the vaccine. A major differences in this type of assessment between the adult population and the pediatric population is the lower mortality rate in children, and thus mortality rates in children are likely not the most severe outcome to determine the ideal risk:benefit profile of the vaccine. A highly useful risk:benefit comparison for pediatric COVID-19 vaccinations is the risk of myocarditis/pericarditis due to the vaccine versus the incidence of myocarditis, pericarditis, or MIS-C (a life-threatening condition with morbidity implications if severe) due to COVID-19 disease. Adult analyses of a similar question suggest that there is a 7-fold higher risk of myocarditis due to COVID-19 infection compared with the vaccine.⁵² This risk:benefit was also verified in the pediatric population with COVID-19 disease patients being associated with higher risk ratios for myocarditis/pericarditis or MIS-C, with risks 42 days after the immunizations ranging from 4.9- to 20-fold higher risk with COVID-19 disease depending on the age and gender. Notably, risk ratios were not calculable for females 5 to 11 years because there was not an incidence of myocarditis/pericarditis due to vaccine, yet there were complications due to COVID-19.³² As additional evidence of the impact of vaccinations on MIS-C, large-scale epidemiologic studies not obtaining patient-specific vaccination status showed a reduction in MIS-C during the Delta wave pre and post vaccination, albeit somewhat small differences.⁵³ Using patient-level vaccination data, the odds of having MIS-C were approximately 6-fold higher in unvaccinated patients than vaccinated patients during the Delta wave with the Pfizer-BioNTech COVID-19 vaccine.¹⁰ Data showing similar results have also been reported from multiple countries such as Argentina, Denmark, France, and Qatar, with some studies estimating 10-fold reductions in MIS-C with vaccination.^{42,44,45,50,51} Although infection-based outcomes showed decreased effectiveness during Omicron, a decreased rate of MIS-C with vaccination has been described during Alpha, Delta, and Omicron predominance.^10,50 Most studies did not report many, if any fatalities; however, data from Argentina suggest a mortality benefit from vaccinations (66.9%-97% protection depending on age).⁵¹

The efficacy and safety data available for COVID-19 vaccines in children are primarily based on receipt of the monovalent vaccine products designed against the wildtype or Alpha strains of COVID-19. It has become clear that the COVID-19 virus has the ability to adapt and change impacting the efficacy of the monovalent forms. The recent change from monovalent to bivalent COVID-19 booster vaccines, based on efficacy data from the original monovalent series or other Omicron-based variants, could represent a future where COVID-19 vaccines are updated and when needed to target newer strains if they emerge and cause significant population health issues.

Relevance to Patient Care and Clinical Practice

The available data solidifies the CDC recommendations, FDA authorizations, and Advisory Committee on Immunization Practices (ACIP) recommendations to vaccinate children 6 months and older with one of the age-appropriate mRNA or protein-based COVID-19 vaccines as a primary series, followed by an bivalent mRNA booster.^11-14 This review can provide clinicians with much needed information to best educate patients, friends, and family regarding the safety and efficacy profiles of the available COVID-19 vaccines. Important information to include in educational efforts is that the studies used during the authorization process included efficacy outcome methodology that is similar that used in other vaccines already in use. In addition, post-authorization data clearly illustrates efficacy of the vaccine compared with placebo that the benefit from COVID-19 vaccinations against severe complications clearly outweighs the mild common adverse effects and rare chance of severe adverse effects potentially associated with the vaccine. Objective information like this presented to parents by a trusted practitioner may help quell vaccine hesitancy among parents.

This information is very important for pharmacists in particular. All states allow pharmacists to administer immunizations, but states’ laws vary in the details such as the age of the patient or the type of vaccine the pharmacist can administer with or without a prescription. On September 3, 2020, the US Department of Health and Human Services issued guidance under the Public Readiness and Emergency Preparedness Act that authorized state-licensed pharmacists to order and administer FDA-authorized or -licensed COVID-19 vaccinations to patients 3 years of age and older.⁵⁴

As of August 2022, 49 states allow pharmacists to administer the COVID-19 vaccine.⁵⁵ Missouri and the District of Columbia do not allow pharmacists to administer the COVID-19 vaccine and South Carolina requires a prescription. Seventeen states (AL, AK, CA, CO, ID, MI, MS, NE, NV, NH, NM, OK, SD, TN, UT, VT, WA) allow pharmacists to administer the COVID-19 vaccine to a patient of any age without a prescription.

Due to increased accessibility and more recent expansion of practice abilities benefiting pediatric patients, pharmacists also have a large role to play in vaccination. As of December 15, 2022, more that 294.9 million COVID-19 vaccine doses were administered by participants in the Federal Retail Pharmacy Program.⁵⁶ Specifically, 11 weeks after the Pfizer-BioNTech COVID-19 vaccine received EUA for children 5-11 years, 46.4% of the doses administered were provided in pharmacies.⁵⁷ Pharmacists are highly trusted professionals and can play a large role in educating patients and caregivers on the benefits and risks of COVID-19 vaccines as well as administering COVID-19 vaccinations.

Conclusion

This review summarizes the available safety and efficacy data of the authorized COVID-19 vaccines in the pediatric population for clinicians. The immunologic and preliminary infection-based efficacy data used to gain authorization of COVID-19 vaccines for children combined with a substantial amount of post-authorization data solidify the positive benefit to risk profile for COVID-19 vaccinations in pediatric patients 6 months of age and older. Thus, these vaccines are highly recommended for prevention of COVID-19 and COVID-19 complications like MIS-C. The data from the monovalent vaccines could be used to quickly adapt to future vaccine versions with multiple or new valences, as has occurred already for the currently available bivalent boosters. Pharmacists and other health care providers have and will continue to play a significant role in vaccinating children and educating the public regarding efficacy, safety, and recommendations of COVID-19 vaccines.