Update on pediatric COVID-19 vaccination

SARS-CoV-2, the virus responsible for COVID-19, continues to circulate worldwide, causing severe disease, long-term morbidity, and death. It has resulted in hundreds of million infections and nearly 7 million deaths worldwide.¹ In the United States since the pandemic started, the pediatric population has experienced 198,966 hospital admissions for individuals up to age 17 years (through September 2, 2023), 2312 deaths (819 children aged 4 years or younger and 1493 individuals aged 5 to 17 years), 9538 cases of multisystem inflammatory syndrome in children that led to 79 deaths, and an estimated prevalence of long COVID-19 as high as 25% (mood, fatigue, and sleep disorder symptoms being most common).^2-4 Children do transmit the virus but are less likely to do so than adults⁵ and are more likely to have asymptomatic infection than adults.⁶ Although the COVID-19 hospitalization burden is smaller in children than adults, hospitalizations rival the pre–vaccine era burden of other now vaccine-preventable viruses (Table 1).^1-4 It is important to recognize that other vaccine-preventable diseases today result in similar or fewer annual pediatric deaths before vaccines became widely utilized (Table 2).⁷ The burden of SARS-CoV-2 infections among the millions of children in the United States is still large, so improving outcomes is essential to their health and well-being.

There are numerous considerations in determining an individual’s level of protection against SARS-CoV-2. They include age, immune status, underlying medical conditions, how many vaccine doses have previously been received, the number of previous infections, the period during the pandemic when infection(s) occurred, timing of their most recent vaccination or infection, and how well the circulating variant matches the latest vaccine. CDC data document high seroprevalence with a notable majority of children having been infected with SARS-COV-2.⁸ CDC data reflect a 96.3% COVID-19 combined seroprevalence estimate in the US pediatric population ranging from 6 months to 17 years old; this includes both vaccination- and infection-induced SARS-CoV-2 seroprevalence.² These rates increase by age range with 89.9% for newborn to 4 years, 97.1% for 5 to 11 years, and 98.9% for 12 to 17 years.² The SARS-CoV-2 virus, however, continues to steadily mutate, resulting in variants that are different from the original Wuhan strain at the onset of the pandemic.

Fortunately, COVID-19 is a vaccine-preventable disease. Hybrid immunity through vaccination and/or prior infection is better than either form of immunity alone to protect against infection and severe disease. Although scientific and governmental communities highly recommend vaccination against COVID-19, many individuals in the US remain reluctant to be vaccinated and/or to have their children vaccinated. Even before the onset of the pandemic, failure to complete the multidose, universally recommended vaccine series in early childhood was documented. Results of a recent study using 2019 National Immunization Survey-Child data show that more than 1 in 6 children ages 19 to 35 months initiated but did not complete all doses in the early childhood vaccination series.⁹ In addition to parental hesitancy, the investigators noted that moving across state lines, the number of children in the household, and lack of insurance coverage were “the strongest associations with starting but not completing multidose vaccine series.”⁹

Because new COVID-19 variants continue to emerge, reluctance to vaccinate presents a significant public health problem. Just 4.7% of children younger than 2 years have completed their primary COVID-19 vaccination series.¹⁰ This percentage increases to 6.1%, 32.9%, and 61.8% for individuals aged 2 to 4 years, 5 to 11 years, and 12 to 17 years respectively,² but still leaves millions of children under- or unvaccinated. Another study noted approximately one-third of parents in the US with children aged 5 to 17 years expressed unwillingness to vaccinate them against COVID-19.¹¹

FIGURE:

SARS-CoV-2 variants circulating in the US are monitored very closely. Available data on variant proportions at the national and regional levels are useful in making recommendations to target with the latest updated COVID-19 vaccine. This evidence also helps inform how these changes may affect therapeutics and diagnostics, as well as the anticipated transmission and severity of disease. The EG.5 Omicron variant has currently become a dominant COVID-19 strain in the US.² The most recently available updated monovalent COVID-19 vaccine contains the XBB.1.5 variant, and more than 90% of currently circulating viruses are closely related genetically to the XBB lineage.

Results of multiple studies have highlighted that COVID-19 vaccines are safe for use in children and adolescents and are effective in reducing COVID-19 infection and complications. Given the risk of the SARS-CoV-2 virus to the pediatric population and ongoing viral transmission, it is advised that providers emphasize the value of COVID-19 vaccination for children and adolescents. Many parents who have concerns are likely to benefit from recommendations and accurate information regarding vaccine safety shared by trusted pediatricians, potentially increasing COVID-19 vaccination coverage among children. Studies have indicated that parents are less hesitant about vaccinating their children when provided with an explicit recommendation from a trusted health care professional who stresses vaccine safety and efficacy (Figure).¹²

Current COVID-19 vaccines for pediatric populations

Two messenger mRNA-based and a single adjuvanted, protein subunit-based COVID-19 vaccine are approved for use in children as young as 6 months and adolescents. They are Comirnaty (Pfizer-BioNTech) and Spikevax (Moderna). The adjuvanted, protein subunit-based COVID-19 vaccine is a Novavax product. None of these vaccines affect or interact with our DNA.

In the US, the FDA can issue an emergency use authorization (EUA) to allow the use of unapproved medical products or unapproved uses of approved medical products to diagnose, treat, or prevent serious or life-threatening diseases when certain criteria are met, including that there are no adequate, approved, and available alternatives.¹³ An EUA is issued in circumstances where the benefits outweigh the risks. Although the previously declared COVID-19 public health emergency in the US expired on May 11, 2023, the end of the COVID-19 public health emergency does not impact the FDA’s ability to authorize EUAs, and existing EUAs remain in effect. In the case of SARS-CoV-2 vaccines, the effectiveness and safety of adult administration of COVID-19 immunizations supported EUAs being granted for COVID-19 vaccines in younger pediatric populations. All 3 vaccines in use for children in the US have undergone rigorous clinical trials and have been determined to be safe and effective.¹⁴ The manufacturers are further developing these vaccines toward full licensing, which may help increase public confidence.¹⁵ 

The SARS-CoV-2 mRNA vaccines introduce a strand of mRNA encoding the full or partial spike (S) protein of the SARS-CoV-2 virus contained within a lipid nanoparticle.¹⁶ This gives cells directions on how to make S proteins, which are found on the surface of the SARS-CoV-2 virus. The S protein was chosen as the antigenic target because of its role in the ability of the virus to invade the host cell. The lipid moiety protects the mRNA and facilitates its delivery into the cell.¹⁶ Once the mRNA enters the host’s cells, it utilizes the cellular machinery to produce the encoded protein, which is perceived by the host as a foreign antigen. This triggers the host immune response, ultimately yielding antibodies for protection against SARS-CoV-2. Cells will break down the vaccine’s directions after the protein pieces are made.¹⁶

In contrast, a third COVID-19 vaccine containing the SARS-CoV-2 spike protein and Matrix-M adjuvant produced by Novavax received an EUA for use in individuals 18 years and older in July 2022. This was expanded to include individuals aged 12 to 17 years in August 2022.¹⁷ This adjuvanted, protein subunit–based vaccine contains the S protein and allows for the creation of antibodies and defense white blood cells after immunization.^18-20 The Matrix-M adjuvant is a saponin-based adjuvant made of nanoparticles, cholesterol, and phospholipids. The adjuvant has been shown to augment Th1 and Th2 responses, induce multiple subclasses of antibodies, and enhance immune cell trafficking. These antibodies are created to augment the immune response following COVID-19 infection.²¹ A randomized clinical trial (NCT04611802) analyzed the efficacy of the Novavax vaccine in adolescents aged 12 to 17 years.²² The results documented an efficacy of 79.5% with the use of the Novavax vaccine against COVID-19 and an 82.0% efficacy against the Delta variant of COVID-19 infection.²² Because more than 22% of adolescents have yet to receive an mRNA COVID-19 vaccine, Novavax is a safe alternative vaccine option for pediatric populations, the study authors concluded.²³

COVID-19 vaccine safety surveillance

The safety surveillance of COVID-19 vaccines has been historic and continues to be extensively and thoroughly monitored. Three methods of surveillance are actively being used: (1) Vaccine Adverse Event Reporting System (VAERS), (2) Vaccine Safety Datalink (VSD), and (3) Clinical Immunization Safety Assessment (CISA) Project.

VAERS is the US early warning system for vaccine safety comanaged by the CDC and FDA. It is a passive reporting system, accepting national data from the public regardless of plausibility.²⁴ It can rapidly detect safety signals and rare adverse events. VAERS is not designed to assess causality, but it can identify potential vaccine safety concerns that may warrant further study. For example, VAERS received 536 safety reports following the third dose of an mRNA COVID-19 vaccine for children aged 6 months to 5 years. Approximately 98.5% of these reports were nonserious and 78.4% were recorded as vaccination errors.²⁵

VSD gathers data from 9 participating health care organizations with more than 12 million participants. The information is linked to study identification data, including outpatient visits, immunization records, birth and death certificates, and more sources such as charts and electronic health records. For example, though local and systemic adverse effects are possible with the administration of any vaccine, cases of myocarditis/pericarditis (inflammation of the heart muscle or outer lining of the heart) were reported following mRNA COVID-19 vaccination in children 5 years and older.²⁶ VSD identified all potential cases of myocarditis/pericarditis in emergency department and inpatient settings 1 to 98 days after vaccination, using myocarditis/pericarditis–specific International Classification of Diseases, Tenth Revision codes, among 5- to 39-year-old individuals. VSD researchers validated cases through a review of medical records with physician adjudication and classified them according to CDC case definition.²⁶ Cases of myocarditis and pericarditis have occurred most frequently in adolescent and young adult males within 7 days after receiving the second dose of an mRNA COVID-19 vaccine; however, cases have also been observed after dose 1 and booster doses. Myocarditis often occurs usually because of viral infection and can sometimes be caused by vaccine administration, though rare.²⁷ Reports of myocarditis after the second dose of an mRNA COVID-19 vaccine specifically in males aged 5 to 17 years have raised concerns regarding vaccine safety. However, myocarditis is a rare event that has an average incidence rate of 39.4 out of 1 million Pfizer-BioNTech doses administered among 5- to 17-year-old individuals.²⁸ No cases of myocarditis have been found in children younger than 5 years.²⁹ Cardiac dysfunction was uncommon, and recovery of cardiac function occurred in nearly all patients in a matter of days. Reported cases of fulminant disease or death are rare.²⁷ Two-dose Novavax vaccinations are recommended for males aged 12 to 39 years because it has been found to minimize the rare risk of myocarditis.³⁰ The VSD findings help inform risk-benefit analyses, which thus far have consistently found the benefits of mRNA vaccination greatly outweigh the risks.

The CISA Project is a network of 7 participating medical research centers with vaccine safety experts that provides consultative services and also conducts clinical research. An additional method of active surveillance developed for COVID-19 vaccination during the pandemic was V-safe, which involved text message check-ins via cellphone daily for 1 week, weekly for 6 weeks, and then at 3, 6, and 12 months after each COVID-19 vaccine dose. Clinically important events were reported and followed up by the CDC. Since December 2020, 10.1 million V-safe participants completed more than 151 million health surveys after their vaccination.³¹ For example, a third mRNA COVID-19 dose was recorded for 2969 children through V-safe. Within this group, 37.7% had reported no reactions and the rest reported mild reactions.³¹ On May 19, 2023, the CDC closed enrollment in V-safe and is in the process of developing a new version for users to share their postvaccination experiences with updated vaccines.³²

Immunity

Various factors impact the immune response of each individual, whether children or adults. Our innate immune system is the body’s first line of defense against pathogens entering the body (eg, skin and mucous membranes). It acts very quickly and responds in the same way to all pathogens and foreign substances.³³ In contrast, our adaptive immune system takes over when the innate immune system is not able to destroy the pathogens. It responds more slowly but is more accurate; it develops memory to “remember” pathogens, so the next time a known pathogen is encountered, the adaptive immune system can respond faster.³³

The adaptive immune system is made up of T cells, B cells, and antibodies. T helper cells use chemical messengers to activate other immune system cells to start the immune response and some T helper cells become memory T cells following an infection, allowing activation of the adaptive system to be quicker if there is another infection.³³ Additionally, cytotoxic T cells detect cells infected by viruses and destroy them. B cells are activated by T helper cells and then multiply to turn into plasma cells. These produce large amounts of antibodies that are released into the bloodstream. Some of these cells are turned into memory B cells for quicker reaction to the next exposure.³³ Antibodies that are exact matches to the antigens of the pathogen are produced because only B cells that match the pathogen are activated. Antibodies quickly detect pathogens and neutralize them by attaching directly to their cell surface. They also activate proteins that aid in the immune response and activate other immune cells by attaching to their surface. Vaccines primarily assist the adaptive system through the production of protective antibodies against infection.³³

But neutralizing antibodies don’t tell the whole story of protection. With COVID-19 vaccination and infection, T-cell responses are thought to be responsible for longer-lasting protection against serious illness and death from SARS-CoV-2 infection.¹⁵ Though neutralizing antibodies produced with COVID-19 vaccination are correlated with high levels of protection, it is believed that studying the T-cell responses and their correlation with protection against infection is important to understanding the evaluation of vaccine selection. Studying the efficacy of vaccines that produce a stronger T-cell response could help in enhancing protection against different variants.³⁴ Additionally, it has been noted by the World Health Organization that eliminating ancestral SARS-CoV-2 from COVID-19 vaccines increases the antigen concentration for new subvariants, which could raise the degree of the adaptive response and antibody production. Hence, transitioning from the past used bivalent vaccine allows for the avoidance of immune imprinting, or the concept that repeated exposure to the ancestral strain through immunization will lead to a reduced immune response to new target subvariant antigens.¹⁵ Though the clinical impact of immune imprinting seems unclear, there is in vitro evidence of this.

Vaccine effectiveness

Although both Pfizer-BioNTech and Moderna COVID-19 vaccines were shown to be highly effective at preventing COVID-19 infection in children from the predominant Delta variant, they have been less effective against the more recent Omicron variant.³⁵ Two doses of the Pfizer-BioNTech vaccine showed 85% effectiveness for children aged 5 to 11 years against Delta and 20% against Omicron.³⁶ However, third-dose bivalent vaccinations increase effectiveness against Omicron infections in children aged 5 to 11 years to 55%.³⁵ With more emerging variants, updated vaccines are necessary and forthcoming. Immunity is known to wane after infection and vaccination, but T-cell immunity protects against severe disease, hospitalization, and death. COVID-19 reinfection rates have also been positively impacted by the administration of vaccines within the past year. For children aged newborn to 4 years, vaccine effectiveness against Omicron reinfection was 77.3% after 3 months and 64.7% after 6 months. For children aged 5 to 11 years, vaccine effectiveness against Omicron reinfection was 79.9% after 3 months and 53.9% after 6 months.³⁷

As of September 2, 2023, the CDC reports a total of 198,966 hospitalizations because of COVID-19 for children aged newborn to 17 years.² During the week of June 24, 2023, there were 244 pediatric hospitalization cases caused by COVID-19, the lowest number of hospitalizations since September 2020. When divided into age subgroups, children aged newborn to 4 years were 57% of the COVID-19 child hospitalizations in June 2023, but only 13% had received any vaccination.³⁸ In comparison, 68% of children aged 12 to 17 years have received at least 1 dose of the vaccine and are less likely to be hospitalized. Comparing hospitalization numbers caused by COVID-19 with those caused by seasonal influenza, more children were hospitalized because of COVID-19 than influenza in the aged newborn to 4 years subgroup only. In all other age subgroups, COVID-19–related cases were fewer than influenza-related cases (Table 1). Of note, 50% of pediatric COVID-19–related admissions were of children who did not have underlying medical conditions.

Results of a recent study show that the 2-dose Pfizer-BioNTech vaccine was 98% effective against pediatric hospitalizations for individuals aged 12 to 17 years during the period in which the Delta variant was predominant.³⁹ Two-dose vaccine effectiveness against hospitalization during the Omicron period decreased to 45% and 34% for 12- to 15-year-olds and 16- to 17-year-olds, respectively.⁴⁰ The effectiveness of 2 doses of the Pfizer vaccine against any hospitalization for COVID-19 was lower during the Omicron period than during the Delta period in adolescents 12 to 18 years of age, but vaccination prevented most life-threatening COVID-19 in both periods.⁴¹ Monovalent and bivalent boosters increased vaccine effectiveness during both Delta and Omicron phases for all ages.³⁹ Considering the effectiveness of the vaccine in preventing hospitalizations, the vaccination of younger children is essential.

Multisystem inflammatory syndrome in children (MIS-C)

Multisystem inflammatory syndrome in children (MIS-C) is a rare, but serious condition temporally associated 2-6 weeks after a SARS-CoV-2 infection in children 5-13 years of age with a delayed immune response that causes inflammation throughout the body, even if the child’s SARS-CoV-2 infection was very mild or asymptomatic. MIS-C can result in ICU admissions and death. Since May 2020, there have been 9,538 pediatric patients with MIS-C, with 79 deaths.³ As of July 7, 2022, data have reported the association of MIS-C with a decreased likelihood of vaccination among children aged 5-11 years, 12-18 years, and during the Delta and Omicron-dominant periods. In the 12-18 year age group, the association was found until 120 days after the second dose of the vaccine was given. Data documented that 62.9% MIS-C cases in unvaccinated patients required ICU admission, whereas 1 in 5 of those who had been vaccinated required ICU care.⁴² Most children who develop MIS-C improve following medical care;³ most organ-specific complications resolve by 6 months. More specifically, the CDC reports that there is an overall 84% effectiveness of the vaccine in protecting against MIS-C in children and adolescents, with children (5-11 years) receiving 78% vaccine efficacy and adolescents (12-17 years) receiving 90% vaccine efficacy following administration of two doses.² MIS-C appears to be disappearing, perhaps related to the current circulating Omicron variant and its subvariants which overall appear less virulent and therefore less inflammatory.

Long COVID

Long COVID, also referred to as post-acute sequelae of SARS-CoV-2 infection (PASC), is characterized by the persistent loss of smell, chronic cough, gastrointestinal symptoms, fatigue, malaise, myalgias, pain, “brain fog”, and other long-term symptoms following the acute COVID-19 infection. What symptoms can be considered within the definition of PASC are currently being studied, but many of the primary complaints report excessive fatigue, brain fog, dizziness, or gastrointestinal symptoms. These complaints may vary between children and adults.

People who have a severe COVID-19 illness or have underlying health conditions are at higher risk for Long COVID. Unvaccinated individuals who become infected also may have a higher risk of developing Long COVID compared with those who have been vaccinated.

A study investigating PASC prevalence amongst 2231 adults found 224 PASC positive at 6 months after infection, a 10% long COVID rate, and almost one-quarter of these reported significant activity limitations. However, little is known about the prevalence of long COVID among pediatric populations.⁴³ Studies have reported respiratory symptoms, fatigue, sleep disturbance, and concentration difficulties as the most common symptoms experienced by children aged 0-18 years of age.⁴⁴ Those with a higher probability of suffering from these symptoms are likely adolescents aged between 6-18 years, obese, or those with a severe COVID infection at hospital admission. However, retrospective studies have shown that children aged 0-18 years have had a prevalence that ranges from 4% to 66%. The variability is due to data collection methods and various definitions of what constitutes long COVID, thus further research into the prevalence rates among pediatric populations would be useful.⁴⁵

Latest Updated COVID-19 Vaccination Recommendations

The US population has very diverse previous exposures to vaccines and SARS-CoV-2 infections which shape antibody and T-cell-receptor repertoires and has imparted differential quantity and quality of protective immunity.⁴⁶ Hybrid immunity to SARS-CoV-2 infection also has variable durability. So who should be recommended for an updated 2023-2024 COVID-19 vaccine? The Advisory Committee on Immunization Practices (ACIP) continues to review all available evidence on the efficacy and safety of COVID-19 vaccine candidates to support near real-time decision-making on the benefit-risk balance of recommending use in targeted populations.⁴⁷ Its focus continues to include science, implementation, and timely and equitable access to COVID-19 vaccines.

Last month on September 12, ACIP voted to recommend 2023-2024 (monovalent, XBB-containing) COVID-19 vaccines as authorized under Emergency Use Authorization (EUA) or approve by Biologics License Application (BLA) in persons 6 months of age and older. Summary recommendations are:

· Everyone ages 5 years and older is recommended to receive 1 dose of a 2023-2024 mRNA COVID-19 vaccine.

· Children ages 6 months -- 4 years should complete a multi-dose initial series (2 doses of Moderna or 3 doses of Pfizer-BioNTech mRNA COVID-19 vaccine) with at least 1 dose of 2023-2024 mRNA COVID-19 vaccine.

· People who are moderately or severely immunocompromised should complete a 3-dose initial series with at least one dose of the 2023-2024 mRNA COVID-19 vaccine. And may receive 1 or more additional 2023-2024 mRNA COVID-19 vaccine doses.

· Bivalent mRNA COVID-19 vaccines are no longer recommended in the US.

Additional details in the interim clinical consideration are available at https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html.

Note that the monovalent XBB-containing Novavax COVID-19 vaccine has not received FDA authorization as of the September 12 ACIP meeting.

Conclusion

COVID-19 is a vaccine-preventable disease. Yet, children are less likely to be vaccinated against COVID-19 than any other age group in the US. As the new EG.5 variant emerges this fall, updated COVID-19 vaccines are being recommended to optimize protection against COVID-19, including children 6 months of age and older, who make up more than 22% of the US population. Given the ongoing viral transmission and risk of the SARS-CoV-2 virus to the pediatric population, it is advised that providers emphasize the value of COVID-19 vaccination for children and adolescents. Provider recommendation of vaccinations during visits is an essential step in improving pediatric COVID-19 vaccination outcomes, particularly for all children with underlying medical conditions, those who are immmunocompromised, and everyone under 5 years given this age cohort is more likely to require hospitalization. Note that children without any underlying condition still experience severe illness, too.

As of June 2023, there were more than 2 million COVID-19 cases, more than 20,000 hospitalizations, and more than 400 deaths in U.S. children aged 6 months to 4 years.² With protection from infection as a result of prior COVID-19 vaccination(s) and/or infection(s) waning, receiving the latest updated vaccine should be considered to maintain population immunity. While the latest updated monovalent COVID-19 vaccine contains the XBB.1.5 variant, greater than 90% of currently circulating viruses, like EG.5, are closely related genetically to the XBB lineage.

But it’s not just get an updated COVID-19 vaccine, the unvaccinated must be vaccinated. The safety profiles of COVID-19 vaccines for pediatric-aged children are very reassuring. Benefits of vaccination outweigh risks even in age groups with a concern for myocarditis. Although vaccinated individuals can still be infected with SARS-CoV-2, COVID-19 vaccination significantly lowers their risk for severe illness, being hospitalized, or dying from COVID-19. Overall, those who are vaccinated do better in all outcomes than those who are unvaccinated.

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