COVID-19 Vaccination in Pediatrics: Was It Valuable and Successful?

Background: The mass vaccination of children against coronavirus 2019 disease (COVID-19) has been frequently debated. The risk–benefit assessment of COVID-19 vaccination versus infection in children has also been debated. Aim: This systematic review looked for answers to the question “was the vaccination of our children valuable and successful?”. Methods: The search strategy of different articles in the literature was based on medical subject headings. Screening and selection were based on inclusion/exclusion criteria. Results and Discussion: The search results revealed that the majority of the reported adverse events after COVID-19 vaccination in pediatrics were mild to moderate, with few being severe. Injection site discomfort, fever, headache, cough, lethargy, and muscular aches and pains were the most prevalent side effects. Few clinical studies recorded significant side effects, although the majority of these adverse events had nothing to do with vaccination. In terms of efficacy, COVID-19 disease protection was achieved in 90–95% of cases for mRNA vaccines, in 50–80% of cases for inactivated vaccines, and in 58–92% of cases for adenoviral-based vaccines in children and adolescents. Conclusions: Based on available data, COVID-19 immunizations appear to be safe for children and adolescents. Furthermore, multiple studies have proven that different types of vaccines can provide excellent protection against COVID-19 in pediatric populations. The efficacy of vaccines against new SARS-CoV-2 variants and the reduction in vaccine-related long-term adverse events are crucial for risk–benefit and cost-effectiveness assessments; therefore, additional safety studies are required to confirm the long-term safety and effectiveness of vaccinations in children.


Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was discovered at the end of 2019 in Wuhan, China. Since then, SARS-CoV-2 has spread throughout the world, resulting in the COVID-19 pandemic [1].The COVID-19 pandemic has claimed a total of more than 650 million cases and more than 6.6 million deaths worldwide as of 2 January 2023.

Materials and Methods
The review aimed to systematically study the safety and efficacy of COVID-19 vaccines in children and adolescents and evaluate potential adverse events associated with vaccinations. We are not disputing the enormous advantages of mass COVID-19 vaccinations, which undoubtedly have significantly decreased COVID-19 morbidity and mortality. Medical Subject Headings (MeSH) was used in the search strategy. The MeSH terms used included pediatrics, vaccinations, COVID-19, safety, and immunological studies to systematically search the PubMed and MEDLINE databases.
The PubMed databases were searched to collect all types of manuscripts (e.g., reviews, research articles, short communications, book chapters, case reports, etc.) dealing with the safety and efficacy of COVID-19 vaccines in pediatrics and written in the English language until November 2022. Steps including title and abstract screening, full-text review, and duplicate removal were used to screen the studies for inclusion and exclusion criteria.
Our inclusion criteria primarily focused on published literature that assessed the safety and efficacy of COVID-19 vaccines in pediatrics. The studies should have been conducted on males or females belonging to the age group ranging from 6 months to 19 years. Furthermore, comparison of vaccine efficacy and risk-benefit assessment in children and adolescents versus adults was also included.
A total of 6564 articles about COVID-19 vaccinations were found in PubMed. (Figure 1) The articles were screened for inclusion and exclusion criteria, and from the search results, we included 34 articles in this systematic review. A total of 6564 articles about COVID-19 vaccinations were found in PubMed. ( Figure  1) The articles were screened for inclusion and exclusion criteria, and from the search results, we included 34 articles in this systematic review.

Disease Incidence, Symptoms, and Complications
Children and adolescents tend to develop milder viral infection than adults, but all ages are vulnerable to infection and serious complications [7]. COVID-19 is a respiratory disease that appears in children as flu-like sickness with fever and cough [8] (Figure 2).
Approximately one-third of the children and adolescents requiring hospitalization were admitted to intensive care [9]. Children with a history of respiratory or cardiovascular diseases are likely to be more vulnerable to infection with SARS-CoV-2. A recent study highlighted an increased vulnerability to infection in individuals with asthma or renal impairment, but more data are needed to confirm these findings [10].
Furthermore, a newly characterized disease known as multisystem inflammatory syndrome in children (MIS-C) or pediatric inflammatory multisystem syndrome (PIMS-TS) has been found in a subgroup of pediatric patients soon after SARS-CoV-2 infection. Studies describing MIS-C/PIMS-TS are rapidly appearing. Comorbid diseases and conditions have been reported in a few multicenter studies, with rates ranging from 3% to 25%, with wide variation [11]. Obesity and cardiovascular disease were the most common comorbid conditions. Other, far less frequent, co-occurring neuromuscular, oncologic, immunosuppressive, autoimmune, and hereditary disorders have also been reported [12].

Disease Incidence, Symptoms, and Complications
Children and adolescents tend to develop milder viral infection than adults, but all ages are vulnerable to infection and serious complications [7]. COVID-19 is a respiratory disease that appears in children as flu-like sickness with fever and cough [8] (Figure 2). Increased expression of mediators essential for viral entry into airway epithelial cells (ACE-2 and TMPRSS2) in adults combined with the proinflammatory milieu may predispose the adult lung to serious pulmonary injury and progression to acute respiratory distress syndrome (ARDS). The pediatric lung has greater expression of immunomodulatory cytokines and possibly a decreased expression of viral entry mediators.

Different Types of Vaccines
According to the WHO statistics provided on 23 November 2022, 175 vaccine candidates have been authorized for clinical trials, with another 199 in preclinical testing [13]   Approximately one-third of the children and adolescents requiring hospitalization were admitted to intensive care [9]. Children with a history of respiratory or cardiovascular diseases are likely to be more vulnerable to infection with SARS-CoV-2. A recent study highlighted an increased vulnerability to infection in individuals with asthma or renal impairment, but more data are needed to confirm these findings [10].
Furthermore, a newly characterized disease known as multisystem inflammatory syndrome in children (MIS-C) or pediatric inflammatory multisystem syndrome (PIMS-TS) has been found in a subgroup of pediatric patients soon after SARS-CoV-2 infection. Studies describing MIS-C/PIMS-TS are rapidly appearing. Comorbid diseases and conditions have been reported in a few multicenter studies, with rates ranging from 3% to 25%, with wide variation [11]. Obesity and cardiovascular disease were the most common comorbid conditions. Other, far less frequent, co-occurring neuromuscular, oncologic, immunosuppressive, autoimmune, and hereditary disorders have also been reported [12].

Different Types of Vaccines
According to the WHO statistics provided on 23 November 2022, 175 vaccine candidates have been authorized for clinical trials, with another 199 in preclinical testing [13] ( Figure 3). As of today, a total of thirteen vaccines, including inactivated vaccines, viral vector vaccines, mRNA vaccines, and protein subunit vaccines, have received Emergency Use Authorization (EUA) by the WHO [14]. Increased expression of mediators essential for viral entry into airway epithelial cells (ACE-2 and TMPRSS2) in adults combined with the proinflammatory milieu may predispose the adult lung to serious pulmonary injury and progression to acute respiratory distress syndrome (ARDS). The pediatric lung has greater expression of immunomodulatory cytokines and possibly a decreased expression of viral entry mediators.

Different Types of Vaccines
According to the WHO statistics provided on 23 November 2022, 175 vaccine candidates have been authorized for clinical trials, with another 199 in preclinical testing [13] ( Figure 3). As of today, a total of thirteen vaccines, including inactivated vaccines, viral vector vaccines, mRNA vaccines, and protein subunit vaccines, have received Emergency Use Authorization (EUA) by the WHO [14].

Post-Vaccination Adverse Reactions
Although the present COVID-19 vaccines have received EUA and have proven to be safe in clinical studies, they have shown different adverse events, including fever, headache, tiredness, injection site irritation, and nausea ( Figure 4). Complications emerged in certain participants as mass vaccinations took place, leading to some deaths of patients with cardiovascular disorders such as arteriosclerosis [15]. Additionally, cardiac arrest occurred in one subject in a Phase III trial for the BNT162b2 vaccine, although it was not considered to be associated with the vaccination [16]. Potential complications caused by COVID-19 vaccinations fall into the following six categories: heart diseases (such as Vaccines 2023, 11, 214 5 of 13 myocarditis), coagulation disorders (such as thrombocytopenia), immune diseases (such as allergic reactions, autoimmune hepatitis, and autoimmune thyroid diseases), lymphatic system diseases, nervous system diseases (such as functional neurological disorders), and other diseases (such as Rowell's syndrome, macular rash, and chilblain-like lesions) [15]. Despite the rare occurrence of serious adverse events, the association between vaccines and these disorders needs to be investigated [15].
Although the present COVID-19 vaccines have received EUA and have proven to be safe in clinical studies, they have shown different adverse events, including fever, headache, tiredness, injection site irritation, and nausea ( Figure 4). Complications emerged in certain participants as mass vaccinations took place, leading to some deaths of patients with cardiovascular disorders such as arteriosclerosis [15]. Additionally, cardiac arrest occurred in one subject in a Phase III trial for the BNT162b2 vaccine, although it was not considered to be associated with the vaccination [16]. Potential complications caused by COVID-19 vaccinations fall into the following six categories: heart diseases (such as myocarditis), coagulation disorders (such as thrombocytopenia), immune diseases (such as allergic reactions, autoimmune hepatitis, and autoimmune thyroid diseases), lymphatic system diseases, nervous system diseases (such as functional neurological disorders), and other diseases (such as Rowell's syndrome, macular rash, and chilblain-like lesions) [15]. Despite the rare occurrence of serious adverse events, the association between vaccines and these disorders needs to be investigated [15]. (2) heart diseases (myocarditis); (3) lymphatic system diseases; (4) immune diseases (allergic reactions, autoimmune hepatitis, and thyroid diseases); (5) nervous system disorders (functional neurological disorders); and (6) other diseases (Rowell's syndrome, macular rash, and chilblain-like lesions)].

Were COVID-19 Vaccinations Useful and Successful in Pediatrics?
Different studies on SARS-CoV-2 vaccines in children and adolescents have shown that these vaccines appear to be effective and safe [17] (Table 1). Furthermore, the results have indicated similar or better immune responses in children/adolescents than in adults. As a result, an increasing number of nations have started to vaccinate pediatric populations. Vaccines for children aged 12 and above have recently been registered in the US, Canada, and the EU.
Furthermore, the Canadian Pediatric Society, the American Academy of Pediatrics, and the Advisory Committee on Immunization Practices have urged for vaccination of all children and adolescents over the age of 12. However, the UK has delayed this decision owing to lack of convincing data concerning the safety and necessity of SARS-CoV-2 immunization in children [18]. Currently, EU countries have recommended COVID-19 vaccination of adolescents from 12 to 17 years old. On the other hand, 10 countries from the EU recommended booster doses for children below 18 years of age [19].
The obvious benefit of immunizing children and teenagers is protection against COVID-19. Although the symptoms are usually moderate or minimal in children, severe incidences have been reported [20].
Furthermore, as with adults, there is some indication that a significant percentage of children who catch the virus have at least one symptom that lasts longer than four months.

Were COVID-19 Vaccinations Useful and Successful in Pediatrics?
Different studies on SARS-CoV-2 vaccines in children and adolescents have shown that these vaccines appear to be effective and safe [17] (Table 1). Furthermore, the results have indicated similar or better immune responses in children/adolescents than in adults. As a result, an increasing number of nations have started to vaccinate pediatric populations. Vaccines for children aged 12 and above have recently been registered in the US, Canada, and the EU.
Furthermore, the Canadian Pediatric Society, the American Academy of Pediatrics, and the Advisory Committee on Immunization Practices have urged for vaccination of all children and adolescents over the age of 12. However, the UK has delayed this decision owing to lack of convincing data concerning the safety and necessity of SARS-CoV-2 immunization in children [18]. Currently, EU countries have recommended COVID-19 vaccination of adolescents from 12 to 17 years old. On the other hand, 10 countries from the EU recommended booster doses for children below 18 years of age [19].
The obvious benefit of immunizing children and teenagers is protection against COVID-19. Although the symptoms are usually moderate or minimal in children, severe incidences have been reported [20].
Furthermore, as with adults, there is some indication that a significant percentage of children who catch the virus have at least one symptom that lasts longer than four months. These post-COVID-19 symptoms may impede children's everyday activities and development. Furthermore, COVID-19 may cause some permanent health implications [21]. In this context, preliminary findings indicate that COVID-19 may cause long-term symptoms such as tiredness, muscle and joint pain, sleeplessness, breathing issues, and palpitations lasting up to six months. The symptoms are difficult to differentiate from other conditions often found in children and adolescents [22].
Other benefits of vaccination in children and adolescents may include alleviation of back-to-school concerns. For over a year, the mandatory home confinement of children has resulted in the accumulation of developmental, educational, and psychological issues [23]. On the other hand, providing protection against COVID-19 would also stimulate the reintroduction of routine pediatric care, including immunization against other infectious diseases, which was significantly disrupted during the pandemic and lockdown periods [24]. Furthermore, the demand for caregivers for sick children at home would diminish.
Because children and adolescents account for more than one-fourth of the overall population, herd immunity to control COVID-19 spreading and mitigating severe conditions cannot be achieved without extensive immunization of pediatric populations. Children account for 14.3% of people diagnosed with COVID-19 in the US. Although clinical symptoms of COVID-19 in children are often mild or individuals are asymptomatic compared with adults, a small number of individuals develop severe symptoms, necessitating hospitalization, and this may even lead to death [25].
Recent observations in the US revealed a rise in morbidity and severe cases among children and adolescents, which is of great concern. Furthermore, acute respiratory infections are the most prevalent diseases in children, and COVID-19 symptoms in children are difficult to differentiate from other respiratory diseases. As a source of infection, infected children may play a large role in community transmission due to their interaction within families, in nurseries, and in schools. Children thus represent a significant demographic group that needs COVID-19 vaccines [25]. The vaccine was safe and immunogenic against SARS-CoV-2 and its variants. Neutralizing antibodies were identified against the Delta and Omicron variants.
[36] Omicron infection. [38] Since vaccination in children and adolescents is important, the WHO has granted EUA of seven COVID-19 vaccines in pediatric populations [39]. China has granted EUA of inactivated vaccines in children aged 3 to 17 years [40]. The Centers for Disease Control and Prevention (CDC) has also approved emergency vaccination in individuals aged 6 months to 17 years (Table 2) [3].

What Are the Risks of COVID-19 Vaccinations in Children and Adolescents?
Numerous non-life-threatening adverse events related to COVID-19 vaccines have been documented in the pediatric age group. However, these side effects are infrequent, with a reported adverse event frequency of less than 0.2% [48]. The majority of reported adverse events for different vaccine types were minor and temporary. Frequent adverse effects may include pain at the injection site, tiredness, fever, chills, dizziness, headache, crying, and loss of appetite. Furthermore, seizures, stroke, myocarditis, pericarditis, MIS-C, hematuria, chest pain, menstruation disturbance, appendicitis, behavioral and otologic adverse events, and others have been documented [48][49][50][51][52][53][54][55][56].
In a case series that included a group of five adolescents aged 15 to 17 years with obesity/overweight , the individuals showed characteristic myocarditis symptoms after the first or second dose of the BNT162b2 vaccine. A considerable rise in troponin serum concentration was detected, followed by a rapid decrease within 3 to 4 days. COVID-19 vaccine-induced myocarditis appears to be a benign condition with rapid clinical recovery, although total resolution of the inflammatory process may take more than three months. Further studies and follow-ups are necessary to establish the long-term effects of COVID-19 vaccine-induced myocarditis [49].
3.6. Comorbidities and Vaccination Hazards 3.6.1. Children Suffering from the following Allergic Diseases Children with allergic rhinitis, conjunctivitis, atopic dermatitis, and food allergies can be vaccinated in stable disease status, which is defined as no disease exacerbation and stable condition for at least 3 months under standard therapeutic treatment [25]. Furthermore, individuals who are allergic to dust mites, pollen, alcohol, cefotaxime, and penicillin can also be vaccinated in stable status [25].

Children with Asthma
Bronchial asthma does not exclude COVID-19 immunization. In the remission stage of asthma, vaccination should be administered (including inhaled corticosteroids). Vaccination should be avoided during acute asthma episodes, especially when glucocorticoids are taken systemically. COVID-19 vaccination can be given alongside anti-IgE monoclonal antibody treatment and allergen-specific immunotherapy, but not on the same day [56]. Patients are advised to select vaccination on days when no immunotherapy is scheduled.

Children with Impaired Immune Function
Children with congenital or acquired decreased immune function can be vaccinated with the inactivated vaccine, as the same safety standards are met as for immunocompetent children [25]. However, the strength and duration of immunological protection in children with impaired immune function will most likely be inferior due to their weaker immune responses. Furthermore, according to CDC recommendations, mRNA vaccinations can be given to immunocompromised children aged 6 months to 17 years [57].

Children Who Have Been Previously Diagnosed with COVID-19
After 6 months of infection, one dose of COVID-19 vaccine can be given [58].

Children with Cardiovascular Disorders
The incidence of cardiovascular complications (e.g., myocarditis or pericarditis) is low in children (i.e., pooled rate of 37.76 per million) [59] after COVID-19 vaccinations. Due to lack of data on the effect of vaccination on children with cardiovascular disorders, it is advisable to evaluate risks versus benefits before starting vaccinations.

Children with Renal Disorders
There are limited data available on the effect of COVID-19 vaccinations on both adult and pediatric patients with chronic kidney diseases.
However, it has been shown that SARS-CoV-2 infections may cause some rare renal adverse reactions, such as IgA nephropathy, acute interstitial nephritis, antineutrophil cytoplasmic autoantibody vasculitis, and tubulointerstitial nephritis [60,61]. It has been recommended that caution should be taken in vaccinating children with renal disorders.
Vaccines 2023, 11, 214 9 of 13 3.6.7. Children with Diabetes COVID-19 immunization was shown to be safe and did not cause any significant changes in glycemic control in adolescents and young adults with Type 1 diabetes (T1DM) [62].

Children and Vaccine Booster Recommendations
The FDA has further granted EUA of booster vaccinations with the BNT162b2 vaccine in children aged 5-11 years [63]. An intramuscular booster dose of 10 mcg (same as the primary doses) may be given 5 months after completion of two primary doses, or in moderately or severely immunocompromised children, a three-dose primary series.
In a case-control test-negative design, the vaccine effectiveness (VE) of BNT162b2 (Pfizer-BioNTech) in preventing COVID-19 hospitalization was evaluated. The results during Delta variant predominance indicated that in adolescents aged 16-17, vaccine effectiveness 14 to 149 days after the second dose was 76%, while after more than 150 days, VE after the second dose was 46%. On the other hand, VE increased to 86% after more than 7 days from the third booster dose. However, during Omicron variant predominance, the third booster dose restored VE to 81% [64].
A national cohort study in Singapore assessed the incidence of confirmed SARS-CoV-2 infections and hospitalization among 249,763 adolescents aged 12-17 years vaccinated with BNT162b2 during the Delta (B.1.617.2), and Omicron (B.1.1.529) variant wave. The results showed that two vaccine doses compared with no vaccination provided VE of 66% against the Delta variant infection, 25% against the Omicron infection, 83% against the Delta variant-associated hospitalization, and 75% against the Omicron variant-associated hospitalization. On the other hand, the third (booster) vaccine dose provided vaccine effectiveness of 56% against the Omicron variant infection and 94% against the Omicronassociated hospitalization [65].

Readiness of Parents to Vaccinate Themselves and Their Children
Vaccine reluctance and refusal has become more common in those who are younger, poorly educated, less healthy, and have doubts about the efficacy and safety of vaccines. A cross-sectional study in Puyang city, China, was conducted to investigate the hesitancy and willingness of parents to vaccinate themselves and their children with a COVID-19 vaccine booster dose. The results showed that 95.4% and 95.0% of participants who had completed two primary doses but did not match the booster criteria were willing to get a booster vaccine dose for themselves and their children, respectively. On the other hand, 40.3% of those who matched the booster dose requirements were vaccine hesitant [66].
Another study in Taizhou, China, showed that 41.8% of parents were undecided on whether to give their children COVID-19 vaccine boosters or not [67]. This means that better health advising, awareness, and education are required.

Conclusions
From available accumulated data, it seems that COVID-19 vaccinations are safe for children and adolescents, and numerous studies have confirmed that different types of vaccines can provide excellent protection against COVID-19 in children and adolescents. On the other hand, current information has so far suggested potential incidences of vaccinerelated adverse events, some of which may be severe, although no deaths have been reported. Since COVID-19 vaccines became available, their EUA has been granted in children and adolescents in different corners of the world to prevent the further spread of the pandemic. However, as safety is of utmost importance, it is necessary to conduct well-planned and -executed clinical trials on vaccine safety and efficacy in children and adolescents. Precautions should also be taken to minimize the occurrence of adverse events, especially in children with pre-existing health issues.